ABT-263 report on small molecular inhibitor of Bcl-2 family proteins

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Phase 1 Study of ABT-263, a Bcl-2 Family Inhibitor, in Relapsed or

Refractory Lymphoid Malignancies

Sunday, December 7, 2008

http://ash.confex.com/ash/2008/webprogram/Paper13874.html

n = 42 mixed types

ABT-263 is a novel, orally bioavailable ... small molecular inhibitor of

Bcl-2 family proteins

Mechanistic toxicities observed preclinically include inhibition of

spermatogenesis, reduction in circulating lymphocytes and decreased survival

of circulating platelets, presumably mediated by inhibition of Bcl-w, Bcl-2

and Bcl-XL, respectively.

Study M06-814, a phase 1 dose-escalation study is employing a modified

Fibonaci 3 + 3 design to assess ABT-263 safety, pharmacokinetics and

anti-tumor activity of two dosing schedules in patients with relapsed or

refractory lymphoid malignancies.

Enrollment continues with 42 patients (39 on a 14/21 day and 3 on a 21/21

day dosing schedule) enrolled.

ABT-263 given on a 14/21 day dosing schedule began at 10 mg and continued

escalation to 440 mg, with 315 mg defined as tolerable. The pharmacokinetic

profile of ABT-263 on the 14/21 day schedule was linear from 10 - 440 mg

with a t½ of 14 - 20 h. Consistent with preclinical models, a dose-dependent

reduction in circulating platelets was observed.

Typically, platelet nadirs were transient, occurring on days 3-5 with

subsequent recovery during continued dosing, consistent with accelerated

platelet apoptosis and compensatory increased bone marrow release and

production.

Thrombocytopenia (low platelets) was predictable and manageable. A one week

lead-in dosing period at 150mg ABT-263 and a 21/21 day dosing schedule

beginning at 200 mg, are being evaluated as measures to ameliorate the

platelet nadir. Dose limiting toxicities on cycle 1 in the 14/21 day dosing

schedule occurred at 160 mg (bronchitis), 315 mg (elevated ALT and gr 4

thrombocytopenia), and 440 mg (dyspnea).

Responses were observed in 3 patients including a 75% and 99% reduction of

bulky masses in 2 CLL/SLL and a 75% reduction in a NK/T cell lymphoma.

Minor nodal responses occurred in 4 patients with follicular lymphoma and 3

patients with CLL/SLL.

Additionally, 2 patients with CLL/SLL had ≥50% decreases in leukemic cells

for at least 2 months.

ABT-263 is a well tolerated oral small molecular inhibitor of Bcl-2 family

proteins with a linear PK, toxicity profile indicative of on-target activity

and anti-tumor activity in patients with relapsed or refractory lymphoid

malignancies. Accrual continues.

Wyndham H , MD, PhD1, O. O'Connor, M.D.2, Myron S. Czuczman, MD3, Ann

LaCasce, MD4, J. Gerecitano, M.D., Ph.D.5, P. Leonard, MD6, Anil

Tulpule, MD7, Hao Xiong, Ph.D.8*, Yi-Lin Chiu, Ph.D.8*, Todd Busman,

Ph.D.8*, A. Knight, MBA8*, Sari Enschede, M.D.8*, Krivoshik,

M.D., Ph.D.8* and Rod Humerickhouse, M.D., Ph.D8*

1Center for Cancer Research, National Cancer Institute, Bethesda, MD

2Columbia Univ. Med. Ctr., New York, NY

3Roswell Park Cancer Institute, Buffalo, NY

4Dana-Farber Cancer Inst., Boston, MA

5Memorial Sloan-Kettering Cancer Ctr., New York, NY

6Division of Hem./Onc., Weill Cornell Medical College, New York, NY

7USC School of Medicine, Norris Cancer Center, Los Angeles, CA

8Abbott Laboratories, Abbott Park, IL

Disclosures: : Abbott Laboratories: Research Funding. O'Connor: Abbott

Laboratories: Research Funding. Czuczman: Abbott Laboratories and Genentech:

Consultancy. Tulpule: Abbott Laboratories: Research Funding. Xiong: Abbott

Laboratories: Employment. Chiu: Abbott Laboratories: Employment. Busman:

Abbott Laboratories: Employment. Knight: Abbott Laboratories: Employment.

Enschede: Abbott Laboratories: Employment. Krivoshik: Abbott Laboratories:

Employment. Humerickhouse: Abbott Laboratories: Employment.

See more of: Chronic Lymphocytic Leukemia - Therapy, Excluding

Transplantation