Phase 2 DFMO preventative trials

(Sam Saffron) #1

Dr. Giselle Sholler from Helen DeVos Children’s Hospital has been running a phase 2 clinical preventative trial for high risk Neuroblastoma patients.

The original phase 2 trial NCT01586260 has recently closed and a new one has opened:

NCT02679144 also knows as NMTRC014.

Initial press on the success of the phase 1 trial has been overwhelmingly positive:

Side effects are minimal and the results are very positive.

Participating in the trial involves taking a pill twice daily and doing monthly checkups (or in the case of international participants 3 monthly checkups)

As it stands there is 3.5 years of data now that is being analyzed, I am told we are expecting more results to be published in May 2016.

I am very keen on participating in the trial, it seems only to have upsides. But had a few questions:

  • What cost would participating in the trial entail? (for an international vs USA based patient)

  • Are any other countries participating in the trial, is SIOPEN discussing this at the moment?

  • Do parents of kids that participated have any feedback about this trial?

  • What can I do to get my hospital (in Australia) to also participate in this trial? Considering DFMO is widely available it seems like a very simple trial to run compared to some other ones.

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What after the immunotherapy
Introductions, welcome
How do you pick which clinical trials to join?
(Kyle Matthews) #2

As one of the groups helping to fund work on DFMO the past 5 years, I can agree the results have been promising, and the side effects have been very minimal. Really, your best bet in figuring out how to participate from an international standpoint is contacting Dr Sholler’s office. The info on her site is up to date, and she gets back to people fairly quickly.

Costs she or her team would need to help you with. I’ll tap into some of our international friends (Ireland, and UK) to see if they can share feedback on how they manage - I know there’s a lot of fundraising they’ve had to do.

Right now, the NMTRC (the 25+ hospital/university consortium chaired by Dr Sholler which runs this trial) knows many families outside the US are interested, and have been looking into the regulations and such around providing access outside the US. It’s complicated as laws are different in each country, as well as regulatory bodies.

We did a short video on DFMO as well at some point.


(Rochelle Paterson) #3

Hi Sam, My child just started Cycle 7 of 27 on this trial. We are pleased with DFMO so far. It has given us some peace of mind and certainly more hope. There are many diet modifications suggested while taking the drug, which has been the main adjustment for us, but completely reasonable. The follow-ups have been manageable as well. My daughter is the first on the study at our hospital in Florida, so we didn’t know what to expect other than reading everything we could find on the web. We were fortunate enough to meet Dr. Sholler at a Because of Ezra fundraiser. She’s amazing and her study results are promising. We were told initially that the drug was low toxicity and side effects would be minimal, which has proven to be true thus far. My daughter has been doing very well with no noticeable side effects at this point. She’s almost 18 months in remission. Wishing you all the best.


(Sam Saffron) #4

Thank you @rojopat , this is definitely something I would like Shalev to have. Being from Sydney Australia the logistics are a bit more complicated cause I am going to have to fly to Hawaii 8 times during the trial. Still, completely doable.

Very happy to hear you are experiencing minimal side effects. What particular dietary changes did you need to make?

I am hanging here very eagerly to hear the newer results based on 3.5 years of data that are due in a month or two, cause it will really help tons pushing some sort of international trial. Even if this only gives us an extra 5% I would be happy, any edge is worth it, in my opinion.

We are in day 7 now of BMT now, day 60 is when we start radiation and then there are another 4 months of immunotherapy, so I have a bit of time to get the ball rolling.

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(Rochelle Paterson) #5

Best of luck with the remainder of Shalev’s treatment and in getting on the DFMO trial soon after; hopefully as close to your home as possible. Here’s a list of some of the foods suggested we avoid. It’s been difficult to exclude everything 100% so our approach has been more about being cognizant of which foods are high in polyamines and limiting those items as much as possible. We do try to avoid the foods with the highest #s, for the most part, so we just don’t bring them into our home anymore. That way we feel less guilty if we occasionally let her have one of those foods at a restaurant.


(Sam Saffron) #6

I had a chat this morning with my oncologist Doctor Zeigler about the DFMO preventative trials.

He raised some concerns about the science behind this, in particular

  • There were no mouse models ran, he is running one at the moment

  • From our trials he expected DFMO only to be effective at higher doses in combination with chemo

  • The current trial is not a double blind study, it is very hard to interpret results

  • Only results published to date were for phase 1 trials

We started using DFMO at SCH for relapse treatment (in combination with chemo) Dr. Zeigler’s goal is to bring it into frontline chemo, so its an extra drug you take during induction for high risk NB.

The good news is that nobody seems concerned about the safety of the trial, only concern is around efficacy of it.

I am still, very much looking forward to the results that are to be published in 2 months, hoping they give us more information.

@birdni you seem to be quite across a lot of the science around NB any feedback on the DFMO trials?


How do you pick which clinical trials to join?
(Sam Saffron) #7

@KyleMatthews it looks like Doctor Sholler presented some data yesterday, do you have access to the information or presentation etc


(Kyle Matthews) #8

Not on hand, but I will check with her to see what the status is on that.

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(Mark Shirran) #9

In case anyone hasn’t seen it, this is the abstract of Dr Sholler’s presentation on her DFMO trial for ANR2016 taking place in Cairns next month. But it is only a summary and certainly there is information on the slide in the twitter picture that isn’t in this summary e.g. median follow-up time.

DFMO maintains remission and increases overall survival in high risk neuroblastoma: results of a phase II prevention trial (#88)

Giselle Sholler 1 , William Ferguson 2 , Genevieve Bergandahl 1 , Jeffrey Bond 3 , Kathleen Neville 4 , Don Eslin 5 , William Roberts 6 , Randal Wada 7 , Javier Oesterheld 8 , Deanna Mitchell 1 , Jessica Foley 1 , Valerie Brown 9 , Nehal Parikh 10 , Francis Eshun 11 , Peter Zage 12 , Jawhar Rawwas 13 , Susan Sencer 13 , Debra Pankiewicz 14 , Monique Quinn 14 , Maria Rich 1 , Joseph Junewick 15 , Max Wicha 16 , Jacqueline Kraveka 17

Background: High Risk Neuroblastoma (HRNB) remains a challenge in pediatric oncology, accounting for 15% of all pediatric cancer deaths. While most patients are able to attain remission, the natural history of HRNB is well documented with approximately half of patients relapsing within 5 years after completion of immunotherapy. This study evaluated the effectiveness of the ODC inhibitor difluoromethylornithine (DFMO), which targets cancer stem cell pathways in HRNB, as a maintenance therapy to prevent relapse in HRNB patients who were in complete remission at the completion of standard therapy.

Methods: This study was an open label, single agent, multicenter study. Enrollment began in June 2012 and ended in February 2016. Subjects received 27 4-week cycles of oral DFMO at a dose of 500-1000 mg/m2 twice daily. Event free survival (EFS) and overall survival (OS) were determined on an intention-to-treat (ITT) basis.

Results: A total of 94 subjects received DFMO, 91 were eligible for the intention to treat (ITT) population. For all ITT subjects, EFS was 91% (± 4%) and OS 98% (+/-2%) at 2 years. For the subgroup of subjects (n=74) who were previously enrolled on the ANBL0032 study, the 2 year EFS was 95% (± 3%) and OS 98% (+/-2%). This is a significant improvement in comparison to ANBL0032 study which showed a conservative EFS of 76% 2 years post antibody therapy (p <0.01) and OS of 89% (p

Conclusions: Administration of DFMO at 500-1000mg/m2 BID is an effective and safe dose. Following the completion of standard therapy for high risk neuroblastoma DFMO treatment was associated with improved EFS and OS decreasing the high rate of relapse in children with HRNB. An additional prospective trial is ongoing to confirm these results.


(Kyle Matthews) #10

Original link:

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(Patrick Lacey) #11

Hello Sam -

Some feedback from your doctors concerns are listed below - I hope all is well.

The phase I DFMO trial that was for patients with relapsed or refractory disease has 3 long term survivors. It was a standard 3 by 3 dose escalation study and 2 of the long term survivors were treated in the first cohort with the lowest dose of DFMO (lower even than the current preventative trials). As of yet in patients and in trials there is absolutely no information to indicate that a higher dose is better than a lower dose. In fact, the evidence would seem to point in the other direction. However, there is a DFMO/Velcade study that is nearing completion that did dose escalate DFMO - results are pending. In terms of a double blind study - the natural history of this disease is very well understood and more importantly there are about 90 children who enrolled on this clinical trial that were first enrolled in the ANBL0032 study. There is a published comparison of patients - that got the exact same treatment and that did not add in DFMO after therapy. The endpoint of the study was designed to prove statistical significance with that patient population.

There have also been extensive mouse models performed - one that was published illustrating why DFMO may be effective at preventing relapse.

Targeting ornithine decarboxylase reverses the LIN28/Let-7 axis and inhibits glycolytic metabolism in neuroblastoma


(Sam Saffron) #12

Thank you so much Patrick for popping by and adding some more information here!

I am really hoping some progress can be made at the ANR panel and somehow we can extend the trial and make it available outside of the US. The risks just seem so low and the upsides so high.


(Sam Saffron) #13

This was a rather hot issue at ANR2016, in particular Dr. Julie Park took some time to talk about it when discussing new therapies with the parents.

The gist of it was that a 2 year EFS of 91% is not a huge surprise considering the inclusion criteria.

My general question to people running the trial would be why not focus on the first 6 months instead where odds of relapse are highest? (half the relapses happen in the first 6 months)

  • Focus the study on COG or SIOPEN, don’t mix cause outcomes vary depending on protocols. (similarly only look at COG with tandem transplants)

  • Allow everyone into the study that is deemed disease free after frontline, perform the exclusion tests after they are selected, include rejected patients in the study. (this allows for a very clean comparison with a DFMO free cohort)

  • Strictly start DFMO after the all clear scan with no delay to maximise the protective effects. EG: always start DFMO 10 days after last CH 14:18

It seems that answering the question

  • Does 6 months of DFMO protect against relapse when commenced back-to-back after COG high risk protocol with tandem transplant?

Is much simpler and faster to answer than

  • Does 24 months of DFMO protect against relapse?
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(Patrick Lacey) #14

Hello Sam -

At the time this study was opened - 4 years ago this month - there was less than 20 patients with neuroblastoma who had ever take the drug before and that was part of a phase I study. Those patients had relapsed or refractory disease and had tried and failed multiple years of chemotherapy options. At that time there was a question of safety and can the disease be prevented from coming back so this study was designed to test that out in this new patient population.

  • 91% EFS is not a huge surprise? Since when is that not a surprise for high risk stage IV kids 2 years out from finishing therapy? Unfortunately, Dr. Park’s assumptions about the patients on this study are incorrect. These were not ‘cherry picked’ patients - anyone from anywhere could enroll on this study and not all patients were NED before transplant. Or nmyc negative…these were kids (many of whom enrolled in ANBL0032) who were at high risk of relapsing.

  • Historically, the majority of relapses are around the 9 month mark. If it was a 6 month study the same folks saying “91% is not big surprise” would instead be saying “it is only for 6 months”. The fact of the matter is that by and large the patients on this study have not had any side effects and the idea of doing ‘only’ 6 months of drug - frankly - seems unethical given the statistics and quality of life on drug. In fact - from what I have seen most patients are terrified to STOP taking the drug after being on it for 2 years.

  • This study was open to anyone who wanted to enroll. When it started COG was saying that single transplant was the way to go - now that has apparently changed. Tying this study to any standard of protocol 4 years ago would have been difficult. However, 80% of the patients WERE enrolled in ANBL0032 and we have asked COG to use our data to create a matched cohort from their data.

In fact, I offered to pay COG to cover the cost of their statistician to review this DFMO data and to find a matched cohort form ANBL0032. We have been attempting to collaborate so that a COG statistician could see the data and analyzed it but so far that has not happened. It is interesting to see the response to this data from everyone around the world vs. the folks in COG.

There is nothing to hide here.


(Sam Saffron) #15

Yes I agree, this is very upsetting. The reason I am struggling with DFMO is because the message from both COG and SIOPEN is “we are not sure about efficacy”. Nobody has really raised questions on safety which is great.

I just wish there was some way for COG or SIOPEN to work with the NMRTC to validate the trial results. There are so many studies going on at the moment that validating this would be in the interest of all parties. If DFMO is effective then it is messing up all the results of of the SIOPEN and COG long term studies, if it is not effective then there are plenty other avenues to tackle and resources can be deflected to something else.

Meanwhile parents are getting mixed messages from oncologists (for example my oncologists are advising caution) others are advising DFMO.

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(Alexey) #16

Just wanted to add into this topic…
I just read the following story (I think this is a really interesting experience, because mom of that child is a doctor and they live outside of US…):

The drug is called DFMO and is for maintenance. The purpose is to prevent any relapse. It’s a drug that you take twice a day orally.
One course of treatment is one month, and every three months you have an MIBG scan, a CT scan, and any other special tests you may need.
The periodic tests (blood etc.) you can do in Israel however you need to be in Michigan to get the drug because they cannot ship the drugs overseas. They need to see you, check on the kids, and after that you can fly back with the medical drugs. This treatment was very easy on Muli. We didn’t see any side effect.
After nine months he relapsed, so we stopped the treatment. Usually, the protocol for this treatment is two years.

where that family joined a DFMO trial in Michigan a few years ago (difficult to get the exact date, but before 2013) and it didn’t work. I am really really hope that the DFMO works, but there are some stories, where it didn’t…

Does anybody have any news if this trial is available somewhere outside of US?..


(Sam Saffron) #17

I was just watching this video about that very family yesterday, it is heartbreaking. He did not make it.

For full context they also got the Bivalent Vaccine at MSKCC, MIBG therapy and another vaccine trial. I am not sure about the last 2 years of treatment they had, but it was a very very tough case. The DFMO was given after relapse.


How do you pick which clinical trials to join?
(Sam Saffron) #18

Note I came across this video from last year about DFMO by Dr. Sholler

This is a year old, hopefully we will have an updated talk in the next few weeks from CNCF, since she is talking there.

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(Alexey) #19

Just was in contact with Dr. Sholler’s office and this is what I found:

  1. There are no plans right now to extend this trial to outside of US. Only one exception is Canada, but even these plans are uncertain now.

  2. Rough cost of 2 years treatment itself is between $120.000 and $150.000, but you can get 30% discount if you are able to pay before your visits (the full amount will be divided between your visits). As I understood, may be you can do the scans and tests in your local hospital, but Dr. Sholler should confirm it. So hopefully it can reduce the total cost.

I am still looking forward to participate in this trial, but its not clear of why there are no published Phase II results. I know that there is a short summary from ANR 2016 conference, but I would like to get an opinion from our doctor and ideally it should be more information.

Why its not published yet?.. Hope there is nothing to hide.


(Alexey) #20

Just found this very recent article:

Perhaps the most-striking data presented were the outcomes of a phase I trial conducted in the USA in which children with high-risk neuroblastoma were treated with difluoromethylornithine (DFMO) and etoposide. The combination was shown to be safe and well tolerated, and relapse was prevented. These children experienced an improved quality of life; moreover, extended and ongoing follow-up data demonstrate that some children are in remission. Despite these promising results, the company that provided the drug and funded the trial wanted to close the trial before the primary end point was met, as they considered the data collected were sufficient for the purposes of the trial. The parents of the children on the trial, however, decided to take control and set up their own company to produce the drug; they imported the active ingredients and worked with the FDA to get their drug approved and to continue the trial.

Is it something related to this NMTRC trial or something different?..