Wednesday, December 19, 2012

ASH 2012: Combinations of the PI3K∂ Inhibitor GS–1101 (CAL-101) with Rituximab and/or Bendamustine Are Tolerable and Highly Active in Patients with Relapsed or Refractory CLL

GS1101(formerly CAL101) was the first oral, exciting small molecule to show outstanding results in CLL after the failure of many other small pathway blockers.

It had about an 18 month head start on ibrutinib (formerly PCI-32765), but its lead has shrunk considerably in the race to FDA approval.

It too blocks the pathway downstream from the BCR (B cell receptor) that tells the clone to survive and proliferate. Bench research presented at ASH seems to suggest that in some clones of aggressive CLL with a higher tendency to Richter's Transformation, BCR is promiscuous (couples and responses with any old stimulating antigen) or in another poster presentation, may be self stimulating, perpetually turned on and driving the disease with no outside help. Quoting from the conclusions in that paper " These findings suggest the possibility of self-recognition of BCRs within the CLL cell membrane or BCR interactions between neighboring CLL cells. This may potentially result in autostimulation of the leukemic cell independent of “exogenous” antigens and may account for self-sufficient signaling of some CLL-BCRs in driving disease progression. "

Either way, turned on BCR is not our friend.

This basic science work applies to any and all drugs that effect the BCR pathway, and it was work such as this that lead to the idea that compounds such as GS1101 and ibrutinib might someday have a major role to play in controlling CLL. We now know that PI3K∂ drives survival and proliferation of the cancers cells, so blocking it with GS1101 makes good sense. 

That kind of hard work leads to an understanding  of the basic cell biology that leads to a treatment hypothesis that leads to animal studies that leads to human trials that leads to a usable drug.  I am way oversimplifying the story and this ideal path is aborted 99% of the time long before it gives birth to a helpful medical compound, but I wanted to share some of the mostly unseen effort that makes these breakthroughs possible.  The medicine bottle at the pharmacy is just the tip of the iceberg. We owed so much to the medical chemists.

So what were the clinical results with GS1101 that were presented at ASH

The important  abstract 191:Combinations of the Selective Phosphatidylinositol 3-Kinase-Delta (PI3Kdelta) Inhibitor GS–1101 (CAL-101) with Rituximab and/or Bendamustine Are Tolerable and Highly Active in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL): Results From a Phase I Study reported more good news: high response rates.

Here I am sharing an executive summary of the findings but you have a link to all the details included in the abstract. We must wait for the peer reviewed published paper as that is the true test of the validity of the research.

51 patients were studied in three different arms. These were not the easiest  of us to treat. All had relapsed after up to 10 prior therapies, 27 had refractory disease, more that half had bulky nodes, and nearly all had had prior B/R (bendamustine/rituximab).

In the group that was randomized to get B (bendamustine) with the GS1101, the intent to treat overall response rate (ORR) was 82%. Adding rituximab (the BR group) raised that to 87%.

But here is the number that excites me. Leave out the chemo (bendamustine) completely, and use only biological therapies with the combination of CD20 antibody, rituximab, and the new PI3K∂ inhibitor, the response rate was a very respectable 78% in these tough patients. 

Minimum follow-up was 40 weeks for each arm with the one year progression free survival numbers being very similar to the ORR.

Nodes shrunk rapidly in almost everyone. Disease related cytokines, elevated at the start of therapy fell, and that may explain why we feel so much better with these treatments. Elevated cytokines make us feel sick.

In the GS1101 + R (rituximab) group (only 19 patients), 21% (6 patients) got pneumonia, 32% had low neutrophils ( and 11% or two patients had febrile neutropenia) and 21% had low platelets. Only one patient had elevation of the liver enzymes. As expected, the blood work was considerably worse in the  two groups that received bendamustine. Surprising infections were lower in the BR group, but the sample was small with only 15 patients being followed.

The data are very encouraging, but we need much bigger numbers and longer time frames. That is the why we have the phase 3 trials, accruing right now. Check out clinicaltrials.gov for the details. My favorite would be the trial that offers either ofatumumab with or without GS1101 as a way to avoid a chemo arm.

But wait and discuss with your doctors the ibrutinib and ABT-199 trials too if you need to consider therapy soon. I will be reviewing those and some of the related important ASH abstracts here soon. Videos of my interviews with the experts at ASH are being rendered and prepared.

It is good to have choices. Not so long ago, we had almost none. 

Many reasons to be thankful and hopeful.

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4 Comments:

Anonymous Anonymous said...

WOW!!!! Keep the great news coming Brian!

December 19, 2012 at 1:14 PM  
Anonymous Anonymous said...

As a PhD pharmacologist and a CLL patient, I can't wait to see the combination trial of GS-1101 and ibrutinib that most likely will occur at some point.

December 21, 2012 at 10:34 AM  
Anonymous Janet Morrison said...

Encouraging news for sure.

December 21, 2012 at 1:41 PM  
Blogger Diane Mackinnon said...

The video will not play. Keeps telling me viedo is private ...

January 1, 2013 at 2:56 PM  

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