Safety and Tolerability Study of PCI-32765 Combined With Fludarabine/Cyclophosphamide/Rituximab (FCR) and Bendamustine/Rituximab (BR) in Chronic Lymphocytic Leukemia (CLL)

A Phase 1b, Multicenter, Open-label, Parallel-group Safety Study of a Bruton's Tyrosine Kinase (Btk) Inhibitor, PCI 32765, in Combination With Chemotherapy in Subjects With Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

The purpose of this study is to establish the safety of orally administered PCI-32765 in combination with fludarabine/cyclophosphamide/rituximab (FCR) and bendamustine/rituximab (BR) in patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma(SLL).

This is a Phase 1b, open-label, parallel-group, nonrandomized, multicenter study of PCI 32765 420 mg once daily oral (PO) administration in combination with 2 different chemotherapy regimens in subjects with relapsed/refractory chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL).

Inclusion Criteria:

1. Histologically confirmed CLL or SLL and satisfying at least 1 of the following criteria for requiring treatment:

   • Progressive splenomegaly and/or lymphadenopathy identified by physical examination or radiographic studies
   • Anemia (<11 g/dL) or thrombocytopenia (<100,000/μL) due to bone marrow involvement
   • Presence of unintentional weight loss > 10% over the preceding 6 months
   • NCI CTCAE Grade 2 or 3 fatigue
   • Fevers > 100.5° or night sweats for > 2 weeks without evidence of infection
   • Progressive lymphocytosis with an increase of > 50% over a 2 month period or an anticipated doubling time of < 6 months

2. 1 to 3 prior treatment regimens for CLL/SLL

3. ECOG performance status of ≤ 1

4. ≥ 18 years of age

5. Willing and able to participate in all required evaluations and procedures in this study protocol including swallowing capsules without difficulty

6. Ability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information (in accordance with national and local subject privacy regulations)

Exclusion Criteria:

1. Any chemotherapy, therapeutic antineoplastic antibodies (not including radio- or toxin immunoconjugates), radiation therapy, or experimental antineoplastic therapy within 4 weeks of first dose of study drug
2. Radio- or toxin-conjugated antibody therapy within 10 weeks of first dose of study drug
3. Concomitant use of medicines known to cause QT prolongation or torsades de pointes
4. Transformed lymphoma or Richter's transformation Any life-threatening illness, medical condition or organ system dysfunction which, in the investigator's opinion, could compromise the subject's safety, interfere with the absorption or metabolism of PCI-32765 PO, or put the study outcomes at undue risk
5. Any of the following laboratory abnormalities: oAbsolute neutrophil count (ANC) < 1000 cells/mm3 (1.0 x 109/L) oPlatelet count < 50,000/mm3 (50 x 109/L) oSerum aspartate transaminase (AST/SGOT) or alanine transaminase (ALT/SGPT) ≥ 3.0 x upper limit of normal (ULN) oCreatinine > 2.0 x ULN or creatinine clearance < 40 mL/min