ABT-263: novel, orally bioavailable and active small molecule Bcl-2 family protein inhibitor

[Guest guest]

Very encouraging for a single agent in phase I ... very : )

==

A phase 1 study evaluating the safety, pharmacokinetics, and efficacy of

ABT-263 in subjects with refractory or relapsed lymphoid malignancies.

Sub-category:Lymphoma

Category:Lymphoma and Plasma Cell Disorders

Meeting:2008 ASCO Annual Meeting

Abstract No:8511

Citation:J Clin Oncol 26: 2008 (May 20 suppl; abstr 8511)

Author(s):W. H. , M. S. Czuczman, A. S. LaCasce, J. F. Gerecitano, J.

P. Leonard, K. Dunleavy, A. P. Krivoshik, H. Xiong, Y. Chiu, O. A. O'Connor

Abstract:

Background: ABT-263 is a novel BH3 mimetic that binds with high affinity (Ki

1 nanoM) and inhibits multiple antiapoptotic Bcl-2 family proteins. ABT-263

displays potent mechanism-based cytotoxicity (EC50 1 microM) against human

cell lines derived from lymphoid and small cell lung cancers.

The anticipated ABT-263 associated toxicities are mechanism based, in

particular, Bcl- XL mediated decrease in circulating platelet survival,

Bcl-w mediated testicular toxicity, and Bcl-2 mediated effects on

lymphocytes.

Methods: The safety and pharmacokinetic (PK) profile of ABT-263 were studied

in patients with relapsed or refractory lymphoid malignancies. For each

21-day cycle, subjects received ABT-263 orally QD for 14 consecutive days

followed by 7 days off drug.

The drug dose was doubled in each cohort until a grade 3 toxicity occurred,

after which escalations were in 40% increments.

Results: Currently, 30 patients have been enrolled in the lymphoma study

completing the 10, 20, 40, 80, 160, 225 and 315 mg cohorts.

One grade 3 dose limiting toxicity (DLT) occurred in each of the 160 and 315

mg cohorts (a URI and an ALT, respectively) resulting in expansion of those

cohorts.

Responses include: two patients with bulky CLL in the 40 mg cohort had 99%

and 36% tumor reductions after cycles 8 and 7, respectively, one patient

with bulky CLL/SLL in the 60 mg cohort had a 75% reduction at cycle 4, one

patient with follicular lymphoma in the 80 mg cohort had a 20% tumor

reduction after cycle 7 and one patient with NK/T cell lymphoma at 315 mg

had a 75% reduction at cycle 2.

These subjects remain on study with intrapatient dose escalation of the 40

mg patients. The PK profile of ABT-263 was linear and the average terminal

half-life was 14 to 20 hours.

ABT-263 reduced platelet levels in a dose-dependent manner. Grade 3

thrombocytopenia was observed in 5 patients without any bleeding.

Conclusions: ABT-263 is a novel, orally bioavailable and active small

molecule Bcl-2 family protein inhibitor that shows early evidence of

activity in lymphoid malignancies.