Biotech Strategy Blog

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

Posts tagged ‘ASH 2013 CLL’

New Orleans – the hematology diehards were up early yesterday for the 7.30 am oral session on some of the most interesting data at the annual meeting of the American Society of Hematology (ASH) on potential new treatments for Chronic Lymphocytic Leukemia (CLL).

Just to make sure everyone’s Fitbits were well exercised, the organizers put the session in the farthest end of the Convention center! Like many of the CLL sessions, it was a full house with multiple financial analysts sitting in the row behind me taking copious notes and pictures.  Unlike at ASCO, there is no virtual meeting, so you can’t replay any of the oral scientific sessions at a later date. If you didn’t see it, you missed it! There’s no substitute for boots on the ground.

What this post is about is my subjective opinion and top-line impressions of the information presented and some of the key strategic issues and challenges that came across listening to a full presentation of the latest data. I’m not going to rehash the press releases and the abstract data, most readers have already assimilated that.

It is what it says — notes from the road — the kind of things I’d write in a trip report if I were in a company.

The four presentations covered in this post are:

Abstract 871: Dinaciclib (SCH 727965) Is a Novel Cyclin-Dependent Kinase (CDK) Inhibitor That Exhibits Activity In Patients With Relapsed Or Refractory Chronic Lymphocytic Leukemia (CLL).

Abstract 872: Bcl-2 Inhibitor ABT-199 (GDC-0199) Monotherapy Shows Anti-Tumor Activity Including Complete Remissions In High-Risk Relapsed/Refractory (R/R) Chronic Lymphocytic Leukemia (CLL) and Small Lymphocytic Lymphoma (SLL).

Abstract 873: Randomized, Phase II Dose Optimization Study Of Chimeric Antigen Receptor Modified T Cells Directed Against CD19 (CTL019) In Patients With Relapsed, Refractory CLL.

Abstract 874: Phase I Trial Of Autologous CD19-Targeted CAR-Modified T Cells As Consolidation After Purine Analog-Based First-Line Therapy In Patients With Previously Untreated CLL.

Subscribers to Premium Content can read more below:

This content is restricted to subscribers

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.

Readers 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.

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

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.”

14 Comments

New Orleans – Saturday at the annual meeting of the American Society of Hematology (ASH) is mainly focused on education and science, although there are also several hundred posters available for those in need of a data injection.

What I like about the ASH education and scientific program is the high quality of the presentations from thought leaders who not only share where things are at, but just as importantly, where they may be going.

Yesterday, I attended a scientific session on Targeting Apoptosis in Lymphoid MalignanciesT. Organized by the Scientific Committee on Lymphoid Neoplasia, it featured three world-class speakers:

  • Douglas Green, PhD (St Jude Children’s Research Hospital)
  • Andreas Strasser, PhD (Walter and Eliza Hall Institute of Medical Research)
  • Anthony Letai, MD, PhD (Dana Farber Cancer Institute).

Regular readers of this blog will know that I have been following the development of ABT-199/GDC-0199 a novel Bcl-2 inhibitor in development by Abbvie & Genentech for a while now.

It’s a drug with a lot of promise, notwithstanding the tumor lysis syndrome (TLS) deaths seen in the phase 1 CLL dose escalation trial.

In the ASH 2013 scientific session, Dr Letai shared his insights on potential new drug development targets for a small molecule inhibitor of Bcl-2 such as ABT-199 that have come about as a result of BH3 profiling.

To learn more insights on this intriguing topic, subscribers can log-in or you can purchase access to BSB Premium Content. 

This content is restricted to subscribers

ASH for me always starts on a Saturday, as Friday is taken up with travel and a Super Friday corporate symposium, if any manage to catch our interest.

The start this year was somewhat disrupted by an ice storm that hit many southern states, causing considerable chaos for many ASH attendees – flights, hotels, bags, meetings, interviews, Ad Boards, investigator meetings, poster sessions and presentations etc.

I did enjoy the B cell malignancies CME session yesterday afternoon. Although it was sponsored by Gilead, it was well balanced and included discussion on FCR, ibrutinib, idelalisib, IPI-145, TGR-1202, ABT-199 and several earlier investigational compounds.

The highlight for me was Dr Susan O’Brien’s thoughtful and philosophical talk on where are we going with CLL?

It’s an important question for physicians to start asking themselves with Gazyva approved in CLL, Imbruvica (ibrutinib) is pending in CLL and idelalisib expected to gain approval in 2014.

To learn more insights on this intriguing topic, subscribers can log-in or you can purchase access to BSB Premium Content. 

This content is restricted to subscribers

The FDA approval earlier this week of ibrutinib (Imbruvica) for the treatment of mantle cell lymphoma (MCL), and the recent approval of GA101 / obinutuzumab (Gazyva), for previously untreated chronic lymphocytic leukemia (CLL) is good news for patients.

The forthcoming annual meeting of the American Society of Hematology (ASH) in New Orleans (Dec 7 – 10, 2013) is set to be an exciting event with the launch of new products to treat blood cancers.

Both ibrutinib in MCL and obinutuzumab were granted “breakthrough therapy” designation (BTD) from the FDA. Over the past several months I have been researching what a BTD may mean for cancer drug development.

The catchy “breakthrough” title has given companies and the FDA a noticeable bonanza of good PR, but there’s been a paucity of critical analysis by the media. I have yet to see a convincing argument that that there was a compelling need for a new approval pathway for cancer drugs, or that innovative and breakthrough cancer drugs such as imatinib (Glivec/Gleevec) and crizotinib (Xalkori) could have got to market any faster.

One of the key FDA decision makers is John K. Jenkins, MD, Director, Office of New Drugs in the Center for Drug Evaluation and Research (CDER); he’s Richard Pazdur’s boss. I had the privilege to conduct a phone interview with him over the summer.

In my first post from this interview, subscribers to Premium Content will obtain Dr Jenkins’ perspective on what constitutes a breakthrough? If you are an investor you want to try and predict what may be a “breakthrough” before it becomes one…

To learn more insights on this intriguing topic, subscribers can log-in or you can purchase access to BSB Premium Content. 

This content is restricted to subscribers

error: Content is protected !!