Phase 2 trials of Bivalent Vaccine

Treatment / Research
1

Memorial Sloan (MSKCC) have a current trial for a neuroblastoma vaccine:

https://clinicaltrials.gov/ct2/show/NCT00911560

The purpose of this study is to test the safety and what effects, good and/or bad, treatment with a vaccine against neuroblastoma has on the patient and the cancer. In the first part of this study we found the highest dose of the vaccine that did not have too many side effects. We are now trying to find out what effects the vaccine has when given at the same dose to all patients.

The main treatment in this protocol is a vaccine. It is called a " bivalent vaccine" which means it has 2 antigens. An antigen is a specific protein on the surface of a cell. The antigens are called GD2L and GD3L.

We want the vaccine to cause the patient’s immune system to make antibodies against the antigens. Antibodies are made by the body to attack cancer (and to fight infections). If the patient can make antibodies against the 2 antigens in the vaccine, those antibodies might also attach to neuroblastoma cells because a lot of each antigen is on neuroblastoma (and very little on other parts of the body). Then, the attached antibodies would attract the patient’s white blood cells to kill the neuroblastoma. This protocol also uses β-glucan which is a kind of sugar from yeast. β-glucan is taken by mouth and can help white blood cells kill cancer. The best way to get the body to make antibodies against the 3 antigens is to link each antigen to a protein called KLH (which stands for: keyhole limpet hemocyanin) and to mix them with a substance called QS-21. But it is hard to get enough QS-21 so we are using an identical substance called OPT-821, which we can get easily in large amounts for use in patients.

The promise of this vaccine is that it is a very simple (and probably not too expensive) treatment with minimal side effects:

Patients receive a total of 7 subcutaneous injections, at weeks 1, 2, 3, 8, 20, 32, and 52. Induction of antibody response against the target antigens will be assessed. A fixed dose of oral β-glucan (40 mg/kg/day) is started at week 6 or 7(to allow time for generation of antibodies), and continued as approximately 2 weeks on, 2 weeks off, up to 1 cycle after the last vaccination. Neutrophils will be tested for glucan effects on cytotoxicity. Antineuroblastoma activity will be monitored using standard radiographic and bone marrow studies, as well as RT-PCR for measurement of minimal residual disease in blood and bone marrow. The treatment schedule may require minor adjustment as clinically indicated or due to unforeseen circumstance (e.g., due to PDH closure for holidays or due to inclement weather).

The MSKCC site says:

https://www.mskcc.org/cancer-care/clinical-trials/05-075

Patients must have high-risk neuroblastoma that is in second remission.

However the document on clinical trials indicates it is:

High-risk NB (as defined above) and now in 1) first CR/VGPR at 6 months from initiation of immunotherapy using anti-GD2 mAbs, or 2) second or subsequent remission. Remission is defined as complete (CR) or very good partial (VGPR)remission, according to the International Neuroblastoma Response Criteria.

Reading through this I am trying to figure out if we (stage 3 MYCN amplified CR) would be eligible or not.

Regardless, some initial data is very promising, and it is something worth exploring:

The study was completed with 15 patients because there was no dose-limiting toxicity at 150 μg/m(2) of OPT-821 (the dosing used in adults). Thirteen of fifteen patients received the entire protocol treatment, including 12 who remain relapse-free at 24+ to 39+ (median 32+) months and 1 who relapsed (single node) at 21 months. Relapse-free survival was 80% ± 10% at 24 months. Vaccine and β-glucan were well tolerated. Twelve of fifteen patients had antibody responses against GD2 and/or GD3. Disappearance of MRD was documented in 6 of 10 patients assessable for response.

This immunotherapy program lacks major toxicity and is transportable to any outpatient clinic. Patient outcome is encouraging but the efficacy is uncertain because of the complexity and heterogeneity of prior therapies. A larger phase II trial is underway.

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What after the immunotherapy
How do you pick which clinical trials to join?
2

Hi Sam,

It looks like you are correct: our MSKCC website does appear to be out of date. This trial IS now open to patients with high risk neuroblastoma in 1st remission or greater (meaning relapsed patients who are again in remission, are still eligible like before, as are patients who are in remission but have never relapsed). I will let our clinical trials staff know that the website needs to be updated.

If you are potentially interested in this trial, the contact info is listed there on the website.

Thanks for letting me know!

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Wow that is awesome, absolutely going to make contact with MSKCC to get some more information.

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4

I came across this video by Dr Brian Kushner from 2015 about the vaccine

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Sam

Have you made contact with MSKCC to get some idea on costings for their vaccine trial? Obviously I’m talking about health-care related expenses only, accommodation+travel from the other side of the world is a whole additional expense!

Mark

Phase 2 DFMO preventative trials
6

I don’t know and its very hard to estimate.

I contacted intnlprg@mskcc.org via the website the office requested:

  • Photocopy of the patient’s passport
  • A recent medical summary from the patient’s physician detailing medical history, current condition, and treatment
  • All medical reports related to your diagnosis in English
    • Radiology reports from the past 3-6 months
    • Laboratory reports within 14 days
  • All treatment records (chemotherapy and radiation therapy)
  • All operative reports and discharge summaries
  • All original pathology reports in the original language and complete English translation (both the original and the English translation of the pathology report must include the following: patient name, date of birth, specimen number, date of the procedure, and hospital name/address where the procedure was completed)
    If applicable, a copy of the front and back of the insurance card (once received the insurance information will be submitted for verification)
  • A cover letter with specific questions or concerns you would like to have addressed (optional)

Originally I put this on hold cause I was waiting for ANR to get more information.

My understanding is that to receive any treatment in MSKCC you must have the entire cost of the treatment in escrow prior to getting the treatment. This will probably include cost of scans and other unforeseen (which is where it gets tricky). I think the pricing is all individualized based on the patient’s risk factors (even if you just go for a vaccine).

To cut through some of the red tape I am thinking of contacting a charity that works with MSKCC to see if they can help me properly navigate this.

7

Hi @sam
Have you got any visibility in terms of the price for that trial (since your last post)?.. May be some very rough idea?..
Thank you!

8

To be honest, the huge beurocracy and the international office in sloan scared me enough that I abandoned that avenue and instead am reaching out to a charity to assist in navigating this maze.

My understanding is that MSK international patients must have an escrow account with enough funds not only to pay for the treatment but also account for unknowns. I was told, second hand, that for something like the vaccine you would need 500k in an escrow account (which is deducted from during the treatment). As an international you get charged “premium” prices. For example a scan that would cost a US insured patient 100 dollars could easily be charged at double, you basically have no bargaining power.

I am seriously considering moving to the US for a few years (for the highest relapse risk year) cause my company is based in the US (so an E3 visa is easy for me) and being a resident we would be entitled to healthcare.

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500K… Wow! That’s huge! :frowning:

When I though about that option (moving to US) and for some reason I though that there is no way to get an insurance with such serious precondition. For example, in Switzerland all people by law must have a basic medical insurance (which covers almost all treatments for kids) and the insurance companies (by law again) are not able to refuse your application regardless of your current illnesses. There is even nothing in the application about your medical history.

Are you still considering a DFMO option? From the price perspective it looks better and from the outcome I hope its similar…

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I am actually still considering both the vaccine and DFMO, moving to the US is quite practical for me and there seems to be ways to get health cover for children if I am a resident of NY.

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We recently did the MSKCC vaccine trial as an international patient from the uk. After 4 of the 7 cycles my daughter relapsed severely so it didn’t work for us, but may work for others so I’m not discouraging it. A few things:

  • the Mskcc team are excellent and the facility is superb
  • treatment has no acute toxicity. It’s outpatient only and injection is little more than a Gcsf injection. Takes 5 mins. But they won’t let you use Ametop or cold spray or a cannula/insuflon and the give you very little time to prepare as the drug has a very short expiry date (30mins or so) so they get it up to the ward and then stick your child very quickly. So be warned If your kid is not good with needles. Was no problem for us. (Explains why they can’t ship it around the world btw)
  • there is no update on published data since phase 1. I tried hard. They’re not opening the kimono.
  • cost: the vast majority of the huge headline cost is in the scanning and not the drug or physician time itself. Different patients have had different levels of success of having Mskcc accept scans from abroad. I think this depends on the reputation and relationship with your home hospital. To give you a sense, BMA cost $25k and you need 8 of them over two years… So that is $200k if you have to do them at Mskcc.
  • there are healthcare negotiators, in the USA, who take a cut in reducing a medical bill for international patients. I’m not getting into the ethics of this but we did it and it make a big difference. In short… Mskcc will negotiate.
  • overall I was very impressed by the experience, the clinical quality, the aggressive approach and staff. It’s a great hospital… With an unusual business model and a different attitude to publishing data. The cost of course makes an already unfair situation even more inequitable, but I’ve never know anyone who has tried and failed to fundraise the amount required.
    Hope that helps.
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12

Thanks so much Parker for the info, I am so sorry about the relapse, I hate this disease I find it paralysing sometimes.

Regarding the length of the treatment, my understanding is that they only give the vaccine injections for 1 year (starting 6 months after immunotherapy started)

Do they expect scans even after you are done receiving the vaccine?

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We did the vaccine independently of immunotherapy (Moab) for complex reasons I won’t bore people with here. The entry requirement was total remission and to start within 20 days of clear scans.
Yes - follow up scans expected for year after the active treatment. Basically it’s 8 quarters of scanning - the full works. I think the followip regime is great discipline and far more scanning than we would have done in the uk. It caught the relapse.

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Sam, yes, for an additional year, but in your case you could probably do at home. They also want research blood every 3 months for a year. My daughter did the vaccine but we decided to continue with dfmo (2nd relapse, so no stone left unturned). That required scans at another hospital but we do send blood. I hope to follow up with them again at the end of this trial (next year). We started vaccine as soon possible from immunotherapy, I think one month.

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15

I wonder what the policy is for no bone marrow involvement, we had stage 3 amplified, but BM was never involved also for some reason the tumor was quite faint on MIBG scans.

I guess they just have to be very thorough.

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I think you’ll find they won’t compromise at all on scanning criteria.

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Parker, sorry to hear your daughter relapsed.

Just to clarify, you are saying that MSKCC charge US$25k for one bone marrow aspirate/biopsy (presumably that includes sedation/anaesthetic, procedure and pathology costs)? I am well aware US healthcare can be expensive but that’s something else!

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Correct and yes including sedation.

19

How did you handle the logistics? Did you move to NYC for the year, or just spend the first 6 weeks and then travel back-and-forth?

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We went back and forward. The first 3 cycles are in week 1,2,3 so we stayed for that block and went to Disney in between cycle 1 and 2. But after that we went back and forward, though we didn’t finish the course. Treatment itself is very light. One injection as an outpatient - takes about an hour.