Monday, May 27, 2013

ASCO 2013 Abstract: ABT-199 in Relapsed and Refractory CLL Patients


I have posted before on ABT-199. I like this drug because it works. And it is a pill, not an IV.

It is clearly a very potent therapy.

We know that not just from the impressive 85% response rates, even for those difficult to treat 17p del and F refractory patients where an amazing 88% and 75% respectively achieved at least a partial response (PR), but we also know it from its dark's side, namely tumor lysis syndrome (TLS).

Until the dosing was adjusted after the first cohort, the first three patients all had TLS, a life threatening complication (and one die did in this trial) from the massive killing of the cancer overloading the liver and especially the kidneys' ability to prevent all that toxic waste from cell death from building up to dangerous levels.

We need to move carefully, but I am glad that ABT-199 is back in trial after the studies were suspended due to deaths from TLS.

The present approved options for F-refractory and 17p deleted patients are severely limited and these results are very promising.

Complete responses (CR) are only 13%, but that's not bad for any mono therapy, especially in these tough patients.

Our future depends on the researchers taming both the disease and the drugs that we use to treat it.

We also need to constantly recognize the sacrifice of those who bravely jumped into this "first-in-human" phase 1 trials. CLL is not for wimps.

The question I am asking myself is will ABT-199 offer enough of a therapeutic potency edge over the other novel oral therapies such as the gentler inhibitors of BTK and PI3K∂ that will justify its risks and earn a place in our therapeutic arsenal.

Or will its risks become acceptably manageable? Whatever that means.

Still is nice to have more viable choice options for those of us with bad disease.

I hope it move forward. I imagine a time that we will take a cocktail of oral pathway blockers to completely slay our dragon, much as is done today with HIV. Blocking BCL-2 is part of that vision.

Here is the abstract.

Updated results of a phase I first-in-human study of the BCL-2 inhibitor ABT-199 (GDC-0199) in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL).
John Francis Seymour, Matthew Steven Davids, John M. Pagel, Brad S. Kahl, William G. Wierda, Thomas P. Miller, John F. Gerecitano, Thomas J. Kipps, Mary Ann Anderson, David C.S. Huang, David E. Darden, Lori A. Gressick, Cathy E. Nolan, Jianning Yang, Todd A. Busman, Alison M. Graham, Elisa Cerri, Sari H. Enschede, Rod A. Humerickhouse, Andrew Warwick Roberts; Peter MacCallum Cancer Center, Melbourne, Australia; Dana-Farber Cancer Institute, Boston, MA; Fred Hutchinson Cancer Research Center, Seattle, WA; University of Wisconsin Carbone Cancer Center, Madison, WI; The University of Texas MD Anderson Cancer Center, Houston, TX; University of Arizona Cancer Center, Tucson, AZ; Memorial Sloan-Kettering Cancer Center, New York, NY; UC San Diego Moores Cancer Center, La Jolla, CA; Royal Melbourne Hospital; Walter and Eliza Hall Institute of Medical Research, Parkville, Australia; Walter and Eliza Hall Institute of Medical Research, Parkville, Australia; AbbVie, Inc, North Chicago, IL; Royal Melbourne Hospital, Melbourne, Australia
Background: Targeting BCL-2 is a promising strategy for treating CLL, including disease refractory to fludarabine (F), or with (del(17p). ABT-199 is a selective BCL-2 inhibitor with >500-fold higher affinity for BCL-2 (Ki< 0.10 nM) than for BCL-XL (Ki = 48 nM). Methods: Objectives of this Ph I dose-escalation study include evaluations of safety, pharmacokinetics and preliminary efficacy of ABT-199 in patients (pts) with R/R CLL. A single oral dose was given followed by 6 days off drug, before continuous once daily dosing. After cohort 1, the initial dose was reduced and daily dosing modified to include a 2 or 3 step dose-escalation to the target dose for each cohort. Results: As of January 11, 2013, 56 pts have been enrolled; median age 67 y (range 36-86); 41 males; median 3.5 prior therapies (range 1-10). 16 (29%) had del(17p) and 18 (32%) F-refractory CLL. Median follow up is 6.3 months (range 0.03-16.5); 7 pts have been on study for more than 1 yr. 13 pts discontinued; 7 due to PD, 6 for other reasons: tumor lysis syndrome (TLS; 2), other illness (2), thromboembolic event (1), consent withdrawal (1). The most common non-hematological AEs (>15% pts) were nausea (36%), diarrhea (30%), fatigue (25%), upper respiratory tract infection (23%), and cough (16%). Grade 3/4 AEs occurring in > 5 pts were neutropenia 21(38%), thrombocytopenia 6 (11%) and TLS 5 (9%). TLS occurred in 3/3 pts in cohort 1 and 2/53 pts with the modified stepped dosing schedule (DLTs). Additionally, 1 fatal AE occurred within 48 hrs of dose- escalation to 1200 mg in a pt with laboratory evidence of TLS (DLT). 46 of 54 pts (85%) evaluable for efficacy achieved a response to ABT-199; 7 (13%) a CR or CR with incomplete count recovery and 39 (72%) a PR (30 confirmed by consecutive scans). 14/16 (88%) and 12/16 (75%) of pts with del(17p) and F-refractory CLL, respectively, achieved at least a PR. Conclusions: ABT-199 is highly active achieving a 85% overall response rate in R/R CLL, independent of high risk markers such as del(17p) and F-refractory disease. Additional dosing and scheduling modifications are currently being explored to minimize the risk of TLS. Clinical trial information: NCT01328626. 


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3 Comments:

Anonymous Dave Miller said...

Brian,

Agree with your comment "Still is nice to have more viable choice options for those of us with bad disease" especially if each new pill/approach/drug attacks a different independent pathway or target on CLL cells.

Therefore, BiTE Blinatumomab seems to be working well attacking CD19 in ALL, but Blinatumomab seems to have dropped off CLL radar? If you can obtain any update at ASCO on potential plans/trials for treating CLL with BiTE/Blinatumomab, that would be interesting in my opinion.

May 27, 2013 at 11:05 AM  
Anonymous Mike said...

The news keeps better and better for non-chemo treatment options. This is another treatment that shows real hope for smart targeted aimed at destroying cancer at source.

Let's hope they can sort out the implementation of dosage and manage the treatment successfully to help those brave people in the trials who are the forerunners for others who hopefully one day will find this treatment is a life saver.

May 27, 2013 at 12:50 PM  
Blogger Greg said...

I am so anxious as to why the trails are still in limbo and not going ahead, even despite all announcements.

And, frankly, Randy's family should ask the question to some of AbbVie trial co-ordinators as to why anybody in their sane state of ind would escalate the dose from 150mg to 1200(!!!!!)mg a day. This not only was deadly for Randy (G-D bless his name) but also was not a good news for the company and us, fellow participants. Privided that this small molecule does cause TLS so it was prudent to be safer than sorry.

May 27, 2013 at 9:53 PM  

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