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@spreadsheet guys rephrase
1. If the 298th event occurred today and SOC survival was 60% at 3 years and 48% at 5 years, then how much percentage increase in survival would the MK arm show compared to the SOC arm?
2. Same question above, except use 58% SOC survival for 3 year and 46% at 5 years.
Not good at spreadsheets, so asking spreadsheet guys.
@spreadsheet guys
1. What is the increase in survival percentage for MK arm and when would the 298th occur if use 60% SOC survival rate at 3 years and 48% SOC survival at 5 years?
2. Same question except 58% SOC survival at 3 years and 46% SOC survival at 5 years?
Not good with spreadsheets, so asking "spreadsheet guys" who know.
@george
Re: 337 events
We want Multikine to show fewer events (deaths), not more events.
Anything above 298 events is a bad thing.
Anything below 298 events is good thing (because it means Multikine is working great).
Your post stated you saw 337 events "as of today" as a good thing.
How can 337 events be a good thing?
@ 337 events
In his post, George figured 337 events have occurred already.
The post to George was to let George know the phase 3 is still below 298 events.
George was thinking it was already way up at 337.
298 events would mean CVM would said something.
George's post was him trying to figure out why CVM has not said the 298 has been reached because he sees 337 events already happened.
George was including the events of the third arm (which do not count toward the 298). Only the first two arms count toward the 298.
According to his reply, George now understands why his 337 was wrong...he was posting late at night etc.
@georgebailey
Appreciate the numbers.
1. From the 377, how many events are we supposed to subtract for the third arm?
2. Also, separate topic: Where am I wrong: In 2014, for example, 195 enrolled...say all enrolled in first two arms....half to SOC and half to SOC + MK....that is 98 per arm...40% events in SOC is 39 events and say 30% events in SOC + MK arm is another 29....39 + 29 = 68 events (before deducting even more events for the adjustment to how many of the 195 enrolled in 2014 were for third arm).
3. Also, separate topic: what assumptions using for the 10 and the 8 in 2013 and 2014?
After making some needed adjustments to your post, I would like to see then new number of events your way uses.
Thanks.
From link george provided: The last patient was enrolled in the study in September 2016. Approximately 135 patients were enrolled in the study from 2011 to 2013, about 195 were enrolled in 2014, about 340 in 2015, and about 260 in 2016. The study protocol assumed an overall survival rate of about 55% at 3 years for the SOC treatment group alone.
One of the other boards had the discussion.... about two years ago.... on how many patients were possibly replaced and why...
...but the discussion ended on that board.
The board where it discusses it extensively is the yahoo board...
...and two guys go back and forth debating their arguments....
..it is pretty funny....
...one is "Kyle" and one is "Johnny."
Does anyone know how many patients were replaced? Spreadsheet math and Phase 3 assumptions on when 10% threshold was reached depends a lot on it. Correct?
125 patients from first CRO
Q: What was the conclusion of the "125 patients?"
When the Phase 3 was put on hold, the first 125 patients of the Phase 3 from the initial CRO had protocol deviations, right? (CVM winning the CRO litigation proved there were protocol deviations right?
And CVM wanted to have the 125 patients replaced with 125 new patients, right?
Did CVM replace none of the 125, 125 of the 125, 48 of the 125 (another board said 48 were replaced)...
...or did the FDA determine the protocol deviations were safety concerns and not severe enough deviations to affect the outcome of the end point of the study....or ? If so, then why did CVM want to replace those 125 patients?
Reason for asking: If the initial 125 patients in 2011 did not get the right protocol.... and were replaced with either 48.... or 125..... or some number of patients in 2015 or 2016, then the Phase 3 endpoint to reach the 10% threshold date would be different than January 2019.
@ Fasco re: HGSI
Would you take us back to HGSI?
How is the story in Multikine similar to what story you used on HGSI? Was it math of Phase 3 having passed an endpoint threshold and just waiting for a 298 type event? or ?
Are you using the same type of reasons to invest in CVM as you used for HGSI?
The board would benefit from your experience in being part of large gainer.
55% or 63% SOC
The 55% SOC survival rate at 36 months includes stage 3 and stage 4 patients.
The 63% SOC survival rate at 36 months only includes stage 3 patients.
The FDA and CVM agreed at the start of the trial that the Phase 3 patient characteristics including age, gender, geography, stage of cancer, etc would show "about 55%" SOC survival based on data from 10's of thousands patients from various age groups, gender, geography, and stage of cancer (very reliable data).
I can see where the SOC may have moved up slightly over the last 8 years, however, not THAT much, especially since no new drugs have improved the SOC in the last 8 years. A new drug could improve the SOC survival rate a large distance from 55% to 63%, but no drug has been approved to help SOC.
Questions:
1. If the Phase 3 is using a mix of stage 3 and stage 4 patients, then how come the spreadsheets want to keep using 63% for SOC arm?
2. The U.K. study showed stage 3 patient survival rates of 63%....so why would spreadsheets guessing on the 298 use only stage 3 patients data instead of a mix of stage 3 and stage 4 patients in the Phase 3? (
3rd arm of Phase 3.
What is the reason for the third arm of Phase 3?
If the 298 only concerns the death rates of "SOC" vs "SOC + MK", then why is the there a third arm? Will the results off the third arm in any way make "adjustments" to the 298?
21 days or 10 days: How long were patients treated with Multikine in the Phase 2?
4 other links on immune system drugs
https://medicalxpress.com/news/2018-10-immunotherapy-effective-first-line-treatment-advanced.html
https://medicalxpress.com/news/2018-04-immunotherapy-lung-cancer-success.html
https://medicalxpress.com/news/2018-10-immunotherapy-survival-metastatic-recurrent-neck.html
https://medicalxpress.com/news/2018-10-immunotherapy-effective-first-line-treatment-advanced.html
@ response rate thread
Fasco,
The one strong point about response rate method is in this link:
https://ecancer.org/news/15170-immunotherapy-keeps-some-patients-with-advanced-head-and-neck-cancer-alive-for-more-than-three-years.php
The article says when an cancer patient responds to an immune system drug, then the patient responds a large amount.
This is very consistent with the CVM Phase 2 where 8 of 19 patients responded to Multikine and 2 of the 8 had their tumor vanish in 3 weeks.
This is also positive for Phase 3 because a lot of the patients responding will live to the 36 month endpoint and longer after that, too.
I still think the spreadsheet is the primary method to make an educated guess on Phase 3 meeting endpoint, but the response rate method does at least confirm how tumors can vanish and/or become 50% smaller in 3 weeks with Multikine.
@lightrock Timeframes
What are your spreadhsheets saying as to what the final increase in survival rate will be for using Multikine, and what month?
What are your spreadsheets showing as to when the 10% threshold was met, if use 55% SOC? If use 62% SOC?
How similar are your spreadsheet conclusions to Fosco?
@lightrock
So, with 55% SOC survival and 9% MK benefit, the Phase 3 would have ended in December 2018?
@lightrock spreadsheet
What does spreadsheet say on what month Phase 3 would end (or have already ended) if:
1. SOC 55% and MK arm exceeded SOC by 9%.
2. SOC 62% and MK arm exceeded SOC by 9%.
In other words:
What month would Phase 3 end (or have already ended) if MK arm had barely failed to meet endpoint? (9% increase in survival instead of minimum 10% increase in survival)
Post on Response Rate
The Phase 2 SOC + MK arm:
19 patients
63% survival rate at 3.3 years for "SOC + MK arm"
48% survival rate from "SOC part" of "SOC + MK arm" because "SOC only" arm had 48% survival rate.
42% response rate (from lightrock post last week) to Multikline.
Putting it all together:
12 of the 19 patients survived at 3.3. years because 63% survival rate on 19 patients means 12 patients in "SOC + MK arm" survived at 3.3 years.
9 of the 12 surviving patients survived from the "SOC part" of the "SOC + MK arm" because control arm showed 48% survival from SOC only and "SOC" was given in "SOC + MK arm" too.
3 of the 12 surviving patients survived from the "MK part" of the "SOC + MK arm" because 9 survived from the reliable "SOC" data above.
Additionally:
19 patients were given Multikine and 42% "responded" to Multikine.
19 x 42% = 8 patients out of 19 responded to Multikine.
Out of the 8 who responded to Multikine, the above shows 3 out of those 8 survived to 3.3 years.
Summary:
Phase 2 showed 3 out of the 8 patients "responding" to Multikine were still alive at 3.3 years.
In fancy percentage terms: "37% of the 42%" who responded to Multikine were still alive at 3.3 years.
The Phase 3 would show that Multikine gives a 22% to 29% increase in survival at year 3 if apply the above to the Phase 3.
Using 55% survival for SOC for Phase 3 (which CVM used at start of Phase 3) and applying the above method using 42% response rate to Multikine, results in about 67% to 71% survival for "SOC + MK arm."
55% survival rate SOC vs 67% to 71% survival rate for SOC + MK = 22% to 29% increase in survival.
The approximate 25% increase in survival rates using Multikine is in the same general ballpark for the survival rates which Fasco and lightrock spreadsheets consistently show.
It is sort of a different way to arrive at the same guess.
It confirms, but without a spreadsheet.
The only issue is the Phase 2 had only 19 patients in the "SOC + MK arm" and the Phase 3 has almost 400 patients in the "SOC + MK arm."
The primary way to guess survival rates in Phase 3 is the spreadsheet method with logarithmic curve etc;however, the above method does confirm the spreadsheet.
Constructive criticism welcomed!
Response rate
@CVM interested investors
What do you come up with for how many of the 12 patients who survived to 3.3 years in "Phase 2 MK + SOC arm" was from taking Multikine?
Using response rate of 42% and SOC survival rate of 48%.
Once you post, I will share what I believe it was and how it might be showing positive things for the Phase 3.
Re: Mix of stage 3 versus stage 4 patients in Phase 3
Given that the phase 2 used "47.5%" OS for SOC at 36 months (and based it on historical OS SOC data)....
...and now the Phase 3 is using "about 55%" OS for SOC at 36 months...
...this implies that the Phase 3 is using a different mix of stage 3 and stage 4 patients.
This implies phase 3 has more stage 3 patients in the mix because a stage 3 patient has a much better chance of being alive at 36 months than a stage 4 patient at 36 months.
If the above is true, then the 42% response rate for Multikine which @lightrock noted for Phase 2...
...will be higher in the Phase 3 because the Phase 3 has more stage 3 patients in the mix...
...and stage 3 patients respond better to MK than stage 4 patients because immune systems of stage 3 patients are healthier than stage 4 patients.
One more reason to be optimistic on Phase 3 being a success.
Where am I wrong? (if at all) Constructive criticism welcomed.
That is one big reason we are all on ihub!
Why stock fell
Two reasons probably
1. Imagine you are one of the people who held a tranche of warrants which you can exercise at 1.75 and turn around and sell the same day at the 2.75 area. You make a 1 point gain. There were 4M of these warrants which this could be done on starting Jan 02, 2019.
Lots of the warrant holders are just selling the common shares they receive when they exercise the warrants on a 1 for 1 basis.
A warrant holder could exercise a warrant at 1.75 and hold the shares they receive, yes, but most of the warrant holders have other shares in the company already for long term, so they exercise and quickly sell the shares received from the warrant conversion in the short term and continue to hold the shares they have always owned for the long term.
The good news is twofold though: When that tranche of 4M warrants exercise, CVM gets cash of $7M. (Because 4M times 1.75 is $7M). And the second good news is that warrant holders can only exercise and turn around and sell...one time.
So, as the weeks have gone by from Jan 2 until today, more and more of that large tranche of warrants are being exercised (turned into common shares) and more and more cash is going to CVM balance sheet.
At some point, all of those particular 4M tranche of warrants will have been exercised.
2. The second reason stock drops like last week is from those hedge funds which specialize in trading companies which have both warrants and shares. The hedge fund owns both.
So, they short the shares while holding the warrants long.
So, if the stock goes up a lot, they break even because the warrant gains offset the short losses.
But, in the meantime, if they short the stock and cover...and keep doing that consistently...."trade the stock"...they make good ROI until such time as the stock goes up a lot.
Stage 3 and Stage 4 mix of patients
Zacks analyst is saying that CVM is using somewhere between 52% to 55% SOC survival at 3 years and 42% at 5 years. Analyst said CVM filed that a long time ago.
(Remember, the "62%" SOC UK survival rate from the seekingalpha author was only for stage 3 patients...so throw that in the garbage can because the Phase 3 is both Stage 3 and Stage 4 cancer patients.)
So, if CVM is using "about 55%" SOC survival rates (the "about 55%" is taken from the CVM corporate presentation slide deck) for the mix of both Stage 3 and Stage 4 cancer patients, then the Phase 3 must have a lot more Stage 3 patients than Stage 4. Correct?
Does the math, spreadsheet, or logarithmic curve say that MK has much better survival percentages against SOC at 3 year mark for Stage 3 patients than with SOC Stage 4 patients?
If so, that could be a major reason why the Phase 3 is extending so long.
@lightrock
Fasco clarified that only Phase 3 patients were used for the 62% OS in the UK study.
So, the 62% SOC for Phase 3 hurdle rate I am now throwing in the garbage can.
The seekingalpha author had it wrong.
Fosco lightrock... there were 3 separate posts with three separate topics. And each post has the same subject heading. Next time, I will make sure that does not happen.
Have comments on the other 2 topics also?
@ Fosco @ lightrock #3 Post today
Is the hurdle rate which MK arm has to exceed by 10%... going to be whatever the SOC survival rate is in the Phase 3...
...or is the hurdle rate a predetermined percentage?
For example:
"The new SOC survival rate is 62%" seems to be the new buzz phrase. So, if the Phase 3 shows the SOC arm survival rate is, say, "58%"....will the regulators use the 58% or the 62% as the hurdle which MK arm has to exceed by 10%?
(Phase 3 has been ongoing for years and years and years...such that...the SOC survival rate has increased since the first patient in Phase 3. So, the SOC survival rate may have been "55%" when the Phase 3 began, but currently, it seems to be 62%).
If the above is true, then what is frustrating, is that even though the absolute number of patients increases by same amount in both arms, since MK arm has more patients surviving, the percentage increase in MK arm survival rate will be a smaller percentage amount increase relative to the SOC arm because the MK arm has more survival patients in it.
@Fosco @lightrock
What is the spreadsheet assumption on how much affect SOC survival rate going from 55% to 62% has on MK arm survival rate?
For example:
"800 patients" for both arms: 400 SOC and 400 MK+ SOC
Old SOC assumption: 55% survival rate on 400 SOC is 220 patients survive using SOC.
New SOC assumption: 62% survival rate on 400 SOC is 248 patients survive using SOC.
So, the SOC arm will have 28 more patients surviving at 36 months.
So, is the assumption that the SOC + MK arm will have the same increase of 28 patients surviving in it's arm?
Could we assume MORE than 28 patients survive in the SOC + MK arm because of the logarithmic curve changing shape?
i.e. If MK has no positive affect on survival at all, then the minimum increase in survival for SOC + MK would be 28 patient increase for SOC + MK arm?
@Fosco @lightrock
Should the biggest concern for a spreadsheet be that "the goal posts have moved" since the Phase 3 began on what survival rate MK has to show for Phase 3 to be a success?
55% was the original hurdle. 62% is the new hurdle rate (according to the author on Seekingalpha).
Original: MK arm had to exceed the 55% hurdle rate by 10%. So, if MK arm survival rate achieves a 55 x 110%= 61% survival rate, then Phase 3 would be a success.
New: MK arm has to exceed a 62% hurdle rate by 10%. So, if MK arm survival rate achieves a 62 x 110% = 68% survival rate, then Phase would be a success.
The goal post shave moved so much that the previous survival rate MK had to show for Phase 3 to be a success (62%), is now the new hurdle rate (the 62% which has to be exceeded by 10%)....so 68% is new survival rate MK arm has to show for for Phase 3 to be a success instead of the original 62% survival rate for MK arm.
Hi Fosco,
Been researching and organizing.
For example: Researched Pachinko on youtube. I realize how it relates to the Phase 3, so know the similarities you gave much better now.
Will narrow question list to a lower number of higher quality questions by Friday, Saturday.
Hi Fosco Spreadsheet Assumptions
Fosco,
I see you are using two different spreadsheet models, correct?
1. 55% survival for SOC year 3 and 45% survival for SOC year 5.
2. 64% survival for SOC year 3 and 54% survival for SOC year 5.
If the above is correct and it is compared to CVM's Phase 2 results which shows 63% survival for MK at 3.3 years for the 55 Phase 2 trials (From company's presentation).....then:
....what is the simple error I must be making for why your models show up to 25% better survival rate for MK because:
When compare your spreadsheet assumptions in #1 above, MK is only 14% better OS than SOC. 8 on 55 = 14%. Not much wiggle room if the Phase 3 endpoint is 10% improvement.
And when compare your spreadsheet assumptions in #2 above, MK has a worse OS than SOC. 64% v 63% .
Thanks.
Next update
When will the next update be regarding the number of deaths to date?
That would help the Phase 3 spreadsheet math.
298th Event
Clarity on the 298th event.
Are each of the following true or false regarding 298th event?
1. There will be NO press release and/or 8-K the day (or the week) of the 298th event having been reached.
2. The company will be informed the day of or the week of the 298th event, but the company cannot inform shareholders with an 8-K and/or press release until they verify the 298. And the verification takes up to 6 months.
3. If today is end of February 2019, then the 298th event may have been reached up to 6 months ago. 6 months ago is early September 2018.
4. The 298th event may have been reached months ago...somewhere between September 1 and today...and the verification is ongoing.
5. If the 298th event occurred months ago, then the chances of the Phase 3 being a success are significantly lower than if the 298th event occurs in April 2019 or July 2019 as some spreadsheets are predicting.
6. If the 298th event occurred in September, October, November, or December 2018, then the Phase 3 endpoint of 10% increase in OS will not have been reached according to the spreadsheet math.... and the news of that would be forthcoming soon.
7. If the 298th event occurs in, say, April 2019, then the shareholders will be notified up to 6 months later by September 2019.
I could go on and on, but these are the highlights for discussing a very important topic for which I think the entire board MUST have clarity on when making their decisions on CVM.
Currently, when I read the message boards, the assumption is the 298th event has not yet occurred, either because the company has not yet announced the 298th event or because spreadsheet assumptions assume the 298th event has not yet occurred, or for any other logical reason.
It is a VERY big assumption to think the Phase 3 is still ongoing. In other words, that the 298th event has not yet been reached yet.
Yet, I have not seen any message on the board (correct me if I missed it) discussing that the 298th event may have been reached months ago.... and due to the regulations, the company cannot notify shareholders until months after the fact...how many months depends on the length of time it takes the company to verify.
For clarity on this topic: Which of the above 7 topics are true or false? (Especially #6).
Thanks.