PCI-32765 for Special Cases of Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

Study Overview
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Brief Summary
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Background: - Chronic lymphocytic leukemia and small lymphocytic lymphoma (CLL/SLL) are types of blood or lymph node cancers that mostly affect the elderly. CLL/SLL both create abnormal white blood cells that hurt the immune system and make it more difficult to fight infections. These cancers are usually diagnosed after age 50; more than half of the people with CLL/SLL are over age 70. Elderly people often do not respond well to standard chemotherapy for CLL/SLL. They may have other health problems that make chemotherapy difficult. In addition, individuals who have a genetic abnormality called 17p deletion also do not respond well to standard treatments for CLL/SLL. Researchers want to test a new cancer treatment drug, PCI-32765, to see if it can treat CLL/SLL in these hard-to-treat groups. Objectives: - To see if PCI-32765 is a safe and effective treatment for CLL/SLL in older people and people with 17p deletion. Eligibility: Individuals over 65 years of age who have CLL/SLL. Individuals at least 18 years of age who have CLL/SLL and 17p deletion. Design: Participants will be screened with a medical history, physical exam, and imaging studies. Blood and urine samples will be taken. Optional bone marrow and lymph node biopsies may also be taken. Participants will take PCI-32765 capsules every day for 28 days (one cycle of treatment). Treatment will be monitored with frequent blood tests and clinic visits. PCI-32765 will be given for six cycles of treatment. Those who benefit from the drug will continue to take it as long as there are no side effects and the disease does not progress. Those who do not benefit will stop treatment and have regular followup exams.

Detailed Description
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CLL/SLL is a malignancy of B cells that predominantly affects the elderly population. Diagnosis is typically made in adults over the age of 50 and more than half of the people with CLL/SLL are over the age of 70. Elderly patients in particular have other comorbidities that limit the tolerability of standard CLL/SLL chemoimmunotherapy regimens and they often have inferior response to these particular regimens. In addition, those patients with a 17p deletion also have inferior outcomes due to rapid progression of disease as well as refractoriness to standard treatment regimens. It is still unclear what leads to the development of CLL/SLL. However, recent studies indicated that B cell receptor (BCR) signaling is an important contributor to the disease and could be a target for therapy. Bruton s Tyrosine Kinase (Btk) is an enzyme required for BCR signaling. Ibrutinib is a potent and selective inhibitor of Bruton Tyrosine Kinase (Btk). In vitro lymphoma models have demonstrated that ibrutinib inhibits Btk. Inhibition of Btk blocks downstream BCR signaling pathways and thus prevents B cell proliferation. A phase 1 study of ibrutinib shows activity in multiple lymphomas including CLL/SLL. This study will investigate the efficacy of ibrutinib for patients with CLL/SLL in patients that are older than 65 who are in need of therapy.This protocol is intended both for patients who have been untreated and those who have undergone other therapies.

Official Title
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A Phase II Study of PCI-32765 for Patients With Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL) Who Need Therapy and Are Older Than 65 or Have a 17p Deletion

Conditions
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Leukemia, Leukemia, Lymphocytyc, CLL (Chronic Lymphocytic Leukemia), SLL (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: Cohort 1: Treated and untreated patients age 65 or older and need for therapy Cohort 2: Treated (maximum accrual n=16) and untreated (n=27, evaluable) patients at least 18 years old with 17p deletion or p53 expression by immunohistochemistry or p53 mutation by sequencing analysis. Men and women with histologically confirmed disease as defined by the following: B-lymphocytosis greater than 5000 cells/microL (may be less than 5000 cells/microL if lymphadenopathy is present with histologic confirmation of lymph node involvement by SLL) Immunophenotypic profile read by an expert pathologist as consistent with CLL. This will include CD5, CD19, and CD20 expression by the CLL cells typically also with CD23 expression, but CD23 negative cases may be included if there is no t11;14 translocation present. Active disease as defined by at least one of the following: Weight loss greater than or equal to 10% within the previous 6 months Extreme fatigue Fevers of greater than 100.5 degrees F for greater than or equal to 2 weeks without evidence of infection Night sweats for more than one month without evidence of infection Evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia and/or thrombocytopenia Massive or progressive splenomegaly Massive nodes or clusters or progressive lymphadenopathy Progressive lymphocytosis with an increase of greater than 50% over a 2 month period, or an anticipated doubling time of less than 6 months Compensated autoimmune hemolysis Eastern Cooperative Oncology Group (ECOG) performance status of less than or equal to 2 ANC greater than 500/microL, platelets greater than 30,000/microL Agreement to use contraception during the study and for 90 days after the last dose of study drug if sexually active and able to bear children 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: Previous radiotherapy, radioimmunotherapy, biological therapy, chemotherapy, or treatment with an investigational product fpr CCL treatement in the last 4 weeks (i.e. intravenous immunoglobulin). Transformed CLL Autoimmune hemolytic anemia or thrombocytopenia requiring steroid therapy Impaired hepatic function: Total bilirubin greater than or equal to 1.5 times upper limit of normal unless dute to Gilbert's disease, AST/ ALT greater than or equal to 2.5 times institutional upper limit of normal unless due to infiltration of the liver. Impaired renal funtion: Creatinine greater than or equal to 2.0 mg/dL or GFR less than or equal to 50ml/min 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 Concomitant immunotherapy, chemotherapy, radiotherapy, corticosteroids (at dosages equivalent to prednisone > 20 mg/day), or experimental therapy Active Hepatitis B infection HIV infection Female patients: Current pregnancy or unwilling to take oral contraceptives or refrain from pregnancy if of childbearing potential or currently breastfeeding. Male patients who are unwilling to follow the contraception requirements described in this protocol. Psychiatric illness/social situations that would limit the patient s ability to tolerate and/or comply with study requirements. Unable to understand the investigational nature of the study or give informed consent. Individuals < 18 yrs old Known hypersensitivity to any component of PCI-32765 Any prior therapy with PCI 32765 or any other BTK inhibitors. Requires anticoagulation with warfarin. Requires treatment with strong CY3A4/5 and/or CYP2D6 inhibitors (unless no alternative is available).

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: Elderly greater than 65<br> | Drug: PCI 32765<br>* 420 mg daily<br>|
| Experimental: 17p Deletioin<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 |
| --- | --- | --- |
| Overall Response Rate at 6 Months | The primary endpoint was response after 6 cycles of therapy. Overall response rate was calculated as complete response plus partial response, based on the International Workshop on Chronic Lymphocytic Leukemia (iwCLL) 2008 criteria.as follows: Complete response (CR): all group A and group B criteria are met Group A criteria: resolution of enlarged lymph nodes, normal size spleen and liver, absolute lymphocyte count < 4,000/uL, normocellular bone marrow with < 30% lymphocytes without nodules Group B criteria: improved blood count (platelet count > 100,000/uL, hemoglobin > 11.0 g/dL, neutrophils > 1,500/uL) Partial response (PR): at least 2 of the group A criteria plus one of the group B criteria are met Group A criteria: >=50% decrease in target lymph nodes, >=50% decrease in spleen size, >=50% decrease in liver size, 50% reduction in marrow infiltrates Group B criteria: platelet count > 100,000/uL, hemoglobin > 11.0 g/dL, neutrophils > 1,500/uL | 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CLL, Treatment, CLL (Chronic Lymphocytic Leukemia), SLL (Small Lymphocytic Lymphoma), Leukemia, Lymphocytic Leukemia, Chronic Lymphocytic Leukemia, Small Lymphocytic Leukemia, SLL