Biotech Strategy Blog

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

Posts from the ‘CLL’ category

Over the last five years the face of the chronic lymphocytic leukemia (CLL) landscape has changed quite dramatically with the advent of new approvals in several categories. These include anti-CD20 antibodies, BTK inhibitors, PI3K inhibitors and apoptotic Bcl–2 inhibitors.

In yesterday’s wide ranging interview we explored in-depth how these therapies are impacting the broader landscape, as well as emerging trends in how these regimens might be used.

In Part 2 of the ongoing series, we spoke with another CLL expert and explored promising new and earlier agents in development for a different perspective on how outcomes might be improved further.

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Targeted therapy and Chemo-Immunotherapy in CLL

At last December’s 2016 annual meeting of the American Society of Hematology, one of the areas that attracted attention was the latest clinical data on the treatment of chronic lymphocytic leukemia (CLL).

ASH 2016 in San Diego

In recent years, we’ve seen tremendous advances in the field with several new agents approved such as obintuzumab, ibrutinib, idelalisib, and venetoclax. There are also new treatment options available for CLL patients with high risk disease such as 17p deletions (Del17p).

Other new targeted therapies such as acalabrutinib are now in clinical development, plus we have CAR T cell therapies and combination strategies also being evaluated in the clinic.

So what was the hot news from #ASH16 in CLL?

  • Does chemotherapy still have a role or is it a targeted therapy world?
  • Are we further forward towards a cure?
  • Have we worked out how to identify those at risk of relapse?
  • Will CAR T cell therapy be a game changer in CLL?
  • Is financial toxicity going to be an issue with combination strategies?

BSB interviewed two experts in CLL while in San Diego who kindly shared their thoughts on which CLL data impressed them at the ASH annual meeting and discussed some of the big strategic issues facing the field right now. These interviews are being posted in a two-part series.

Part 1 today answers some of the questions highlighted above and explores the changing face of the broader CLL landscape.

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Dr David Porter, U Penn

Dr David Porter, U Penn

Honolulu: The BMT Tandem meeting kicked off yesterday with an excellent plenary session on “CAR T Cell Therapy: CD19 and Beyond.” The three presenters were:

  • David Porter (University of Pennsylvania) CAR T cells for Leukemia
  • Martin Pule (UCL) Building a CAR
  • Michael Jensen (Seattle Children’s) CD19-Specific CAR T Cells as a Post-Allo HSCT Relapse Salvage Therapy

Dr Porter (pictured) is Director of the Blood and Marrow Transplant Program at the University of Pennsylvania. I spoke with him after his talk. This post gives a quick overview of some of the key points I took away.

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ASH Exhibit HallIn recent years, there’s been a lot of progress in the treatment of chronic lymphocytic leukemia (CLL). New targeted therapies such as ibrutinib (Imbruvica) and idelalisib (Zydelig) have been approved and have helped extend the lives of patients with this disease further. However, there still remains a need for new treatment options.

Several new drugs are on the horizon for CLL.  At ASH there were a number of presentations for venetoclax, formerly known as ABT-199/GDC-0199, it’s a BCL-2 inhibitor, which is being co-developed by AbbVie and Genentech.  We’ve written extensively about it on the blog.  One of the challenges with venetoclax is the potential for Tumor Lysis Syndrome (TLS) – we heard at ASH that starting a patient on the drug needs to be carefully managed and monitored, with high risk patients hospitalized.

Other new drugs on the longer term horizon for CLL include acalabrutinib (Acerta) and BGB-3111 (BeiGene), both next generation BTK inhibitors and potential competitive threats to ibrutinib. The CLL market is becoming interesting again!

At ASH 2015, I spoke with Ian W. Flinn, MD, PhD. Director, Blood Cancer Research Program at the Sarah Cannon Research Institute in Nashville, TN. At ASH, Dr Flinn presented data for a CLL trial of venetoclax combined with obinutuzumab, a CD20 targeted monoclonal antibody; data was obtained in both the upfront and relapsed/refractory setting.

In a wide ranging conversation, we talked about some of the data of note in Orlando, what the future direction is in CLL, and what to look forward to at ASH 2016.

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ASH15 LBA Session

ASH 2015 LBA Session

The annual meeting of the American Society of Hematology (ASH) has a few quirks compared to other meetings. One of these is that all the “Late Breakers” are presented together on the last morning of the meeting.

It’s a rather unfortunate time given many have already headed back to their busy clinics or left for SABCS in San Antonio and ‘late breakers’ by definition, often offer new data that’s really noteworthy.

The result can also be a bit of a hodgepodge session that you have sit to listen through to get to those presentations you really want to hear.

At ASH this year there were two late breakers on new treatment options for CLL patients with a 17p deletion (Del17p). This is a pretty challenging group to treat.  Although ibrutinib is indicated for this patient group, many sadly relapse. There’s an unmet medical need for new treatment options. At ASH we heard data for idelalisib (PI3K-delta) and venetoclax (Bcl2).

After the session, I briefly spoke with Dr Kanti Rai (New York) for his reaction to the data. Dr Rai (pictured below) received the 2014 Wallace H. Coulter Award for Lifetime Achievement in Hematology.

Dr Kanti Rai receives 2014 ASH Lifetime Achievement Award

Dr Kanti Rai receives 2014 ASH Lifetime Achievement Award

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Whew, after posting the interview with Dr Tom Gajewski this morning from the American Association of Immunologists (AAI), we headed across town to the American Society for Gene and Cell Therapy (ASGCT) morning session and then dashed back to complete the first of the American Society of Clinical Oncology (ASCO) Previews for 2015!

What a busy week it’s been, never mind the hurly burly of today.

The ASCO 2015 abstracts went live at 5pm ET, with the exception of the late breaking abstracts, which are usually embargoed to the day of the actual presentation.

ASCO 2015 Abstracts

There are a number of topics well worth highlighting this year, so today kicks off the first of our annual Preview series on BSB. There will be much more to come – we wrote nearly 30 articles before, during and after the conference last year – this year will probably be similar with so much data to review and discuss.

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One of the things I most enjoy in cancer research is hearing wonderful patient stories from oncologists who are at the coal face of clinical trials. They get to deal with death and dying every day and like those in Pharma R&D, also live for the successes, the drugs that make it through pipeline despite great odds against them and make a meaningful impact on the daily lives of ordinary people.

We’ve all heard topline data presented at medical conferences around the world, but what the summary data can’t tell you is how a drug can impact people in ways that are clinically meaningful yet are more obtuse to capture in the aggregate. This is why case studies at CME sessions are increasingly popular, because they add value and context to common issues in a way that a Kaplan-Meier curve can never do.

Zydelig_logoWith the flurry of recent US and EU approvals for obinutuzumab (Gazyva), ibrutinib (Imbruvica) and the newest kid on the block, idelalisib (Zydelig), in CLL and indolent lymphomas, I wanted to take a look at these drugs from a different perspective.

A reader wrote in asking which of these new agents would emerge the winner and why?

Today’s post therefore offers some thoughts on the emerging CLL landscape now that we are shifting from new product development to the marketplace.

Drugs mentioned: Gazyva, Imbruvica, Zydelig, ABT–199/GDC–0199, Arzerra, IPI–145, CTL–019
Companies: Roche/Genentech, J&J/Pharmacyclics, Gilead, GSK, Infinity, Novartis

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Chronic Lymphocytic Leukemia (CLL) was one of the hot topics at this year’s annual meeting of the American Society of Hematology (ASH), and a new CLL drug that caught my attention was the second-generation Bruton’s Tyrosine Kinase (BTK) inhibitor ONO-4059 from Ono Pharmaceuticals.

Professor Gilles Salles (Lyon, France) presented promising efficacy data from a phase 1 study of ONO-4059 in relapsed/refractory CLL and high risk CLL (#676).

Unfortunately after his presentation, Prof Salles declined my request for a quick interview citing a prior commitment with a large pharma company and subsequently failed to turn up for an agreed interview the next day. Talking about ONO-4059, at least with the media, did not appear to be a priority!

However, as a potential competitor to other BTK inhibitors in development such as ibrutinib (Pharmacyclics/JNJ) and CC-292 (Celgene/Avila) it’s worthy of a mention in the conference coverage and a quick post about the data presented.

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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.

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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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