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An open-label, phase 1b/2, safety and efficacy study of the Bruton's tyrosine kinase
(Btk) inhibitor, PCI-32765, and ofatumumab in subjects with relapsed/refractory chronic
lymphocytic leukemia/small lymphocytic lymphoma and prolymphocytic leukemia

HYPOTHESIS: Administration of ofatumumab either consecutively or simultaneously with PCI-32765 will improve response rates compared with PCI-32765 alone and prolong survival in people with chronic lymphocytic leukemia (CLL).

RATIONALE: CLL, the most common leukemia diagnosed in Western countries, is characterized by an accumulation of leukemic cells that occurs in part because the cells receive survival signals from various receptors activated by ligands. CLL subtypes and related malignancies share common pathways, and this has allowed for the development of targeted therapies such as PCI- 32765 and ofatumumab.

This phase 1b/2 study is designed to determine the safety and efficacy of PCI-32765 in combination with ofatumumab in subjects with relapsed or refractory CLL, SLL and related diseases. The combination is expected to be well tolerated by patients; nonetheless, the trial evaluates three dosage schedules. The study will also estimate the efficacy of the combination treatment as measured by overall response rate and progression-free survival.

PCI-32765, which is taken orally, is a selective inhibitor of Bruton's tyrosine kinase (Btk). The Btk protein is expressed mainly in B lymphocytes. It is critical for B-cell development, differentiation and signaling, and for B-cell proliferation and survival. Individuals who lack functioning Btk lack circulating B cells and are thus unable to produce immunoglobulins or mount humoral immune responses.

Btk plays a key role in B-cell growth and proliferation via the B-cell receptor. A constitutively active mutant can induce IL-5- independent growth in a pro-B-cell line, and a body of evidence suggests that B-cell receptor signaling may be necessary to sustain the viability of CLL and other B-cell malignancies.

The fact that mutational status of the BCR is a strong predictor of disease outcome in CLL emphasizes the importance of the BCR signaling pathway in CLL pathogenesis and suggests the importance of Btk as a therapeutic target.

Ofatumumab is a humanized monoclonal antibody that targets CD20, a B-cell surface protein that is also critical for B-cell development and differentiation. It is highly expressed on malignant B cells. Ofatumumab shows activity in patients with fludarabine- and alemtuzumab-refractory CLL, including patients previously treated with rituximab. Ofatumumab was chosen for this trial over rituximab, which also targets CD20, for its superior single-agent activity, for superior complement-dependent cell killing and antibody-dependent cell killing, and because it has a weekly dosing schedule.

OSU-10053 has three cohorts. In the first cohort, PCI-32765 is administered for 28 days alone before ofatumumab is added. In the second cohort, the two drugs are started concurrently. In the third cycle, ofatumumab is administered alone for two cycles before PCI-32765 is added. Data from correlative studies will improve the understanding of the mechanism of action of PCI-32765 and of the drug combination.

Clinical trial OSU-10053; NCT01589302


Phone: 614-293-8858


Eligibility:Subjects with histologically confirmed CLL, small lymphocytic
lymphoma or prolymphocytic leukemia as defined by WHO classification of hematopoietic neoplasms, or Richter's transformation arising out of CLL/SLL. Additional criteria are available upon request.


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