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

Study Overview
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Brief Summary
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The purpose of this study is to determine the efficacy and safety of a fixed-dose, daily regimen of orally administered PCI-32765 combined with ofatumumab in subjects with relapsed/refractory CLL/SLL and related diseases

Official Title
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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

Conditions
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B-cell Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma, Prolymphocyctic Leukemia, Richter's Transformation

Intervention / Treatment
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* Drug: PCI-32765
* Drug: ofatumumab


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1<br>In Group 1, PCI-32765 420 mg PO was administered daily for 1 cycle (28 days) before the start of ofatumumab IV dosing | Drug: PCI-32765<br>* 420 mg PO daily<br>* Other names: ibrutinib;Drug: ofatumumab<br>* per package insert as an IV infusion<br>* Other names: Arzerra;|
| Experimental: Group 2<br>In Group 2, PCI-32765 420 mg PO daily was initiated concomitantly with ofatumumab IV (PCI-32765 initiated on Day 2 of Cycle 1) | Drug: PCI-32765<br>* 420 mg PO daily<br>* Other names: ibrutinib;Drug: ofatumumab<br>* per package insert as an IV infusion<br>* Other names: Arzerra;|
| Experimental: Group 3<br>In Group 3, two cycles of ofatumumab IV were administered prior to the start of PCI-32765 420 mg PO daily | Drug: PCI-32765<br>* 420 mg PO daily<br>* Other names: ibrutinib;Drug: ofatumumab<br>* per package insert as an IV infusion<br>* Other names: Arzerra;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Achieving Response | The primary endpoint for the study was overall response rate (ORR), defined as the proportion of participants who achieved a best overall response of complete response (CR), CR with incomplete blood count recovery (Cri), or partial response (PR), according to the guidelines from the International Workshop on Chronic Lymphocytic Leukemia (IWCLL1) published in 2008 for CLL participants and International Working Group for non-Hodgkin's lymphoma (IWG NHL) 2007 criteria for SLL participants, with the modification that treatment-related lymphocytosis will not be considered progressive disease, as evaluated by the investigators. Assessment of disease is based on radiological exams, physical exam, hematological evaluations and, when appropriate, bone marrow results. | The median follow-up time on study for all treated participants is 12.5 (range 0.5-19.6) months | 
| Safety During Dose-Limiting Toxicity (DLT) Observation Period | Number of dose-limiting toxicities observed in the first 6 participants enrolled in treatment Groups 1 and 2 | 56 days for Group 1 and 28 days for Group 2 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment Emergent Adverse Events (AEs) | Number of participants who had experienced at least one treatment emergent AE | From first dose of study treatment to within 30 days of last dose or until study closure | 
| Progression Free Survival (PFS) at 12 Months | Progressive disease for CLL (Hallek) is characterized by ≥1 of the following: Appearance of any new lesion, eg lymph nodes (> 1.5 cm), de novo hepatomegaly or splenomegaly, or other organ infiltrates Increase of ≥50% in longest diameter of any previous site in hepatomegaly or splenomegaly in blood lymphocytes with ≥5x109/L B cells with enlarging lymph node, liver, or spleen Progressive disease for B cell lymphoma (Cheson) is characterized by any new lesion or increase by ≥ 50% of previously involved sites from nadir: Appearance of a new lesion(s) >1.5 cm in any axis, ≥ 50% increase in the SPD of >1 node, or ≥50% increase in longest diameter of a previously identified node >1 cm in short axis Lesions PET+ if FDG-avid lymphoma or PET+ before therapy 50% increase from nadir in the SPD of any liver or spleen lesions New or recurrent BM involvement Increase of ≥50% in blood lymphocytes with ≥5x109/L B cells within enlarging lymph node, liver, or spleen | From first dose of study treatment until disease progression, death, or until 12 months |