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Commentary on Pharma & Biotech Oncology / Hematology New Product Development

Posts tagged ‘non-Hodgkins lymphoma’

Thoughts on the pixantrone FDA ODAC meeting

By on March 23, 2010

Yesterday was quite day, with one thing and another.  For starters, the FDA ODAC committee finally held a session for Cell Therapeutics pixantrone in 3rd line NHL and ChemGenenex's omacetaxine, for people with the T315i mutation in CML.  The previously scheduled meeting was cancelled due to the Snowpocalyse that hit DC last month. 

I had to dash off to a doctor's appointment myself so missed most of the action on Twitter and rushed back to catch up at lunchtime by checking Twitter buddies such as Kerri Wachter who was live tweeting from the meeting and Adam Feuerstein of The Street's excellent live blog.

:Original raster version: :Image:Food and Drug...Image via Wikipedia

You can see my original review of the February FDA documents here.  Sadly, the analysis turned out to be accurate and Adam had noted:

"That was brutal."

Approximately 20 minutes into Richard Pazdur's opening introduction. 

In particular, the FDA felt that:

"Pixantrone has demonstrated evidence of biologic activity, but the mere demonstration of biologic activity is not sufficient for approval."

Ouch!  At that point it becomes incumbent upon the company presenters to argue persuasively to the nine panel members to convince them otherwise.  However, that was going to be a tall order given the FDA concerns regarding:

  1. Neutropenia and infections were higher in pixantrone than the control
  2. Cardiac toxicity was higher in pixantrone than control, including heart failure and ejection fraction

As highlighted in the original analysis of the pixantrone filing, the FDA were also unhappy about the shortened study given only 140 people were enrolled out of the planned 320, leading them to conclude:

  1. Study was not well executed or complete.
  2. Study was inconsistent (only 8 people enrolled in the US and none had a complete response).
  3. Trial did not demonstrate statistical significance or robust findings.

What was weird about the proceedings though, was a clear disconnect between the two parties, as Adam Feuerstein reported live via the webcast:

"Pazdur: FDA not consulted about halting enrollment in trial, not pre-specified in study's statistical plan."

"Bianco: In March 2008 after 140th patient was enrolled, study was closed to enrollment. We consulted with FDA about this."

Checking my Twitter stream, Kerri reported:

Picture 36
Personally, I was surprised that CTI thought that the statistical parameters would not change if they only recruited 140 of the 320 people expected and could proceed on that basis.  This is basic college level statistics – if you majorly change one input, the outliers must also be adjusted.  For this reason, the FDA's decision to treat the data as if an interim analysis had been done is fair and reasonable.

Going forward, it is likely that either all 320 patients would need to be enrolled in a study to meet the minimum FDA requirements or new studies in combination with other agents would be needed.  This latter approach is probably more likely, because the US sites (28 of them) only enrolled 8 people because the preferred treatment in the 3rd line refractory setting is combination chemotherapy, not single agent therapy. 

Perhaps the snowpocalypse last month was a portend of what was to happen.  Either way, yesterday was a bad day in DC for CTIC.

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#ASH09 meeting report: Non-Hodgkins Lymphoma

By on December 28, 2009

There was so much new data presented at the recent American Society of Hematology (ASH) meeting in New Orleans that I'm still digesting it all!

Today, I thought it was time to summarise what's hot in lymphomas, in particular, NHL.

Non-Hodgkins lymphomas (NHL) are a heterogeneous group of diseases affecting white blood cells with distinct clinical, morphologic, immunohistochemical, and molecular subtypes as defined in the 2008 World Health Organization (WHO) classification (PDF download).

In Europe, the German and French NHL groups are very methodical in taking each new potential regimen and comparing it in a randomised trial to the current stand of care to determine which is better, whether that be in terms of safety, tolerability or efficacy.  In New Orleans, a number of particularly interesting studies were presented for discussion in indolent NHL.

Impact on the current standard of care

One of the most interesting findings
was a realisation that the standard of care for non-Hodgkins lymphoma
(NHL) is likely changing soon with the new data on the
bendamustine-rituximab combination looking to overtake standard R-CHOP
in first line treatment of newly diagnosed patients.

At ASH, Mathias Rummel presented data on an upfront study of bendamustine plus rituximab (BR) versus R-CHOP in patients with indolent (slow growing) lymphoma.  The study population included mostly patients with follicular lymphoma, which accounted for probably 50% or so of the population, but about 20% or so of the patients had mantle cell lymphoma and the remainder had other indolent lymphomas. 

What was interesting about the results was the complete response rate significantly favoured BR, as did the progression-free survival.  When looking at the safety profile, the two-drug regimen versus the five-drug R-CHOP regimen seemed to be associated with a far superior safety profile, with patients having much less neutropenic fever and all of the other associated hematologic toxicities seen in patients with R-CHOP. 

When I interviewed Dr Owen O'Connor from the NYU Cancer Institute for Clinical Research about the data, he described the study as "potentially paradigm changing" in indolent lymphomas.  This may well turn out to be an accurate conclusion clinically, although it should be noted that the BR regimen will inevitably cost more than R-CHOP.

A long standing issue that has been unaddressed in diffuse large B-cell lymphomas has been the debate on whether a shorter R-CHOP regimen over 14 days would lead to better results than the standard 21 day regimen.  The Germans, lead by Dr Pfreundschuh and colleagues, have long suggested that accelerated CHOP-based chemotherapy was superior to classic or conventional R-CHOP21 therapy based on data from the RICOVER trial. 

This year, a heated debate apparently broke out in the NHL oral session after the French presented data from the GELA trial, demonstrating that R-CHOP21 was superior to R-CHOP14, both in terms of safety and toxicity profile, as well as efficacy, presumably because the shorter regimen was associated with more adverse events.  It should be noted that the French study inclusion criteria was for patients over 65, so these results may well be applicable to that specific population, where tolerability is very important.

W2W4 (Watch to watch for) in the future?

A walk round the poster sessions left me struck with how many interesting compounds are now being tested in NHL, after a bleak period of disappointing data.  Such compounds included AT-101, a gossypol and Mcl-1 inhibitor, and ABT-263, a Bcl-2 inhibitor. 

It is early days yet for determining true efficacy, but both compounds appear to have manageable tolerability in the phase I trials completed to date.  The rationale for ABT-263 is probably strongest in follicular lymphoma given the t(14:18) translocation, which gives rise to constituitive overproduction of Bcl-2. 

In the future, we may well see studies with either agent in combination with rituximab to determine if efficacy and tolerability can be further improved.

I missed the oral NHL sessions as they clashed with the CML sessions (more on that tomorrow), but a quick check of several experts who attended them brought the following additional suggestions of new agents in development in NHL from Novartis and Roche:

  1. Use of mTOR inhibitors such as everolimus (Afinitor) in refractory Waldenström macroglobulinemia (WM), a rare, indolent non-Hodgkin lymphoma, was considered very interesting. The data showed that everolimus had high single-agent activity with an overall response rate of 70% and manageable toxicity in patients with relapsed WM, and offers a potential new therapeutic strategy for this patient group.
  2. RO5072759 (GA101) is the first humanized and glycoengineered type II monoclonal anti-CD20 antibody to enter clinical trials and is being developed by Roche.  In vitro data show RO5072759 exhibits increased antibody-dependent cytotoxicity and strongly enhanced cell death (apoptosis) compared to rituximab.  The ORR in refractory NHL data presented in a phase I study at this meeting was 43%, with many of the patients being heavily pre-treated.  RO5072759 is now being explored as a single agent in phase II in relapsed/refractory indolent/aggressive NHL and B-CLL and in combination with chemotherapy in a phase Ib study.

Conclusions

Overall, the bendamustine-rituximab data was probably one of the stories of the conference and will likely see take-up in favour of R-CHOP in first-line NHL given the efficacy and tolerability benefits.  Trials are also ongoing in CLL, and thus if positive, we may well see some CLL patients being given with BR over fludarabine-based regimens such as FC and FCR in 2010.

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