Phase 2 DFMO preventative trials

(Kyle Matthews) #41

The paper has been submitted, and is awaiting publication…

(Riza) #42

Do you know estimated publication time? And is the paper about preventive or maintenance treatment?

(Mark Liu) #43

Any update for DFMO?

(Sam Saffron) #44

Not sure, perhaps @KyleMatthews or @Patrick_Lacey would have an update? I have not come across anything new published in the last 12 months or so.

(Kyle Matthews) #45

The most recent numbers I’ve heard are 97% OS and 86% EFS.

Even more encouraging is the durability of these numbers (they are showing to stay true at 4 years, 5 years).

This is huge compared to the results the ch14.18 antibody (UNITUXIN/dinutuximab) has shown. They showed a big jump at 2 years in OS/EFS. Sadly, at 5 years there is no statistical difference in EFS or OS for kids that did - or did not - get antibody.

(Nick) #46

p-value was 0.03 at 5-years
74.2% vs 57.0%
for OS on ANBL0032 (antibody vs. isotretinoin)

(Nick) #47

@KyleMatthews when will the maintenance trial complete and manuscript published and peer-reviewed? If those numbers persist then people will have to take a serious look - and possibly think about bringing it in earlier somehow? If DFMO is going to start being given with ch14.18 + GM-CSF + Temo-Irino for R/R then theoretically starting it concurrently with, say, the last round of antibody (or sooner) shouldn’t prove an issue? Unless it interacts with 13-cisRA somehow? I do wonder about the argument that pre-clinical evidence is it doesn’t have efficacy at the dose used in the preventative trial. I’m no a scientist but clearly there are literally dozens of examples of things that do work in vitro and in vivo and then, because cell lines and mice are not human beings, have no effect in children. Is it completely beyond the realms of all possibility for the opposite to also be true? I don’t know.

(Mark Liu) #48

is there any official release of this statistics?

(Kyle Matthews) #49

No published paper yet, no.

(Nasos Mwraitis) #50

what do you mean by this ? that immunotherapy just hold for 2 years relapse and after numbers are same ?? can you provide us please with research on this?

(Kyle Matthews) #51

I don’t believe this is published yet.

Yes, I mean that at 5 years it seems the survival rate is the same for kids who have or have not received Unituxin.

(Neven Dawaf) #52

So which one is better ? The DFMO after remission or the vaccine at the MSKCC ?
Can both be given?

(Sam Saffron) #53

Yes, as long as you do the vaccine first I know of cases where people who follow on to DFMO.

Impossible to answer this question of what is better cause not enough peer reviewed data is published.

That said… if it was me… in a time machine… I would have probably headed to MSK for the protocol post resection (or pre, depending on how complicated the operation was). Hu3F8 is significantly more potent than CH14:18 and can be given as an outpatient. Additionally, MSK skip transplant which is a hotly debated topic especially since COG now do 2 transplants routinely for high risk.

(Alexey) #54

A new recent article:

(Alexey) #55

One more update regarding DFMO - now its available in Canada as well:

(Neven Dawaf) #56

Any recent update ( numbers ) about the DFMO study on kids after their first remission?

(Sam Saffron) #57

This was just published a few days ago:

It is extremely hard to interpret the results as there are at least 3 protocols being compared here with a reasonably small sample size per protocol. Some had tandem transplants, some had single transplants, some had no transplants. Additionally, not everyone was eligible for DFMO cause frontline was refractory or sadly we lost them prior to DFMO.

For example, if an survival graph usually looks at time since diagnosis

Since this trial starts AFTER treatment, you need to correct the comparison to look at a subset and then extrapolate backwards:

Some people started this say 15 months post diagnosis and others started it 18 months after diagnosis.

In all cases people were in complete remission when they started DFMO. This means that for an accurate comparison we need to compare the subset of patients that completed full treatment by COG/SIOPEN/MSKCC comparing yes DFMO to no DFMO. Extrapolating here is very very very hard.

One graph COG/SIOPEN and MSKCC never publish is “survival rate of NB patients that completed NB treatment and achieved full remission, starting one month after treatment”. Graphs they publish tend to include all the hard cases.

From the paper:

Given that the entire cohort includes subjects who had received various standard-of-care therapies prior to
starting DFMO, it is important to review the outcomes from other groups. While numbers are small, analysis of the subject cohorts that received non-COG frontline therapies also suggests benefit for DFMO maintenance therapy. A European study reports that high risk NB patients who were treated with a similar overall therapy strategy (including anti-GD2 antibody) had 3 year EFS of 46.5% ±4.1% and OS of 86.5% ±3.9%; analysis of their survival curves to correct for a lead-in period suggests that those who were event free at the completion of antibody therapy experienced a subsequent 2-year EFS of < 60%.

This in particular was looking at: which was published in 2004 back before SIOPEN used Bu/Mel as the standard of care transplant (in fact half the people in the paper above had a no transplant). This correction for lead-in is not something that is easy to do especially given you don’t even have a clean cohort to compare to.

Also from the paper:

The median time from start of antibody to start of DFMO was 7.2 months. After statistical correction for this “run in” period, the proportion of ANBL0032 patients remaining event-free for an additional 2 years (the duration of DFMO therapy) is conservatively estimated at 75%, and EFS continues to decrease between 2 and 4 years post therapy. In contrast, the observed two-year EFS for subjects in Stratum 1 who received DFMO after ANBL0032 therapy was 86% ±4%

I am a bit confused about this 75% number cause per: EFS across everyone including the hard cases, if you erase a year or so out of there I would expect it to be much higher.

The basic argument here is that the paper is claiming that without DFMO you would expect 75% survival and with DFMO you would expect 86% ±4%. Everything depends on how good the comparison is and the cohorts are quite small and the data is quite hard to compare.

@ludwinski do you have any contacts at COG or SIOPEN? What are their thoughts on the paper?

(Neven Dawaf) #58

Although Our Oncologist thinks the same way and that these results are likely biased , I would still go for the MSKCC vaccine and then the DFMO , Its so scary to stay off treatment .
We are still midway in the treatment and my son just had his surgery but If he will be eligible at the end of his treatment , I would do everything to prevent this evil from coming back .

(Kyle Matthews) #59

Here’s an article exploring that published paper a bit more.

(Roland King) #60

Neven, what you have decided in the end? more than a month has passed and i’m really interested in any updates if you have for us. thanks!
Kyle thanks for the article!