Celsion Corporation (CLSN)

[Biobonic]

No, not a fail. It keeps going.

The upcoming second interim review:

So to be clear, I'll say it another way. The bar for success is lower than what we have seen in the prospective HEAT Study subgroup analyses. So as I said and I'll say it again, I remain very optimistic that we have a much better chance for success at the upcoming second interim analysis following the DMC's review.

Now if the study does not meet the standard for success at 158 deaths, we uniquely have another opportunity, a third bite of the apple if you will. We have a final [indiscernible] data following 197 patient deaths. At this point the bar will be much lower. The p value and hazard ration required for positive trial at the final analysis are 0.043 and 0.75 respectively, which is even further below the valance observed in the prospective HEAT Study subgroup and certainly bodes well for successful trial.

I'm not risking a lot in this,...

[stockweiser]

Yes thats what i was just thinking but will trial fail if secondary is not met?

[Biobonic]

From the 3Q CC 2019 comes this statement:

RE: The OPTIMA Phase 3 study: We’ve also said that there is a higher probability of success at the second interim analysis, now anticipated by June of next year, just 7 or 8 short months from now. We stand by that guidance.

From the March 2020 Corp Presentation.

OPTIMA Study, a global Phase III trial in HCC/Primary Liver Cancer, with 2nd interim data expected in early 3rd Quarter of 2020

Hmmm, It appears that it is taking longer than first thought. That is a good thing, when people live longer in a trial that measures how long participants live...

[dia76ca]

March. 2020 presentation. Some interesting new data.
http://investor.celsion.com/static-files/70e45734-e80b-41dd-b6af-e19f435f46c0

[john1045]

Celsion’s OVATION 1 Study with GEN-1 in Ovarian Cancer Shows Strong Progression-Free Survival Treatment Effect Utilizing Medidata Synthetic Control Arm
GlobeNewswire GlobeNewswire•March 26, 2020
Hazard Ratio of 0.53 for PFS in the Phase I Intent-To-Treat Population

Synthetic Randomization Provides Means to Evaluate Strategies to Accelerate GEN-1 Clinical Program for Newly Diagnosed Stage III/IV Ovarian Cancer

https://finance.yahoo.com/news/celsion-ovation-1-study-gen-120010020.html

[dia76ca]

I have invested in CLSN because of the potential of Gen-1 to dramatically extend the lives of late stage ovarian cancer patients. I hope Thermodox results' are also good but Gen-1 alone is worth far more than the current share price.
1. The potential market for Gen-1 is over 100,000 patients annually.
2. If a course of this first line treatment costs $20-30 thousand the total sales would be about $2-3 billion.
3. This cost is low compared to other less effective IO's with far more adverse events.
4. The company is funded "well into 2021".
5. There are only 35.5 million shares fully diluted.
6. Institutional holdings recently moved from 5% to about 40% f.d.
7. Gen-1 already has both US and European orphan status.
8. It will very soon receive some form of expedited approval (eg.Fast Track) IMO.
9. Partnering could be close. There's partnering interest in Thermodox.
10. I hope Thermodox is approved. Both could be partnered this year. Or there could simply be a buyout. The company is dramatically undervalued.
11. We should learn more on Thursdays' CC.

[dia76ca]

Next Thursday is the Q4 CC. I hope it will answer 3 questions.
1. When will we receive the translational data? Does the higher dose of Gen-1 result in higher levels of IL-12, interferon g, dendritic cells, memory T cells, and CD8+ and CD4+ in tumor? Does it increase the decrease in immunosuppressive biomarkers?
2. What is the FDA saying? Can we expect some form of expedited approval?
3. Is there partnering interest in Gen-1?....as there is in Thermodox? Might a large Pharma be interested in both?

[dia76ca]

Todays GEN-1 ovarian cancer trial results are very encouraging. Dr. Borys summed them up as follows..."The clinical data at the three highest doses of GEN-1 showed an 82% R0 resection rate, compared with a 50% R0 resection rate for the NACT only control arm of the OVATION 2 Study. Historical levels of R0 resections after interval debulking surgery range from 40% to 60%."

[john1045]

Well said!

[dia76ca]

What's NEW that we can learn from the recent CEO letter?
1. Cashed up "well into 2021".
2. 4 "new" institutional investors.
3. Institutional investment moves up from 5.5% to over 40%.
4. Confirmed Thermodox 2nd interim look will occur in Q2 2020.
5. Confirmed phase 1 Gen-1 data by end of this month.
The big institutional move is very bullish. They did not invest to lose their money.
glta.

[Golden Cross]

Reversing nice here

[stockweiser]

Will do just sent out email.

[GD]

Great, please post after you get any answer for your questions.
I am going to listen to next CC, think CEO is back into the wall,
there is no more room for him to talk up CLSN stock without solid
new information, IMO.

[sabadollar]

OK! Let me know. If no answer, i would write also an email. Thx for your reply.

[stockweiser]

I just left a message today with the second but so far no call back I'll probably email next.

[sabadollar]

Ask the great management of CLSN. There is always a delay with their timeframe. I am waiting also for a report!

[stockweiser]

So if we only have to be 70% of the HEAT trial at 80 months pfs wouldn't OPTIMA be there right now according to the graph?

[GD]

No, the graph is showing the real time PFS data collected
at most recent month, last NOV or DEC? There is not much
down side risk here at 1.35 until GEN-1 data, if not stopped
at second look, CLSN may test $1, IMO. I like SAVA much
better risk/reward than CLSN now, I think 60% chance OPTIMA
continue to the final look, IMO. Now I get it why CEO keeps
telling us interim look HR numbers but not P value, he is
trying to keep the stock above $1.5 to sell about 1M shares
each Q, the fact is the P value is the one to decide interim
look to stop or continue, can not blame him by doing so to
fight CLSN survival, but not honest to individual investors
like us, IMO.

[stockweiser]

Isn't the graph showing a projection of future months?

[GD]

Next CC in Mar should be more interesting...analysts should ask
CEO to explain the PFS KM curves tail....

[stockweiser]

I just listened to last quarter CC he's stating Optima is doing better than HEAT sub.

[GD]

No, it means at month 42, there are more patients having
the HCC coming back and the 5 year OS may go lower too.

[stockweiser]

Correct me if im wrong pfs probability looks more encouraging crossing down like that to over HEAT trial.

[GD]

Here is the CLSN new presentation from Jan 28, 2020:

http://investor.celsion.com/static-files/70e45734-e80b-41dd-b6af-e19f435f46c0

On page 18: OPTIMA Study: Blinded PFS Data Consolidated for Both Arms
my consern is HEAT subgroup gets the P value down to 0.02 from OS
wide separation tail of the KM curve, and OPTIMA PFS crossed down
below subgroup PFS at 42 month time mark, and Subgroup flat at 27%
on 38 month time mark vs OPTIMA falt at 18% on 46 month time mark,
raise concern OPTIMA OS tail may not be as good as the subgroup that
affects P value at second look, IMO.

[stockweiser]

Can you post link where i can see this?

[GD]

I sold out my full position again, not so sure
second look can stop the OPTIMA because CLSN
posted the new HEAT subgroup and blinded OPTIMA PFS
data, OPTIMA PFS curve has went down below the subgroup
PFS curve at 42 month time mark, which may mean the
OPTIMA 5 year OS data may not be as good as the subgroup
data and P value may not hit the target of less than 0.02
to stop at second look, fair chance OPTIMA may win at the
final look next year, IMO.

[Biobonic]

The Heat Trial had been recruiting

since 2008 here

It's my understanding that the HR separation becomes pronounced with more months into the study than the number of months in this Optima study's first look.


From the 3rd Q CC:

Number three, the rate of patient deaths for the OPTIMA study appears to be tracking well with the HEAT study perspective subgroup. As we suspected, however, overall survival from the OPTIMA study was not sufficiently mature to draw any conclusions. The study had a median follow up the OPTIMA study events. Had a median follow up of 25 months where's the comparative perspective subgroup had immediate follow up of 67 months. So I just give you a little suggestion here. If you'd like, graph for the prospective subgroup of 25 patients is published in the manuscript that's on our website. I encourage you to take a look, judge for yourself where a meaningful separation occurs.

Courtesy of SA, so the copy may be a bit garbled.

[GD]

Here is the HEAT subgroup data timeline I get from CLSN website:

May 20, 2012: HEAT enrollment completed.
Jan 31, 2013: HEAT results.
May 17, 2013: First time, subgroup data HR=0.65, P=0.105
Sept 16, 2013: subgroup data HR=0.623, P=0.058
Jan 27, 2014: subgroup data HR=0.64, P=0.0495
Dec 30, 2014: subgroup data HR=0.65, P=0.037
July 15, 2015: final subgroup data HR=0.65, P=0.02

It is very clear to me OPTIMA final HR is set which
means success or failure known to DMC, only P value
may change, if Theromodox is working as expected like
HEAT subgroup data has shown, P value may go lower to
increase the level of SS.

[GD]

I was looking for some thing close to this for the first interim look:

"Tecentriq in combination with Avastin reduced the risk of death (OS) by 42% (hazard ratio [HR]=0.58; 95% CI: 0.42-0.79; p=0.0006) "

Well, I guess OPTIMA does not out perform the HEAT subgroup
data, and the best we can see HR =0.65 to 0.7 with the second
interim look. If second look stop for efficacy, I expect CLSN
to partner for Asian market or buyout. I bought my full position
back. One thing is for sure, what ever the first look HR is,
it will be the second look and final HR, only thing may change
is the P value, more the events, lower the P value.

https://www.businesswire.com/news/home/20191122005376/en

https://www.fiercepharma.com/marketing/roche-aims-for-bayer-s-liver-cancer-share-tecentriq-avastin-survival-win?mkt_tok=eyJpIjoiWldKak56Y3hNR05pTnpKaCIsInQiOiJYSStoeWR0MW83Rk5hbTAzQ2xvQ2M0NVVGVjNCcmF3TkREUDJTbXdIN1Blcm5lVkhOQUN1aWxoc2RjdXFcLzU1TEZnTlcxWnpaZmRBVkZ3eWxWeUlcL2FxRkNzSGZlSldBempUYnFrc0Y5MTEwb25PSzByUjlnZkpzcVk3UzIxVkhWIn0%3D&mrkid=47116683

[Biobonic]

Some cutouts from the 3Q cc

(On the possibility of the trial being declared successful)
possible but not probable, This is been our guidance for the past year or so regarding the first interim analysis for our phase 3 optima study.

We also said that there is higher probability of success at the second interim analysis, while anticipated that by June of next year.

Cash:
A position that is sufficient to support an operating runway into the first quarter of 2021.

We now understand that to be a minimum of 45 minutes of RFA treatment in combination with ThermoDox. (This is past, but surely this is a component of the process that should have been identified in phase 2 trials.)

You would know that this one large subgroup followed prospectively for three years, well balance, demonstrated median time to death of more than 7.5 years, that's curative by any standard of measure in oncology

[europtiger]

Got me some

[Biobonic]

Wording in Celsion PR not well thought out.

Am not very familiar with the biotech world, in the learning mode.

The IA PR included these statements:

We believe this tracking bodes well for success at our next pre-planned interim efficacy analysis, which is intended after a minimum of 158 patient deaths.

“The hazard ratio for success at 158 events is 0.70. This is below the hazard ratio of 0.65 observed for the 285 patients in the HEAT Study subgroup of patients treated with RFA > 45 minutes,” Mr. Tardugno added.

To state that interim milemarkers if achieved, would be a success...the implication was assumed by some to mean the trial would be declared a success. It does seem to be a poor choice of words. Trials get labeled a success, don't confuse the landscape by using that word for an IA review.

Yes, in reviewing the Heat study and working at coming up to speed on Celsion, it does appear that the study ended up being more of a phase 2 type of study. Wonder if they put too much on their plate, once the Heat trial was ended they put together a committee to search for other biotechs to buy out.

[exwannabe]

I have never heard of an IA stopping decision being based on H/R and not P value. Not even clear how that would work math wise.

They might be presenting an H/R that "should" hit the needed p value or an H/R that is being used in addition to P value. Doubt I/R would answer unless it has already been made public someplace.

I have not watched these guys since Heat failed. I thought Heat had a good chance, alas not. In retrospect, seems kind of sloppy on them not to have analyzed the bake time issue prior to a large trial.

Anyway, that was past. Might have to buy in this winter, looks like a decent shot.

Good luck.

[Biobonic]

Yes, I stand corrected

The The power point presentation August 2019

page 18 has details concerning the Optima trial.

[stockweiser]

Is 70 or less ?

[Biobonic]

I have emailed Celsion's IR

to ask about the hazard ratio at the next pre-planned interim and if it is 0.70 will that be sufficient to declare the trial a success?

[Biobonic]

The primary outcome measures is OS

From Clinicaltrials

The Primary endpoint is: Overall Survival (OS) [Time Frame: 5 years]
Overall survival is defined as the time (in months) from the date of randomization to the death date.

A secondary outcome:Progression-free survival (PFS) [Time Frame: 5 years]
Progression-free survival is defined as the time (in months) from the date of randomization until the date of the Investigator-assessed radiological disease progression or death due to any cause.


The talk around this preplanned interim efficacy review was the hazard ratio.

In the Celsion PR of Nov 4, 2019: The OPTIMA Study, like other oncology studies, is subject to tumor progression, and the timing of efficacy results is entirely event driven. We estimate that our next interim safety and efficacy analysis will occur during the second quarter of 2020.”

“The hazard ratio for success at 158 events is 0.70. This is below the hazard ratio of 0.65 observed for the 285 patients in the HEAT Study subgroup of patients treated with RFA > 45 minutes,” Mr. Tardugno added.

Edit: If the hazard ratio at 158 deaths is 0.70 or above, does that trigger the finding that the trial is a success?

[stockweiser]

Is the primary end point pfs?

[Biobonic]

A Director of the Company bought 4,000 shares on the open market today.

[stockweiser]

Thank you

[stockweiser]

Surprised you sold

[GD]

I am very dispointed at the PR today, It means
the best case HR is 0.65, still wonderful HR
if OPTIMA can get in second look next year, I
sold my huge position today for a 0.15/share loss,
may come back by the time close to second look
next year, good luck to CLSN longs!

[veni vidi vici]

Here is the YouTube link to Dr. David Needham's presentation that you asked for and that I previously posted on this board earlier this summer:

Just listen to minutes 16-23 of his talk.

Also, this morning Celsion reported the results of the first pre-planned interim analysis of the OPTIMA study.

http://investor.celsion.com/news-releases/news-release-details/celsion-reports-unanimous-independent-data-monitoring-committee

good luck,

VVV

[GD]

If we look at the >90 min subgroug OS KM curves, it is
beautiful and clean OS KM curves, after they are separated,
diverge to the end, and HR is 0.5, The HEAT trial shows
the OS advantage is clearly related to the duration of
RFA time. I do not know how to determine how much RFA time
is required for each OPTIMA trial patients, but I believe
CLSN may ask trial Drs to RFA to the longest time possible
for each trial patients since longer the better chance of
survival in Thermodox arm, hence I speculate OPTIMA may
perform better OS than the heat subgroup HR 0.65, from
this reasoning, I am very buillish on first look HR value.
If first look stops OPTIMA for efficacy, It mean Thermodox
is "the treatment of HCC with curative intent" and I am up my
CLSN stock price target to $25, a $500M markey cap, very very
conservative 1X peak sales estimate of $500M.

[Biobonic]

Thanks

Found the article here

Further info:

We hypothesized that RFA + LTLD efficacy would be superior to RFA alone among patients with unresectable intermediate-size HCC lesions. Instead, median PFS and interim OS were similar in both study arms. In trying to understand these results, we noted a wide variation in RFA dwell times between the 66 active centers. The study did not require minimum dwell times because the manufacturers of the FDA-approved RFA devices used in this study do not recommend minimum dwell times nor do guidelines exist. Beyond the criterion for RFA adequacy, which was ablation of each target lesion plus a 360° 1-cm tumor margin, no attempt was made to manage RFA dwell time in the HEAT Study.

In the end, this was a negative study. The post hoc analyses are clearly hypotheses generating only and require clinical validation. This is now being performed in the prospective phase III OPTIMA study, designed to control for RFA dwell time. We are hoping to learn from the current study and impact future development of LTLD in HCC.

[GD]

Sorry, I deleted it after I listend to it 3 times,
His name is Prof. David Needham.

[GD]

The 285 >45 min subgroup is divided in 138 RFA+Thermodox
and RFA along 147, I read it as a very good double-blinded
concept proof PII trial, and the OS data is believable to me.

[stockweiser]

Do you have that YouTube link to the creator of thermadox talking about duration times and Heat trial failure?

[Biobonic]

Looking at the HEAT Study

Jan 2013 Celsion announced that the Heat study did not reach it's primary endpoint of the Heat study.

They continued to review data on the participants.

From ClinicalTrials the actual PFS for both arms is recorded.

PFS (Progression Free Survival)

RFA and placebo PFS 347 participants with a PFS ave of 13.87 months.

RFA plus Thermodox 354 participants with s PFS ave of 13.97 months.

Hardly any improvement at all.

As Celsion continued to track data this was published in Feb 2014:

Data from the updated HEAT Study analysis suggests that ThermoDox® may significantly improve overall survival, compared to control, in patients whose lesions undergo RFA treatment for 45 minutes or more. These findings apply to patients with single HCC lesions (64.4% of the HEAT Study population) from both size cohorts of the HEAT Study (3-5 cm and 5-7 cm) and represent a subgroup of 285 patients (41% of the patients in the HEAT Study).

Have this straight? 354 were in the Thermodox arm.

A subgroup of 285 had treatment for 45 minutes or more.

That is 80% of the Thermodox arm.

With those 80% the PFS barely passed the placebo arm.

Now there is a study designed with all participants having a 45 minute or more treatment.

So the 20% that didn't get the extra time is going to move the needle when 80% didn't?

[GD]

May be I am reading into too much, but to me these changes in Prof. Lencioni's view
is a sign OPTIMA OS results are a repeat or better than subgroup data:
April 12, 2018 CLSN PR:
Prof. Lencioni’s presentation: "The company’s ongoing second Phase III study, the OPTIMA Study, is designed to test this survival benefit hypothesis. If this hypothesis bears out in the OPTIMA Study, this would be very meaningful and highly encouraging as there are few available treatments effective in prolonging survival in HCC.”
Sept 23, 2019 CLSN PR: (Coincidence?, Sept 23 is exactly 6 weeks from Aug 128 event datalock PR, and also in the PR is DMC meeting is scheduled for late OCT,
is the OS data available by Sept 23???!!!)
Prof. Lencioni comments: "The Company’s ongoing second Phase III study, the OPTIMA Study, is designed to test this survival benefit hypothesis. If this hypothesis bears out in the OPTIMA Study, ThermoDox® will be the first and only FDA approved drug for the treatment of HCC with curative intent.”

From "very meaningful and highly encouraging" treatment to "the treatment of HCC with curative intent”, Prof. Lencioni is OPTIMA trial study co-chairman, he is the one should have very clear view how OPTIMA is going from blinded data, IMO.