Efficacy and Safety Study of PCI-32765 Combine With Ofatumumab in CLL

Inclusion Criteria:

Subjects with histologically confirmed chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), prolymphocytic leukemia (PLL), or Richter's transformation arising out of CLL/SLL as defined by WHO classification of hematopoietic neoplasms and satisfying ≥ 1 of the following conditions:

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 degree 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
Need for cytoreduction prior to stem cell transplant
Subjects must have failed ≥ 2 prior therapies for CLL including a nucleoside analog or ≥ 2 prior therapies not including nucleoside analog if there is a contraindication to such therapy
10% expression of CD20 on CLL/SLL cells
ECOG performance status ≤ 2
Life expectancy ≥ 12 weeks

Subjects must have organ and marrow function as defined below:

Absolute neutrophil count (ANC) ≥ 1000/µL in the absence of bone marrow involvement
Platelets ≥ 30,000/μL in the absence of bone marrow involvement
Total bilirubin ≤ 1.5 x institutional upper limit of normal unless due to Gilbert's disease
AST (SGOT) ≤ 2.5 x institutional upper limit of normal unless due to infiltration of the liver
Creatinine ≤ 2.0 mg/dL OR creatinine clearance ≥ 50 mL/min
No history of prior exposure to ofatumumab
Age ≥ 18 years
Body weight ≥ 40 kg

Exclusion Criteria:

A 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
Significant cardiovascular disease
Any condition which could interfere with the absorption or metabolism of PCI-32765 including unable to swallow capsules, malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel or ulcerative colitis, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction
Known history of Human Immunodeficiency Virus (HIV) or active infection with Hepatitis C Virus (HCV) or Hepatitis B Virus (HBV) or any uncontrolled active systemic infection
Any anticancer immunotherapy, chemotherapy, radiotherapy, or experimental therapy within 4 weeks before first dose of study drug. Corticosteroids for disease-related symptoms are allowed provided 1 week washout occurs
Active central nervous system (CNS) involvement by lymphoma
Major surgery within 4 weeks before first dose of study drug
Lactating or pregnant
Known moderate to severe chronic obstructive pulmonary disease (COPD)
History of prior malignancy, except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or other cancer from which the subject has been disease free for at least 2 years or which will not limit survival to < 2 years
History of Grade ≥ 2 toxicity continuing from prior anticancer therapy including radiation