Biotech Strategy Blog

Commentary on Science, Innovation & New Products with a focus on Oncology & Hematology

New Orleans – it is rare to see a doctor publicly hang another out to dry, let alone an investigator in a clinical trial, but that’s what appeared to happen earlier today in the CLL press briefing at the 2013 Annual Meeting of the American Society of Hematology.

ASH 2013 CLL Media BriefingReaders of this blog will recall that the phase 1 first-in-man CLL trial for ABT-199/GDC-0199 (AbbVie/Genentech), a selective bcl-2 inhibitor was suspended earlier this year after 2 patient deaths due to Tumor Lysis Syndrome.  It was shocking to many to hear that a 56 year old man on the trial dropped dead in his bathroom having been dose escalated straight from 150mg to 1200 mg of this highly potent drug.

In response to my question today at the ASH media briefing about the protocol that allowed such an aggressive dose escalation, Professor John F. Seymour, Chair of the Department of Hematology at the Peter MacCullum Cancer Center in Melbourne, Australia told the assembled media:

“There was certainly protocol specified monitoring requirements at 8, 12 and 24 hours after each dose escalation. The circumstances where the death occurred there was not vigilance around the monitoring of those results, nor action around some of those changes. So I think it was a combination of circumstances of previously unrecognized risk at a dose escalation step and inattention to some of the protocol required monitoring criteria.”

I was surprised by the above response, given that my question must have been anticipated by AbbVie, and presumably Prof Seymour was media briefed beforehand given the AbbVie “media minder” was in the press room.

The answer also raises the question of whether the trial was adequately monitored by AbbVie. All clinical trials conducted under an IND have to be monitored by clinical research associates (CRAs) employed by the trials sponsor or a Contract Research Organization (CRO) acting on their behalf.  Their job it is to ensure a site follows the protocol and that everything is conducted according to good clinical practice (GCP) standards.  Did AbbVie trial monitors review the monitoring requirements with the site, and follow-up to ensure these were complied with?

In addition to the ABT-199 single agent first in man CLL dose escalation death, Professor Seymour told the media about another ABT-199 death:

“There is another currently accruing study of combination of ABT-199 + Rituxmab and there was one death on that trial also.”

This has not previously been reported.

You can listen to Professor Seymour’s complete answer to my question in this SoundCloud:

After the press briefing, the AbbVie Program Director for ABT-199 sought to justify the dose escalation clinical trial strategy arguing that although they had seen tumor lysis syndrome in initial doses, they were not aware it could be a problem on subsequent doses, and that having dose escalated from 150mg to 800mg without problem, this justified a dose escalation from 150mg to 1200mg.  I leave it to readers with more experience in hematology to judge the merits of this approach.

As Professor Seymour noted, all the IRB and ethics committees in the trial did approve the study protocol, which raises questions about how effective these are at judging the merits and risks of first-in-man trials with novel agents or whether they are just a rubber stamp.

ABT-199 is an exciting drug with a lot of promise, but the AbbVie handling of the tumor lysis syndrome deaths remains a PR failure in my book.

Not only that, but what I think was an overly aggressive clinical trial strategy, irrespective of who designed it and signed off on it, cost the company several months of time in a highly competitive market when they had to suspend recruitment.

I have no idea whether AbbVie have sought FDA Breakthrough Therapy designation, but it’s hard to believe the FDA would consider granting it to ABT-199 in CLL while there are patient deaths and concerns remain about tumor lysis syndrome.

Professor Seymour will be presenting updated results for ABT-199 in CLL on Tuesday at ASH (Abstract 872).

Update December 14, 2013

Prof Seymour presents ABT-199 CLL data at ASH 2013Premium Content Subscribers can read about::

1) the ABT-199 phase 1 CLL results presented at ASH 2013 by Professor Seymour and the modified clinical trial design put in place when the trial resumed in June 2013: ASH 2013 Novel Treatments for CLL.

2) a new target for ABT-199 for which there is a strong preclinical rational: ASH 2013 BH3 profiling identifies new targets for Bcl-2 inhibitors.

3) the future potential of ABT-199 in combination with obinutuzumab (Gazyva) that was discussed in an interview with Deepak Sampath from Genentech that took place at the AACR-NCI-EORTC Molecular Targets meeting in Boston: Gazyva and ABT-199 in CLL and NHL, an interview with Genentech’s Deepak Sampath.

Update Jan 3rd, 2014: Study CRA says protocol violations and non-compliance were known and ignored by CRO & AbbVie

I was shocked to receive today a comment that you can read below by the former Clinical Research Associate (CRA) for the ABT-199 CLL first-in-man study who says the sponsor (AbbVie) and Clinical Research Organization responsible for study management both ignored protocol violations at the site where a patient subsequently died due to tumor lysis syndrome.

If protocol non-compliance was known to the CRO & Sponsor it’s hard to understand why those concerns were not acted upon and whether the patient death that occurred might have been avoided if they had been addressed or the site discontinued.

Given the public interest in ensuring that anyone participating in a clinical trial can be assured the protocol will be followed, and that trials will be run in accordance with good clinical practice (GCP) & Federal Regulations, I contacted AbbVie and Genentech (who are co-developing ABT-199/GDC-0199) for a response to the allegations made, which if true are quite shocking.

Greg Miley, AbbVie Vice President of Commercial & Health Communications did not respond to a voicemail left. Genentech Product Public Relations responded to an email sent to a company spokesperson by saying they would look into this. I will update the post when a corporate response is received.

Update Jan 6th, 2014: Genentech & AbbVie Response

This evening I received an email from David Freundel, Director of Public Relations for AbbVie, who offered the following reply on behalf of Genentech and AbbVie:

“Patient safety is a priority for both companies, and we take the conduct and management of clinical trials extremely seriously. We are reviewing the details raised in the recent post.”

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14 Responses to “ASH 2013 ABT-199 CLL TLS Death blamed on Failure to Follow Protocol”

  1. Andrew G

    Great reporting Pieter. I’m no MD and I work in a realm far away from hemo/onc, but a 10-fold dose escalation seems pretty outrageous

    • maverickny

      You know, in 20 years in this industry I’ve never seen such a large dose increment. It just seems an odd and overly aggressive approach given that TLS was seen even in low doses.

  2. Peter Courtney

    Thanks for this Pieter. One question, are you saying the death itself was previously unreported, or the trial context (i.e. combo with rituximab) was unreported? It seems that both TLS deaths were reported (superbly by this blog!), totalling two, unless I’m misreading things.

    • 3NT

      Peter, thanks for your comment. My understanding was that the original two TLS deaths reported on the blog were in the monotherapy ABT-199 dose escalation trial, i.e. with the drug on its own. So Professor Seymour saying there is also an additional TLS death on the combination trial of ABT-199 with rituximab was not something I was aware of which is why I said this was unreported. Hope that clarifies my limited understanding.

  3. Aurelien Dupuy

    Hi All, do you know by chance whether or not it was one of those
    adaptive trial design? I am not a specialist of trial design myself but I
    know this would not have happened with a traditional 3+3. Cheers

    • maverickny

      I’m pretty sure it was not an adaptive trial design. Agree a 3+3 approach might have avoided this issue, certainly a 150mg -> 1200mg dose jump would have been less likely to happen that way.

  4. Oncology CRA, 14 years PhD

    I was the primary CRA (study monitor) on this trial. I terminated my contract because of understaffing by the CRO and noncompliance by the sites and a lack of corrective action by the sponsor for compliance issues. I also helped to train the sites on the dose-escalation scheme used in the protocol, as well as the risk of TLS. The dose-escalation you asked about is not allowed by the protocol, so Dr. Seymour responded to you correctly. I am sure I know which site and which PI. These sites were not compliant and we reported this in our reports and recommended that the sites be discontinued, but ABBVIE wanted these investigators on the study because they are thought-leaders, and were dismissive of our concerns. Of more importance in day to day operations, Paragon Biomedical was monitoring the trial, and they were in the process of negotiating their sale to Clinipace – so we were understaffed the entire study, and despite our urgent requests for additional help – we never got the CRAs budgeted for the study to adequately monitor it, as I suspect there was a hiring freeze in place they were sworn not to reveal to us pending the sale. This is probably why my lead CRA quit the week after I did – they just dumped all of the work on her, and it was not doable, and not what we were told when we took the contract. The risk of TLS at subsequent does was well-known and were explained during the initiation visits for each site. ‘Previously unrecognized risk’ is simply not true. Any audit of these sites and this study will reveal the truth – and if anyone needs the paper trail on what the sponsor knew and when they knew it, I will be happy to provide it. It sounds like these patients died needlessly; we would never dose-escalate with such an aggressive scheme, and during the dose-escalation of each subject someone at the sponsor and CRO would be in direct continuous contact with the site coordinator, study nurses, PI and other physicians to ensure safety was covered – but there were sites on board that would NOT communicate with us OR follow the protocol – and this was well-known and documented BEFOREHAND. As you comment, also a disastrous waste of money for investors and the company to hold enrollment while safety is reassessed – actually the safety and risk ratio did not change – they are well known and in the IB – but if you don’t follow the protocol, yes, people will die. Now, can we have the FDA and CDER’s OSI investigate?, or maybe they already are. Again, I’d be glad to assist.

    • Andrew G

      Wow. If you are interested in following up on this, I would definitely recommend you get in touch with OSI

    • JoDee Marshall Poplin

      I am not a DR. and do not know all that I should on this.But I am sure the person you are person you are speaking of is my dear friend.
      I question why anyone would ever think to up a dose by that large amount in one afternoon and not keep him in the hospital to watch him.
      I also would love to know why the family has never been told what really happened.

    • Melissa Tetreault

      My father was one of these unnecessary deaths. I would like to get copies of your paper trail and speak with you further please.

  5. David Sampson

    Great reporting. One note (from a PR guy). I’m not sure this is a PR failure. That would imply that a PR victory would have been to cover this up, right?

    • 3NT

      Good point David. I think on reflection what this is a failure in the integrity of the clinical trials process, and the trust patients put in it. The poor PR management is symptomatic of a corporate failure to run an ethical clinical trial that did not expose patients to unnecessary risk.

  6. Janet O'Brien

    As someone who has fought hard against both CLL and Richter’s Syndrome, I am appalled to read of these deaths. We have a horrible cancer that is incurable and reach out in good faith to the doctors and trials that can help us battle this disease. We literally put our lives in their hands in hopes that we will live to see our children grow, live to see grandchildren; we just want to live! We all know there are risks with trials, heck there are risks with taking an aspirin. But to know that those handling the trial, that those who we allowed to take care of us made such horrible errors leaves me shaking my head in shame. I had spoken with one of the patients who died as a result of this trial on a FB group for CLL. To see such a young life be taken due to dosing mistakes leaves me so very angry.

  7. John Konstantinou

    It is very sad and unfortunate that people die during clinical trials, but that is why they call them trials. How many people have died from CLL while waiting for this study to be completed? Delays do not come free of charge, they have costs as well

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