4 ms·

This was not what I expected to read, and therefore much sadder to me. I had expected to see an article about the emotional strain of not knowing if you're in t

by timr 3y ago

This was not what I expected to read, and therefore much sadder to me. I had expected to see an article about the emotional strain of not knowing if you're in the control arm or the treatment arm for a late-stage trial. You know that you're in an experiment, and you might get a new drug -- or existing standard of care -- depending on a roll of the dice. This was very different. The author is describing a mad scramble to get enrolled in a phase 1 clinical trial, and discussing the scramble as a life-or-death critical choice. Even ignoring the question of whether or not you're in the control arm, these kinds of trials have no guarantee of much of anything. It's even possible the drug itself might hurt you, because that's exactly what they're looking for in phase 1. Per the clinical trial registration for PDL1V: > Part C will use the dose found in Parts A and B to find out how safe SGN-PDL1V is and if it works to treat solid tumor cancers. (emphasis mine) I don't know if the author knows this, but I can't imagine the stress of not being well-informed about the purpose of an experiment like this. And those doctors who are telling him things like "SGNTV had successfully shrunk a lot of tumors" is so maddening, if they didn't follow that with "...but we don't know what it will do in humans, because it's a phase 1 trial". It's not at all clear that they did, because of things like this: > If I was given SGNTV, I’d have three systemic lines of therapy and be ineligible for PDL1V. And the same in reverse. Sophie’s Choice! and later: > A downside of all these phase 1b studies is that there’s little published data, which makes comparisons difficult. Oncologists almost never give numbers: “We dosed 10 patients, and the disease control rate in phase 1a was 50%.” Instead, they’ll be vague, but they’ll also indicate why they think their top trials are their top trials. If true, this is so, so, so irresponsible. Tell people that you don't know the answer! The control could easily be better than the drug! Don't give them false hope! So agonizing.

andyst 3y ago
Having been through similar processes with family, scouring medical journals and trials for the answer as if its stack overflow, you're in a period of high stress I think I can understand that may have led to the authors perspective and expectations shaping the narrative here.
- timr 3y ago
  I'm absolutely not criticizing the author. I can understand how you'd latch on to any little signal of hope in this kind of a situation. Hell, I'd go so far as to say that the oncologists who are saying this stuff probably think they're doing the right thing, and are just trying to give desperate people something to hang on to. It's difficult. But it's still necessary to make it clear what these trials are.
justsocrateasin 3y ago
I believe that most of the time patients are enrolled in these trials, they've already exhausted all other options. It isn't quite "life-or-death" but rather "death-or-death-or-maybe-another-chance-at-life"
- timr 3y ago
  Yes, that's true. There's some question here (the author talks about debating whether to do another round of chemo to shrink the tumors, or to try to get into a trial), but ignoring that, I'm certain that people view it this way. It doesn't excuse the doctors for not being direct about the choices at play: you are trying to get into an experiment where there's a 50% chance you'll get the same treatment you'd get anyway (one hopes -- it's what is supposed to happen, but some trials have been less-than-ethical), or a 50% chance you'll get a drug that might well be worse than the control. Particularly for phase 1 trials, that last part needs to be emphasized. You're not doing it to survive. You're doing it because it's the ultimate altruism -- using your own life to find an answer that might help the next patient.
  - danielheath 3y ago
    > You're not doing it to survive. If the currently-available treatments mean I'm going to die, "try something that might kill me or cure me" is absolutely a thing I would consider "to save my life".
    - bruce511 3y ago
      Yeah, but unfortunately rhat makes you a really bad clinical subject in any trial. Unfortunately, by the time most people reach the "no hope" stage, the disease has processed to the point where no intervention would help. Conversely most interventions work best at the "early detection" phase. Which (ironically) is when you're best off with proven stuff, not new experimental stuff. This catch-22 is precisely why its so hard to get improvements in this field.
    - CogitoCogito 3y ago
      The clinical trial might very well shorten your life and/or make your quality of life worse. It might not only not save your life, but it might be the case that not joining the clinical trial saves your life (at least for a little while longer).
s1artibartfast 3y ago
None of this data will be published for a phase 1 study, but each participating doctor should have a copy of the investigators brochure, which contains all the preclinical data and clinical data up to this point. If you are taking a commercial medicine, the first place to check is the "prescribing information", which is publicly available and has all of the trial data, adverse events, efficacy, toxicology, interactions, ect. I highly recommend everyone read for any drug they take. They are usually clear and accessible, and where they are complex, that is a starting point for a informed conversation with your doctor. It is essentially reading the user manual for the drug you are taking.
- timr 3y ago
  Regardless of the validity of the "user manual" metaphor, it's a pretty thin manual. At the phase 1 trial, you basically have some data from cell lines, mice and other small mammals, and maybe a few early humans. You can't infer much of anything from that. To a first approximation, about half of drug candidates fail in each phase of development (i.e. 50% drop off in every phase, from 1 to 3). Naïvely, then, about 80% of compounds tested in phase 1 will fail to become drugs.
  - s1artibartfast 3y ago
    I'm aware. I'm saying where the data is, to the extent it is available. I also don't why you think the doctor was giving false hope, or being less than candid. I think it is pretty clear that the author knows phase 1 studies are not well characterized and or proven effective.
    - timr 3y ago
      Well, first: I didn't say anything about anyone being "less than candid". I don't believe that, or at least, don't have any reason to believe it from this post. I think people are talking their books, being overly optimistic, or just plain being arrogant. Second: regardless of what the author understands or does not, the quotes about oncologists pointing to their favorite trial, and the like, are not OK. The only valid answer is "we don't know", because literally every drug candidate in a phase 1 trial has some claim to plausibility outside of humans, yet most fail.
austhrow743 3y ago
>If true, this is so, so, so irresponsible. Tell people that you don't know the answer! The control could easily be better than the drug! Don't give them false hope! I don't think what you want is compatible with early stage trials. Them not knowing the answer is well established before any conversation takes place. It's the whole point. OP isn't looking at trials that are close to being approved. They're hunting around for anything that might do anything. The super experimental stuff.
jseliger 3y ago
Tell people that you don't know the answer I should probably clarify that point; oncologists are often dealing with small numbers and a lot of uncertainty. I'm also not sure how much they're supposed to say—I don't see the NDAs or other docs they sign with drug companies. That said, if they see tumors shrink in at least some patients, that's pretty good. I also have recurrent and metastatic squamous cell carcinoma originating in the tongue. A lot of these 1b and even 2 trials are being tested in multiple cancer types. Something can work pretty well in lung but not head and neck, or vice-versa. They will say they don't know the answer, but I prefer having some guidance. "Good" and "bad" are also relative, particularly for what I have, which is nearly always fatal. Is SGNTV good, cause it shrinks some people's tumors, or bad, cause of all those side effects? The answer is both. It's still useful IMO to run sanity checks on what you're told. For example, one onc said that I should try a trial very similar to this one: https://www.oncnursingnews.com/view/lenvatinib-plus-pembrolizumab-generates-responses-but-no-os-benefit-in-hnscc https://www.oncnursingnews.com/view/lenvatinib-plus-pembroli..., or one like it, that had already failed. When I checked to see what research had been published, I was baffled by the rec. I checked w/ my oncologist at UCSD, and she was also like: "I would probably not rank that trial highly."
- timr 3y ago
  > I'm also not sure how much they're supposed to say—I don't see the NDAs or other docs they sign with drug companies. That said, if they see tumors shrink in at least some patients, that's pretty good. I mean, that's all they have to go on, so it's all they can say. But it's a long way from any sort of proof, and they really should only be saying "we don't know, and you're taking part in an experiment to find out". What you're saying about oncologists sounds quite plausible to me...there are sadly a lot of doctors who don't understand science, and it's sort of a fundamental feature of medicine that the people involved want very badly to believe in whatever they're doing. This can/does lead to people making bold claims on thin evidence. That said, I do hope it works out for you, and I wish you the best. It's a selfless thing to take part in a clinical trial, and even more so when the stakes are so high. Edit: regarding the pembro+lenvatinib trial article you linked (LEAP), it's not the only one that showed similar results (PFS benefit, but no OS). The CLEAR trial was similar: https://www.youtube.com/watch?v=CsN0mskqUyU https://www.youtube.com/watch?v=CsN0mskqUyU Edit 2: also, I want to add that nothing I said above was meant to imply that they should hide data, just that they should make it clear what the odds are in a phase 1 trial situation.
m463 3y ago
> the stress of not being well-informed My experience with people working through a serious medical condition at the end of their life is - people are wildly trying to be informed, about themselves, the condition, the health care system, make good decisions, and... ...it is all just happening to you. You're in a wildly careening metal shopping cart, being banged up while bouncing down a long hill surrounded by speeding traffic, and no matter which way you lean, you're not quite steering. Seeing this, I wish there were ways people could prepare for this, short of having to lose people in their life, or personally enroll in medical school. I don't think anyone wants to plan for this stuff. I guess the ones who do have had a few close calls, or lived it vicariously, or really love the ones they'll outlive and are planning mostly for them.

by timr 3y ago

andyst 3y ago

Having been through similar processes with family, scouring medical journals and trials for the answer as if its stack overflow, you're in a period of high stress I think I can understand that may have led to the authors perspective and expectations shaping the narrative here.

timr 3y ago
I'm absolutely not criticizing the author. I can understand how you'd latch on to any little signal of hope in this kind of a situation. Hell, I'd go so far as to say that the oncologists who are saying this stuff probably think they're doing the right thing, and are just trying to give desperate people something to hang on to. It's difficult. But it's still necessary to make it clear what these trials are.

justsocrateasin 3y ago

I believe that most of the time patients are enrolled in these trials, they've already exhausted all other options. It isn't quite "life-or-death" but rather "death-or-death-or-maybe-another-chance-at-life"

timr 3y ago
Yes, that's true. There's some question here (the author talks about debating whether to do another round of chemo to shrink the tumors, or to try to get into a trial), but ignoring that, I'm certain that people view it this way. It doesn't excuse the doctors for not being direct about the choices at play: you are trying to get into an experiment where there's a 50% chance you'll get the same treatment you'd get anyway (one hopes -- it's what is supposed to happen, but some trials have been less-than-ethical), or a 50% chance you'll get a drug that might well be worse than the control. Particularly for phase 1 trials, that last part needs to be emphasized. You're not doing it to survive. You're doing it because it's the ultimate altruism -- using your own life to find an answer that might help the next patient.
- danielheath 3y ago
  > You're not doing it to survive. If the currently-available treatments mean I'm going to die, "try something that might kill me or cure me" is absolutely a thing I would consider "to save my life".
  - bruce511 3y ago
    Yeah, but unfortunately rhat makes you a really bad clinical subject in any trial. Unfortunately, by the time most people reach the "no hope" stage, the disease has processed to the point where no intervention would help. Conversely most interventions work best at the "early detection" phase. Which (ironically) is when you're best off with proven stuff, not new experimental stuff. This catch-22 is precisely why its so hard to get improvements in this field.
  - CogitoCogito 3y ago
    The clinical trial might very well shorten your life and/or make your quality of life worse. It might not only not save your life, but it might be the case that not joining the clinical trial saves your life (at least for a little while longer).

s1artibartfast 3y ago

None of this data will be published for a phase 1 study, but each participating doctor should have a copy of the investigators brochure, which contains all the preclinical data and clinical data up to this point. If you are taking a commercial medicine, the first place to check is the "prescribing information", which is publicly available and has all of the trial data, adverse events, efficacy, toxicology, interactions, ect. I highly recommend everyone read for any drug they take. They are usually clear and accessible, and where they are complex, that is a starting point for a informed conversation with your doctor. It is essentially reading the user manual for the drug you are taking.

timr 3y ago
Regardless of the validity of the "user manual" metaphor, it's a pretty thin manual. At the phase 1 trial, you basically have some data from cell lines, mice and other small mammals, and maybe a few early humans. You can't infer much of anything from that. To a first approximation, about half of drug candidates fail in each phase of development (i.e. 50% drop off in every phase, from 1 to 3). Naïvely, then, about 80% of compounds tested in phase 1 will fail to become drugs.
- s1artibartfast 3y ago
  I'm aware. I'm saying where the data is, to the extent it is available. I also don't why you think the doctor was giving false hope, or being less than candid. I think it is pretty clear that the author knows phase 1 studies are not well characterized and or proven effective.
  - timr 3y ago
    Well, first: I didn't say anything about anyone being "less than candid". I don't believe that, or at least, don't have any reason to believe it from this post. I think people are talking their books, being overly optimistic, or just plain being arrogant. Second: regardless of what the author understands or does not, the quotes about oncologists pointing to their favorite trial, and the like, are not OK. The only valid answer is "we don't know", because literally every drug candidate in a phase 1 trial has some claim to plausibility outside of humans, yet most fail.

austhrow743 3y ago

>If true, this is so, so, so irresponsible. Tell people that you don't know the answer! The control could easily be better than the drug! Don't give them false hope! I don't think what you want is compatible with early stage trials. Them not knowing the answer is well established before any conversation takes place. It's the whole point. OP isn't looking at trials that are close to being approved. They're hunting around for anything that might do anything. The super experimental stuff.

jseliger 3y ago

Tell people that you don't know the answer I should probably clarify that point; oncologists are often dealing with small numbers and a lot of uncertainty. I'm also not sure how much they're supposed to say—I don't see the NDAs or other docs they sign with drug companies. That said, if they see tumors shrink in at least some patients, that's pretty good. I also have recurrent and metastatic squamous cell carcinoma originating in the tongue. A lot of these 1b and even 2 trials are being tested in multiple cancer types. Something can work pretty well in lung but not head and neck, or vice-versa. They will say they don't know the answer, but I prefer having some guidance. "Good" and "bad" are also relative, particularly for what I have, which is nearly always fatal. Is SGNTV good, cause it shrinks some people's tumors, or bad, cause of all those side effects? The answer is both. It's still useful IMO to run sanity checks on what you're told. For example, one onc said that I should try a trial very similar to this one: https://www.oncnursingnews.com/view/lenvatinib-plus-pembrolizumab-generates-responses-but-no-os-benefit-in-hnscc https://www.oncnursingnews.com/view/lenvatinib-plus-pembroli..., or one like it, that had already failed. When I checked to see what research had been published, I was baffled by the rec. I checked w/ my oncologist at UCSD, and she was also like: "I would probably not rank that trial highly."

timr 3y ago
> I'm also not sure how much they're supposed to say—I don't see the NDAs or other docs they sign with drug companies. That said, if they see tumors shrink in at least some patients, that's pretty good. I mean, that's all they have to go on, so it's all they can say. But it's a long way from any sort of proof, and they really should only be saying "we don't know, and you're taking part in an experiment to find out". What you're saying about oncologists sounds quite plausible to me...there are sadly a lot of doctors who don't understand science, and it's sort of a fundamental feature of medicine that the people involved want very badly to believe in whatever they're doing. This can/does lead to people making bold claims on thin evidence. That said, I do hope it works out for you, and I wish you the best. It's a selfless thing to take part in a clinical trial, and even more so when the stakes are so high. Edit: regarding the pembro+lenvatinib trial article you linked (LEAP), it's not the only one that showed similar results (PFS benefit, but no OS). The CLEAR trial was similar: https://www.youtube.com/watch?v=CsN0mskqUyU https://www.youtube.com/watch?v=CsN0mskqUyU Edit 2: also, I want to add that nothing I said above was meant to imply that they should hide data, just that they should make it clear what the odds are in a phase 1 trial situation.

m463 3y ago

> the stress of not being well-informed My experience with people working through a serious medical condition at the end of their life is - people are wildly trying to be informed, about themselves, the condition, the health care system, make good decisions, and... ...it is all just happening to you. You're in a wildly careening metal shopping cart, being banged up while bouncing down a long hill surrounded by speeding traffic, and no matter which way you lean, you're not quite steering. Seeing this, I wish there were ways people could prepare for this, short of having to lose people in their life, or personally enroll in medical school. I don't think anyone wants to plan for this stuff. I guess the ones who do have had a few close calls, or lived it vicariously, or really love the ones they'll outlive and are planning mostly for them.