Submitted by Sorin61 t3_z563cl in technology
H2AK119ub t1_ixuum3x wrote
An interesting study and a long running one (this study started in 2007 and finished recruiting in 2017). "Educating" dendritic cells with tumor lysate to give them "memory" to go and attack tumor cells. I'm not a fan of the controls (historical, external) or the study design (cross over) that were used in the trial but you can make a strong case that a placebo arm is unethical in GBM or any recurrent high grade tumor. Data are promising; this could be the first treatment to be added to frontline care in high grade gliomas after nearly two decades of failed trials.
https://jamanetwork.com/journals/jamaoncology/fullarticle/2798847
The-Fox-Says t1_ixuydyk wrote
I work in the clinical trial space and this is exactly why we developed synthetic control arms. Patients can get the drugs/care they need and we can still get FDA approved trials that are double blind to have a similar outcome from a placebo arm trial.
It also really helps with rare forms of cancer where the cohorts are tiny.
itwasquiteawhileago t1_ixvdc9l wrote
Some of the oncology trials I've been on compare IP to SOC. In many cases SOC is what they call "watchful waiting" (i.e., doing nothing). I'm no oncology expert, but I do work in the clinical trial space and have worked on dozens of various oncology studies over the years and see this regularly. Often times they can cross over from SOC to study drug if their condition worsens within a certain timeframe, but how they make those decisions when developing the protocol is not something to which I am involved.
I know sometimes the best results only really mean maybe a few more months before the inevitable. Those trials are rough because people just want to live the rest of their lives as comfortable as possible, so being in a clinical trial that, best case, may extend their life a few months, is not always appealing. But without these trials, we'll never get anywhere in the long run.
H2AK119ub t1_ixvvblk wrote
Your latter point is probably why this trial took such a long time to accrue patients. Also, the difference between the treatment and external control in primary disease is 3 months for OS. IME - watch and wait is used for low grade disease.
impy695 t1_ixw797b wrote
Would you be willing to explain what a synthetic control arm is and why are they better? I've never heard the term before.
Dzugavili t1_ixwakfp wrote
Basically, you make a fake control group using data from previous patients: eg. 90 days into a clinical trial, you'd expect X% of patients in the control group to have died, and if you know that for certain, you don't need to have a control group actually sit there and die for you to confirm it.
impy695 t1_ixwbat1 wrote
Interesting, how would it work with thr placebo effect? Or is it something you use in separate trials for the same drug that way only some trials have a placebo group?
Dzugavili t1_ixwby4y wrote
I suspect in most cases, you'd be able to recycle control data from a previous study, and hope their placebo effect should be similar enough; or that your treatment effect is substantially stronger than optimism.
But given the kind of conditions we'd be likely to use this methodology for, I don't know if the placebo effect has a strong effect on outcomes.
puffferfish t1_ixy59sb wrote
A “placebo effect” isn’t really applicable in this case. It would be optimal to have a control for patients, something like giving them a pill with every ingredient aside from the drug, but this is likely not going to influence something like brain cancer. Brain cancer will not be influenced psychologically, and there is enough data to know on average how long patients with this cancer will survive. In a phase 3 trial it is important to get enough patients to participate for good statistics, and to do it as ethically as possible. To do this, you can just leave out an active “placebo” arm of the trial.
beesgrilledchz t1_ixwxhx9 wrote
Thank you. Thank you for your work. I hope we can one day help everyone with these tumors.
PNET gives me nightmares.
I have had far too many conversations with families saying “we possibly can’t save your child but if you are willing to try, we might save another child in the future. Leukemia was once a death sentence. It’s treatable now, because there were families like you, willing to try”
I’m going to go cry for every one of those kids and their brave families, who were willing to try.
I see their faces in my dreams.
Edit: that was too nihilistic. I have seen kids signed up for highly experimental trials who were doing really well
DubC_Bassist t1_iy060bk wrote
“Synthetic Control Arms”?!! I’m not negotiating with a Cyborg.
ForProfitSurgeon t1_ixvdoeg wrote
We need to make sure we do enough human testing before it is ready for the rich.
greatnessmeetsclass t1_ixuvzez wrote
In any study for any condition severe/life-impacting enough to require medical intervention, pure sham-arm with no crossover is unethical, cmv. With GBM that's even more true of course.
Whites11783 t1_ixuw07s wrote
Yeah, I was going to say, tough to not offer crossover to that patient population
klipseracer t1_ixuy7av wrote
I presume that means to offer them the medication at some point instead of a placebo?
H2AK119ub t1_ixv0sac wrote
It's effectively a single arm, uncontrolled trial; all patients involved in the "placebo" eventually cross over to the treatment arm. The investigators of the trial state that extracting DC's from GBM patients with poor prognosis is unethical without providing treatment.
Z-Chomosome t1_ixvmzpz wrote
Can’t you just look at historical data? The way statistics are used in medicine seems deeply Byzantine.
H2AK119ub t1_ixvn8f6 wrote
You need exquisite controls when looking at historical data. Modern medicine has advanced incredibly in the past 20 years with technology and that can significantly blur the data.
Kraz_I t1_ixwj8i4 wrote
Can useful statistical data be gleaned from many hundreds or thousands of case studies, considering how common case studies are recorded for cancer patients?
Rodot t1_ixx2lzk wrote
Yes, to highest order the fractional error (percentage of the outcomes the error represents) goes as the inverse square root of the number of samples. Barring other factors such as experimental design and representation of the samples, you're usually hitting around 1% error at 100 samples.
One doesn't actually need a ton of samples to get good statistical significance depending on the design and results of the study. Of course, there are factors that can increase or decrease these rates depending on if you are getting a little Bayesian or not
BaLahKie t1_ixwrbry wrote
Maybe this is a dumb question but why would you need a placebo for something like this? A person can’t really have a placebo effect where they think they’re getting better here right? It’s either improving or it’s not, like it’s tangible evidence you can track.
Or am I misunderstanding the point of placebos?
H2AK119ub t1_ixwrw26 wrote
Your control arm in a clinical trial can be placebo, standard of care (SOC), watch and wait, or a combination. The FDA has approved first in class medicines in high unmet need populations using ph1, single arm, non-randomized/blinded trials; they have stated recently they will probably do this no longer which is causing a big stir in pharma/biotech space. The DCVAX trial was plagued by many issues. Pseudo-progression of patients being a major one. They had to change the efficacy readout from PFS (time to disease progression) to OS (death) because they could not accurately readout from MRI's if people were getting better due to pseudo-progression. This is probably why the trial was so long.
BaLahKie t1_ixwsfxe wrote
As someone who came here from the Reddit news section, I appreciate your reply and you used a lot of complex jargon so I assume you are correct
H2AK119ub t1_ixwsmu6 wrote
LOL. The FDA will approve the drug if they believe it provides a meaningful clinical benefit to patients. That's all that matters.
twnbay76 t1_ixx14c5 wrote
Your link is broken
d0ctorzaius t1_ixxu25k wrote
Just as an aside, I work on H2BK120Ub so I appreciate your username.
bilyl t1_ixvskew wrote
This will for sure be approved shortly.
H2AK119ub t1_ixvuxi7 wrote
The effect on OS for primary disease from point of randomization is 3 months (compared to the external controls). The FDA will need to decide if that is clinically meaningful.
bilyl t1_ixw1apo wrote
Considering that there are plenty of oncology drugs that give one month of OS because of the dismal outcomes of specific cancers, this is a sure thing. Getting this data in a phase III trial just seals it.
H2AK119ub t1_ixw1tnd wrote
Can you name an example of this "one month life extension" drug in oncology?
bilyl t1_ixwgjia wrote
I’ll have to do a bit of research, but off the top of my head there are a couple of drugs that are in that range: Vemurafenib (metastatic lung cancer, ~3-4 months OS improvement), Crizotinib (~4 months), trodelvy (3.2 months for metastatic triple negative BC), trastuzumab (gastric cancer, <3 months), cetixumab (CRC, 1.5 months).
H2AK119ub t1_ixwrb6q wrote
Not sure why you've focused on (mostly) old drugs and kinase inhibitors (known to be very dirty). Vemurafenib (BRAFi) is indicated and used in melanoma not NSCLC (another first for FBDD), Crizotinib (ALKi) is focused on ALK fusions, Trodelvy is a first in class ADC, Trastuzumab makes billions annually and is SOC in HER2+ breast cancer, and cetuximab is an old EGFR mAb that has been mostly supplanted by anti-VEGF mAb's in CRC (with FOLFOX chemo).
bilyl t1_ixxoyi6 wrote
I didn’t specify anything about whether newer drugs fall into this category, but it was very routine that older targeted inhibitors (especially kinase inhibitors like you said) were approved in the past 15 years (not that long ago!! I was in graduate school at that time) for very marginal benefits. So yeah, there are way better drugs now but drugs with marginal benefit were being approved “back then” because there was nothing better and because survival was really dismal.
[deleted] t1_ixwjh5s wrote
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H2AK119ub t1_ixwptan wrote
This is not how a clinical trial works at all. Nor is it how SOC treatment works for primary disease. Doctors (ie, oncologists) don't just try "random" treatment options.
twnbay76 t1_ixx29ez wrote
The question was about how the average was calculated, i.e. simple mean, weighted average, etc...
And they are correct in the sense that patients that are unresponsive to medications are placed on other medications and modes of care. But yeah, certainly not randomly!
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