PCI-32765 (Ibrutinib) in Treating Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma, or B-cell Prolymphocytic Leukemia

Study Overview
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Brief Summary
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This is a Phase II, single institution open-label, non-randomized monotherapy study to evaluate the clinical efficacy and durable disease control of PCI-32765 administered to patients with relapsed/refractory CLL/SLL/PLL of all risk categories with patients having deletion 17p13 independently evaluated.

Detailed Description
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This is a clinical trial, a type of research study, involving treatment with an investigational (experimental) drug called PCI-32765 (Ibrutinib), a kinase inhibitor. Kinases are proteins that are inside of cells and help them to live and grow. The specific kinase inhibited or blocked by this study drug is believed to help blood cancer cells grow and live. By inhibiting or blocking the activity of this kinase, it is possible that the study drug may be able to kill the cancer cells or stop them from growing. This study will involve treating patients with chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), or B-cell prolymphocytic leukemia (B-PLL) that has not responded to or has relapsed after standard treatment. This trial is studying how effective PCI-32765 is at treating CLL, SLL, or B-PLL and all the effects, good and/or bad, treatment with this drug has on patients and their cancers.

Official Title
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A Phase 2 Study of the Bruton's Tyrosine Kinase (Btk) Inhibitor, PCI-32765(Ibrutinib), in Relapsed and Refractory Patients With Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL) and B-cell Prolymphocytic Leukemia (B-PLL)

Conditions
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Prolymphocytic Leukemia, Recurrent Small Lymphocytic Lymphoma, Refractory/Relapsed Chronic Lymphocytic Leukemia

Intervention / Treatment
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* Drug: ibrutinib
* Other: Correlative laboratory samples
* Other: quality of life assessment


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Confirmed diagnosis of relapsed/refractory CLL/SLL who require treatment and have failed at least one prior therapy. Patients must have available results of interphase cytogenetics CLL fluorescent in situ hybridization (FISH) panel; the cytogenetic analysis must be done prior to starting therapy but after any recent therapy Eastern Cooperative Oncology Group (ECOG) performance status =< 2 Life expectancy greater than 2 months Bilirubin =< 1.5 X the institutional upper limit of normal unless due to Gilbert's disease or disease related to Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) =< 2.5 X the institutional upper limit of normal unless disease related Creatinine =< 1.5 X the institutional upper limit of normal unless disease related Absolute neutrophil count (ANC) >= 0.75 X 10^9/L Platelet count >= 30 X 10^9/L Agree to use contraception during the study and for 30 days after the last dose of study drug if sexually active and able to bear children Ability to understand and the willingness to sign a written informed consent document Patients with uncontrolled or active infection requiring antibiotic therapy; patients with controlled infections who are receiving extended antibiotics or prophylactic therapy are not excluded Exclusion Criteria: Patients who have had chemotherapy, radiotherapy or immunotherapy within 4 weeks prior to the first dose of study drug (corticosteroids for disease-related symptoms allowed but doses equivalent to > 20 mg prednisone orally per day require 1 week washout before study drug administration or steroid dose must be equal to =< 20 mg prednisone orally daily) Patients who have not recovered from adverse events of >= grade 3 toxicity due to agents administered more than 4 weeks ago Receiving any other investigational agents Previously randomized to any PCI-32765 clinical trial Known secondary malignancy that limits survival to less than two years Patients with 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 Patients requiring anti-coagulation with warfarin or other Vitamin K antagonists or heparin products including low molecular weight heparin (LMWH) Currently active, clinically significant hepatic impairment Child-Pugh class B or C according to the Child Pugh classification Patients requiring treatment with a strong cytochrome P450 3A4/5 (CYP3A4/5) and/or cytochrome P450 2D6 (CYP2D6) inhibitor Patients with 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 such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of screening, or any Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification Active central nervous system (CNS) involvement by lymphoma Pregnant or women who are breastfeeding

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (ibrutinib)<br>Patients will be treated with PCI-32765 capsules administered orally once daily at a dose of 420 mg for 28 day cycles. Weekly monitoring during the first month will occur followed by monthly evaluations for 2 additional months. Monitoring for patients at this point would be every 3 months with monthly CBC(complete blood count)and phone follow-up with a co-investigator on the study. A standard questionnaire will be used in this monthly phone assessment. Patients will continue to receive the study drug indefinitely as long as they are deriving clinical benefit (Complete Response or Partial Response or Stable Disease) and not experiencing any unacceptable toxicity. Subjects with disease progression will be removed from the study. Correlative laboratory samples, quality of life assessment, and immunologic data would be collected over time of therapy. | Drug: ibrutinib<br>* Patients receive ibrutinib orally (PO) once daily (QD) on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.<br>* Other names: PCI-32765;Other: Correlative laboratory samples<br>* Blood samples will be collected and used for pharmacodynamic testing. Samples will be collected pre-dose on Cycle 1 Day 1 and 2 hours post-dose Cycle 1 Day 1, pre-dose on Day 2 and Day 8 of Cycle 1 and pre-dose on Day 1 of Cycles 2 and 3 and then every 3 cycles thereafter for 1 year (Cycle 15 Day 1). Samples will also be collected at the time of relapse and at any time when bone marrow biopsy is performed.<br>* Other names: laboratory biomarker anyalysis;Other: quality of life assessment<br>* During screening, sociodemographic information (e.g., age, race, marital status) and reports of recent (last year) stressful events will be obtained. The assessment will consist of measures of emotional distress, depressive symptoms, and quality of life. Quality of life measures will be administered during screening and on Days 1 (±3), 8 (±3),, 15 (±3),, 22 (±3), of Cycle 1, Day 1 (±3), of Cycle 2 and on day 1 (±7) of Cycles 3, 6, and then every 3 months thru month 24.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determine the 2 Year Progression-free Survival (PFS) of Single Agent PCI-32765 in Patients With Relapsed and Refractory CLL. | We will summarize our findings for this endpoint independently as well within each cohort (del17p vs other cytogenetic groups). We will evaluate the proportion of patients who are progression-free and alive at two years or have gone on to transplant (treatment successes) over the total number of evaluable patients; eligible patients who received at least one dose of therapy are considered evaluable. Assuming that the number of treatment successes as defined above is binomially distributed, we will also include 95% binomial confidence intervals for the estimates corresponding to each cohort. | up to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best Overall Response Rate Using the Revised International Workshop on Chronic Lymphocytic Leukemia (IWCLL) Working Group Guidelines | Responders were subjects who achieved a complete response (CR), partial response (PR) or PR with persistent lymphocytosis. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. | up to 2 years | 
| Number of Patients With 6 Month ORR of Single Agent Ibrutinib in Relapsed and Refractory CLL Patients | The 6 month overall response rates overall response rate (ORR). Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR | Up to 6 months | 
| Percentage of Patients With Overall Survival (OS) | Time from date of first treatment with ibrutinib until the date of death from any cause or the date of last contact for those alive. | 2 years | 
| 2-year Kaplan-Meier Estimate of OS for Relapsed and Refractory CLL Patients Treated With Single Agent PCI-32765 | Time from date of first treatment with ibrutinib until the date of progression or death from any cause. Those alive and progression free are censored at the date of last clinical assessment. | 2 years | 
| Number of Patients With Adverse Events, Graded According to the NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Adverse events grade 3 or higher using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 with the attribution of either definite, possible or probable related. | Up to 2 years post treatment | 
| Resistance Studies of Ibrutinib | Percentage of patients with BTK C481S mutation or PLCG2 mutation | Up to 4 years | 
| Decrease in Immune Suppression of CLL Cells |  | up to 3 months | 
| Effectiveness of Ibrutinib Bridging Patients to Allogeneic Stem Cell Transplant and Outcome of Patients Following This Intervention | The number of participants with successful Allogenic Stem Cell Transplant | Up to 2 years | 
| Cancer-Specific Stress as Measured by the Impact of Event Scale-Revised (IES-R) | Cancer-Specific Stress was measured by the Impact of Event Scale-Revised Participants rated the intensity of these feelings using a five-point Likert scale ranging from 0=not at all to 4=extremely. Patients rated the frequency of their feelings or events for the previous week before treatment. The items were summed for a total score that ranged from 0 to 64 | Up to 2 years | 
| Cognitive-Affective Depressive Symptoms as Measured by the Beck Depression Inventory-2nd Edition (BDI-II) | The Beck Depression Inventory-2nd edition is a 21-item measure of depressive symptoms. Scores were calculated representing the cognitive-affective and the somatic symptoms associated with depression (e.g. sadness, pessimism, loss of pleasure) during past month on scale from 0 to 3. Items were summed, with higher scores indicating more depressive symptoms. The scores on the scale from range from 0 to 42. | at 5 months | 
| Negative Mood Quality of Life Measured by a 37-item Questionnaire | The Profile of Mood States-Short Form (POMS-SF) yields six subscales, Tension, Depression, Anger, Vigor, Fatigue, and Confusion. A total mood disturbance score is found by summing the six subscales. Total Mood Disturbance (TMD) scores range from -24 to 124 with higher scores indicating greater mood disturbance. | at 5 months | 
| Mental Health Quality of Life Was Measured by the Mental Component Summary Score of the Medical Outcomes Study | SF-12 assesses aspects of quality of life including physical functioning, role functioning-physical, bodily pain, general health perceptions, vitality, social functioning, role functioning-emotional, and mental health. Subscale raw scores are transformed to put each subscale on a 0-100 range with higher scores indicative of greater functioning. Subscale scores are standardized based on US General Population norms and aggregated based on factor score coefficients into two component scores: the Physical Component Summary (PCS) and the Mental Component Summary (MCS). Component scores are norm-based t-scores meaning scores above 50 indicate better functioning than average functioning while scores below 50 indicate worse functioning. | at 5 months | 
| Fatigue Symptom Inventory (FSI) Interference Quality of Life as Measured by a 11-item Total Disruption Index Sub Scale of Fatigue Symptoms Inventory | The Fatigue Interference quality of life measures is a 11-item self reported questionnaire used to measure frequency, severity and daily pattern of fatigue Symptoms as well as impact of QOL in the past week. The Total Disruption Index (TDI) an 7 item subset of FSI was used. Items were rated on a 11-point Likert scale from 0=no interference to 10=extreme interference. Total scores could range from 0 to 70, with higher scores indicating greater fatigue interference. | at 5 months | 
| Sleep Through Quality of Life as Measured by a Medical Outcomes Study-Sleep Scale | Sleep problems quality of life measures is a six-item sleep problems index I of the Medical Outcomes Study-Sleep Scale used to assess sleep problems. Participants reported how often they experience six specific difficulties with sleep on a 6-point Likert scale (1=All of the time to 6=None of the time). Scores transformed into a 0-100 scale with higher scores indicating greater sleep problems. | at 5 months | 
| Physical Health Quality of Life as Measured by a 12 Item Short-Form Health Survey | Physical Health Quality of life measures were administered during screening and on Days 1 (±3), of Cycle 1, Day 1 (±3), of Cycle 2 and on day 1 (±7) of Cycles 3, 6, and then every 3 months thru Cycle 24 and at time of progression and /or end of treatment. SF-12 assesses aspects of quality of life including physical functioning, role functioning-physical, bodily pain, general health perceptions, vitality, social functioning, role functioning-emotional, and mental health. Subscale raw scores are transformed to put each subscale on a 0-100 range with higher scores indicative of greater functioning. Subscale scores are standardized based on US General Population norms and aggregated based on factor score coefficients into two component scores: the Physical Component Summary (PCS) and the Mental Component Summary (MCS). Component scores are norm-based t-scores meaning scores above 50 indicate better functioning than average functioning while scores below 50 indicate worse functioning. | up to 5 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Bruton's Tyrosine Kinase, CLL, SLL, B-PLL