Several times here in the forum, people have posted saying that patients who have had an allo transplant are not eligible for most clinical trials for myeloma patients.
Is that really true? What's the basis for that statement?
Also, if it's true, what's the basis for the exclusion?
I did some checking at clinicaltrials.gov and, from what I can tell, there doesn't seem to be as hard an exclusion of allo patients as has been claimed. Based on my basically random check of 7 trials for relapsed myeloma, I found
4 trials with no allo transplant exclusions whatsoever listed in their description
2 trials who exclude allo transplant patients who have evidence of graft versus host disease
1 trial completely excluding patients who have had allo transplants
That doesn't suggest as broad-based an exclusion as has been claimed.
Or am I missing something?
Here are the trials I checked. Again, I selected them basically randomly.
A Phase I Study Evaluating ABT-199 in Subjects With Relapsed or Refractory Multiple Myeloma
http://clinicaltrials.gov/ct2/show/NCT01794520
Partial exclusion: "Subjects with a history of autologous or allogenic stem cell transplantation must have adequate peripheral blood counts independent of any growth factor support, and have recovered from any transplant related toxicity(s) and be at least 100 days post-autologous transplant prior to first dose of study drug or at least 6 months post-allogenic transplant prior to first dose of study drug and not have active graft-versus-host disease (GVHD), i.e., requiring treatment."
Study of the Bruton's Tyrosine Kinase Inhibitor in Subjects With Relapsed or Relapsed and Refractory Multiple Myeloma (Phase 2 Study)
http://clinicaltrials.gov/ct2/show/NCT01478581
No allo exclusion that I can see.
Combination Plerixafor (AMD3100)and Bortezomib in Relapsed or Relapsed/Refractory Multiple Myeloma (Phase 1/2 Study)
http://clinicaltrials.gov/ct2/show/NCT00903968
No allo exclusion that I can see.
Study of ACY-1215 Alone and in Combination With Bortezomib and Dexamethasone in Multiple Myeloma (Phase 1/2 Study)
http://clinicaltrials.gov/ct2/show/NCT01323751
Hard allo exclusion policy: patients who have had an allo cannot participate in the trial.
A Phase I Study Of Panobinostat/Lenalidomide/Bortezomib/Dex for Relapsed And Relapsed/Refractory Multiple Myeloma (PanRVD) (Phase 1 Study)
http://clinicaltrials.gov/ct2/show/NCT01965353
Exclusion for "Participants who have had prior allogeneic stem cell transplantation with evidence of active graft-versus-host disease requiring immunosuppressive therapy"
Open-label Study of TH-302 and Dexamethasone With or Without Bortezomib in Subjects With Relapsed/Refractory Multiple Myeloma (Phase 1/2 Study)
http://clinicaltrials.gov/ct2/show/NCT01522872
No allo exclusion that I can see.
A Study of JNJ-54767414 (HuMax CD38) (Anti-CD38 Monoclonal Antibody) in Combination With Backbone Treatments for the Treatment of Patients With Multiple Myeloma (Phase 1 Study)
http://clinicaltrials.gov/ct2/show/NCT01998971
No allo exclusion that I can see.
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Re: Allo transplants and clinical trial eligibility
Jonah,
I am one of the people that have previously raised this concern.
As far as my statements, I'd like to alleviate any confusion that I might have caused. I didn't mean to suggest that there is a broad-based uniform exclusion. To the best of my knowledge, there is no absolute rule for admission/exclusion criteria for clinical trials. Each administrator sets its own criteria depending on the goals of the trial.
In my mind this is hardly a consolation if the one trial that can save your life excludes allo patients. I believe Arnie, a columnist here at the Beacon, went through a similar experience where he was being shut down for trials due to his previous allo and had to beg Bristol-Myers Squibb to give him elotuzumab under compassionate use (granted he had nonsecretory disease, which poses an additional problem). I'd say that's a bad place to be, particularly if the exclusion criteria comes to you as a surprise.
To the extent one can do some research upfront on potential trials that could be applicable and whether those exclude allos, I think people should do it. At least I would, for what is worth.
For future trials for which one can't do research, I'd say, if one considers an allo as salvage (as I do), the exclusion criteria plays a role in the decision of whether to do the allo after you exhaust all approved meds, or after you've covered trial meds as well.
Anyways, that's my personal line of thought. Best of luck to you.
I am one of the people that have previously raised this concern.
As far as my statements, I'd like to alleviate any confusion that I might have caused. I didn't mean to suggest that there is a broad-based uniform exclusion. To the best of my knowledge, there is no absolute rule for admission/exclusion criteria for clinical trials. Each administrator sets its own criteria depending on the goals of the trial.
In my mind this is hardly a consolation if the one trial that can save your life excludes allo patients. I believe Arnie, a columnist here at the Beacon, went through a similar experience where he was being shut down for trials due to his previous allo and had to beg Bristol-Myers Squibb to give him elotuzumab under compassionate use (granted he had nonsecretory disease, which poses an additional problem). I'd say that's a bad place to be, particularly if the exclusion criteria comes to you as a surprise.
To the extent one can do some research upfront on potential trials that could be applicable and whether those exclude allos, I think people should do it. At least I would, for what is worth.
For future trials for which one can't do research, I'd say, if one considers an allo as salvage (as I do), the exclusion criteria plays a role in the decision of whether to do the allo after you exhaust all approved meds, or after you've covered trial meds as well.
Anyways, that's my personal line of thought. Best of luck to you.
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ivanm - Name: Ivan Mitev
- Who do you know with myeloma?: self
- When were you/they diagnosed?: August, 2011
- Age at diagnosis: 37
Re: Allo transplants and clinical trial eligibility
Hi Jonah,
One thing I noticed is that all of the trials that you listed are Phase 1 or 2. Maybe it is the Phase 3 trials that tend to use previous allo transplant as an exclusion criteria?
The other thing I noticed is that only 1 of the trials that you listed contains an IMID and that trial excludes patients that have GVHD. IMIDs are known to work better for patients that previously did allo transplants as compared to those that did not. They are also known to cause GVHD to flare up in certain situations. That would explain some potential exclusion from trials that contain IMIDs.
"Lenalidomide (Len) is a highly effective drug against multiple myeloma (multiple myeloma). It acts through several mechanisms, such as a direct cytotoxic effect, anti-angiogenesis, microenvironment modifications, and immunomodulation. The latter property is particularly interesting in the setting of allogeneic stem cell transplantation (AlloSCT), since Len may interact favourably with the graft-versus-myeloma (GVM) effect. On the other side, the possibility of an over activation of the donor immune system raises some concerns about the safety of this treatment. In order to verify if Len is more effective when given after AlloSCT, we conducted among 7 Italian transplant centers a case-matched analysis comparing Len after autologous SCT (AutoSCT) vs. Len after AlloSCT. The hypothesis is that Len is more active when administered after AlloSCT. A secondary end-point of the study was the safety profile."
"The comparison between Auto and Allo pts has shown a benefit in terms of PFS and OS in the Allo group. This observation supports the hypothesis that Len may be synergic with the GVM effect. Interestingly, despite the same response rate between the 2 groups, clinical responses in Allo pts were more durable, reinforcing the hypothesis of the immunological control. On the other side, since Len has a potent immunomodulatory effect, this can raise concerns about its use after AlloSCT. The Dutch HOVON 76 trial has shown that the early administration of Len 10 mg after AlloSCT induces aGVHD in a substantial proportion of patients, causing unacceptable toxicity and the premature discontinuation of the study. However, in our retrospective study the median time between AlloSCT and Len administration was 21 months, and we did not observed any increase of GVHD. This suggests that the mechanisms of immune tolerance can mitigate the activation induced by Len, allowing a safe administration. Moreover, since in all cases dexamethasone was given with Len, its immunosuppressive effects may have harnessed the Len-induced immune activation, contributing to the treatment tolerability. In conclusion our case-matched study suggests that Len is more active when given after AlloSCT, still retaining a favorable toxicity profile. "
https://ash.confex.com/ash/2012/webprogram/Paper52081.html
Mark
One thing I noticed is that all of the trials that you listed are Phase 1 or 2. Maybe it is the Phase 3 trials that tend to use previous allo transplant as an exclusion criteria?
The other thing I noticed is that only 1 of the trials that you listed contains an IMID and that trial excludes patients that have GVHD. IMIDs are known to work better for patients that previously did allo transplants as compared to those that did not. They are also known to cause GVHD to flare up in certain situations. That would explain some potential exclusion from trials that contain IMIDs.
"Lenalidomide (Len) is a highly effective drug against multiple myeloma (multiple myeloma). It acts through several mechanisms, such as a direct cytotoxic effect, anti-angiogenesis, microenvironment modifications, and immunomodulation. The latter property is particularly interesting in the setting of allogeneic stem cell transplantation (AlloSCT), since Len may interact favourably with the graft-versus-myeloma (GVM) effect. On the other side, the possibility of an over activation of the donor immune system raises some concerns about the safety of this treatment. In order to verify if Len is more effective when given after AlloSCT, we conducted among 7 Italian transplant centers a case-matched analysis comparing Len after autologous SCT (AutoSCT) vs. Len after AlloSCT. The hypothesis is that Len is more active when administered after AlloSCT. A secondary end-point of the study was the safety profile."
"The comparison between Auto and Allo pts has shown a benefit in terms of PFS and OS in the Allo group. This observation supports the hypothesis that Len may be synergic with the GVM effect. Interestingly, despite the same response rate between the 2 groups, clinical responses in Allo pts were more durable, reinforcing the hypothesis of the immunological control. On the other side, since Len has a potent immunomodulatory effect, this can raise concerns about its use after AlloSCT. The Dutch HOVON 76 trial has shown that the early administration of Len 10 mg after AlloSCT induces aGVHD in a substantial proportion of patients, causing unacceptable toxicity and the premature discontinuation of the study. However, in our retrospective study the median time between AlloSCT and Len administration was 21 months, and we did not observed any increase of GVHD. This suggests that the mechanisms of immune tolerance can mitigate the activation induced by Len, allowing a safe administration. Moreover, since in all cases dexamethasone was given with Len, its immunosuppressive effects may have harnessed the Len-induced immune activation, contributing to the treatment tolerability. In conclusion our case-matched study suggests that Len is more active when given after AlloSCT, still retaining a favorable toxicity profile. "
https://ash.confex.com/ash/2012/webprogram/Paper52081.html
Mark
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Mark
Re: Allo transplants and clinical trial eligibility
Thanks, Ivan and Mark, for your feedback.
I appreciate the clarification, Ivan, regarding what you meant about the potential for an allo transplant creating a barrier to clinical trial exclusion. I had to admit that I understood your previous postings to be more definitive in terms of how broad-based the exclusion was, but I also admit that I may not have read what you wrote as carefully as I should have.
Mark - Interesting point about the potential conflict between Revlimid-containing regimens and allo transplantation. I hadn't thought about that.
You are also correct that, subconsciously, I ended up selecting mainly Phase 1 and Phase 2 trials. I can tell you, however, why I did that.
My thinking was that most people here who are reading about the possibility of an allo transplant are probably considering it as something to pursue at relapse -- perhaps even after their second relapse.
Given that assumption, I felt that, if an allo transplant does not provide long-term remission for these patients, and they want to pursue a clinical trial, they are probably going to be looking at clinical trials for drugs early in the development process.
These patients probably will have tried most of the approved drugs. Also, drugs early in the development process are usually tested in trials for relapsed patients who can have had any number of previous therapies.
That "previous lines of therapies" restriction is more important than you think. Phase 3 trials, I believe, are usually for either newly diagnosed patients or for patients who have had 1-3 previous therapies. So someone looking for a clinical trial after a post-relapse allo transplant probably wouldn't be eligible for most Phase 3 trials anyway.
I'll try to look sometime, however, to see about what sort of restrictions there are related to allo transplants in Phase 3 trials.
I appreciate the clarification, Ivan, regarding what you meant about the potential for an allo transplant creating a barrier to clinical trial exclusion. I had to admit that I understood your previous postings to be more definitive in terms of how broad-based the exclusion was, but I also admit that I may not have read what you wrote as carefully as I should have.
Mark - Interesting point about the potential conflict between Revlimid-containing regimens and allo transplantation. I hadn't thought about that.
You are also correct that, subconsciously, I ended up selecting mainly Phase 1 and Phase 2 trials. I can tell you, however, why I did that.
My thinking was that most people here who are reading about the possibility of an allo transplant are probably considering it as something to pursue at relapse -- perhaps even after their second relapse.
Given that assumption, I felt that, if an allo transplant does not provide long-term remission for these patients, and they want to pursue a clinical trial, they are probably going to be looking at clinical trials for drugs early in the development process.
These patients probably will have tried most of the approved drugs. Also, drugs early in the development process are usually tested in trials for relapsed patients who can have had any number of previous therapies.
That "previous lines of therapies" restriction is more important than you think. Phase 3 trials, I believe, are usually for either newly diagnosed patients or for patients who have had 1-3 previous therapies. So someone looking for a clinical trial after a post-relapse allo transplant probably wouldn't be eligible for most Phase 3 trials anyway.
I'll try to look sometime, however, to see about what sort of restrictions there are related to allo transplants in Phase 3 trials.
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Jonah
Re: Allo transplants and clinical trial eligibility
Hello from Seattle Jonah,
The conversation on this topic has been excellent and I agree with most or all of it.
Another reason that patients who have had allo transplants are excluded is that generally they are by definition considered to be "high risk" patients. After relapsing from an allo, patients are less likely to achieve a remission and more likely to progress on therapy than most patients with myeloma. That could skew the results of a study negatively.
The conversation on this topic has been excellent and I agree with most or all of it.
Another reason that patients who have had allo transplants are excluded is that generally they are by definition considered to be "high risk" patients. After relapsing from an allo, patients are less likely to achieve a remission and more likely to progress on therapy than most patients with myeloma. That could skew the results of a study negatively.
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Dr. Edward Libby - Name: Edward Libby, M.D.
Beacon Medical Advisor
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