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

Study Overview
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Brief Summary
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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).

Detailed Description
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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).

Official Title
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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

Conditions
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B-cell Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma

Intervention / Treatment
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* Drug: PCI-32765


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 1 to 3 prior treatment regimens for CLL/SLL ECOG performance status of ≤ 1 ≥ 18 years of age Willing and able to participate in all required evaluations and procedures in this study protocol including swallowing capsules without difficulty 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: 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 Radio- or toxin-conjugated antibody therapy within 10 weeks of first dose of study drug Concomitant use of medicines known to cause QT prolongation or torsades de pointes 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 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

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: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PCI-32765 plus fludarabine/cyclophosphamide/rituximab (FCR)<br> | Drug: PCI-32765<br>* 420 mg daily<br>|
| Experimental: PCI-32765 plus bendamustine/rituximab (BR)<br> | Drug: PCI-32765<br>* 420 mg daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Prolonged Hematologic Toxicity Started in Cycle 1 |  | From First day of dose to 30 days after last dose of any study medication. Participants were followed with a median follow-up time of 15.8 months. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Adverse Events Requiring Dose Delay or Discontinuation of Ibrutinib |  | From First day of dose to 30 days after last dose of any study medication. Participants were followed with a median follow-up time of 15.8 months. | 
| Overall Incidence of Grade ≥3 Adverse Events (AEs) Per NCI CTCAE V4.0 |  | From First day of dose to 30 days after last dose of any study medication. Participants were followed with a median follow-up time of 15.8 months. | 
| Overall Incidence of Serious Adverse Events (SAEs) |  | From First day of dose to 30 days after last dose of any study medication. Participants were followed with a median follow-up time of 15.8 months. | 
| Overall Response Rate (Complete Response [CR] + Complete Response With Incomplete Marrow Recovery [CRi] + Nodular Partial Response [nPR] + Partial Response [PR]) | Response criteria are as outlined in the IWCLL 2008 criteria (Hallek 2008) and as assessed by investigator, e.g. response requires 50% reduction in lymph node size. Assessment of response to treatment will be done every 2 cycles for the first 6 months and then every 3 months thereafter until disease progression or prior to the administration of a new anticancer therapy and at follow-up visits. | From first response assessment to last response assessment. Participants were followed with a median follow-up time of 15.8 months. | 
| Sustained Hematologic Improvement in Subjects With Neutropenia, Anemia, or Thrombocytopenia at Baseline |  | From first response assessment to last response assessment. Participants were followed with a median follow-up time of 15.8 months. | 
| Progression Free Survival Rate at 12 Months | Criteria for progression are as outlined in the IWCLL 2008 criteria (Hallek 2008) and as assessed by investigator, e.g. progression defined as a 50% increase in lymph node size. | From first dose of any study medication to 12 months after first dose to progressive disease or death or the last clinical assessment before receiving new anticancer therapy or loss to follow-up, whichever occured the earliest. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Lymphoma, B-Cell, Leukemia, Lymphoid, Leukemia, B-Cell, Bruton's Tyrosine Kinase