Ibrutinib in Treating Minimal Residual Disease in Patients With Chronic Lymphocytic Leukemia After Front-Line Therapy

Study Overview
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Brief Summary
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This phase II trial studies the side effects and how well ibrutinib works in treating patients with chronic lymphocytic leukemia who responded to initial treatment used to reduce a cancer (front-line therapy) but have residual disease. Ibrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

Detailed Description
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PRIMARY OBJECTIVES: I. Determine the rate of minimal residual disease (MRD)-negative responses (in both blood and bone marrow) at any time during treatment with ibrutinib maintenance. SECONDARY OBJECTIVES: I. Median time to achieve MRD- (negative) status (in blood and in bone marrow) after initiation of ibrutinib maintenance treatment. II. Toxicity profile of ibrutinib as maintenance therapy after frontline induction. III. Durability of the MRD- state (determined from the time of first documentation of MRD- until the first documentation of MRD+ (positive) (or last date shown to be MRD- for a censor). IV. Determine the number of patients who improve their remission category (i.e., upgrade clinical response achieved after the induction such as from partial response [PR] to complete response [CR]) after initiating the maintenance therapy. V. Time to requirement of next therapy for patients who achieve confirmed MRD- vs. those who remain MRD+ disease at 48 weeks (end of 12 cycles). VI. Progression free survival (as determined by the International Workshop on Chronic Lymphocytic Leukemia [IWCLL] criteria) among patients who achieve confirmed MRD- vs. those who remain MRD+ disease at 48 weeks (end of 12 cycles). TERTIARY OBJECTIVES: I. To conduct correlative studies for further understanding of the mechanism of antitumor activity of ibrutinib in eradication of the MRD. II. Determine the impact of ibrutinib on depression and anxiety symptoms to better understand toxicity profile of ibrutinib maintenance. III. Determine impact of social support or lack thereof on mood symptoms in chronic lymphocytic leukemia (CLL) patients receiving maintenance treatment. OUTLINE: Patients receive ibrutinib orally (PO) once daily (QD) on days 1-28. Treatment repeats every 4 weeks* for up to 36 courses in the absence of disease progression or unacceptable toxicity. Note: *The last course may last up to 56 days to accommodate the study drug discontinuation visit. After completion of study treatment, patients are followed up every 3-6 months for up to 2 years.

Official Title
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Minimal Residual Disease Eradication With Ibrutinib Therapy (MERIT) in Patients With Chronic Lymphocytic Leukemia After Frontline Therapy

Conditions
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Stage I Chronic Lymphocytic Leukemia, Stage II Chronic Lymphocytic Leukemia, Stage III Chronic Lymphocytic Leukemia, Stage IV Chronic Lymphocytic Leukemia

Intervention / Treatment
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* Drug: Ibrutinib
* Other: Laboratory Biomarker Analysis


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Understand and voluntarily sign an informed consent form Able to adhere to the study visit schedule and other protocol requirements including willing to provide blood, baseline bone marrow aspirate, and control deoxyribonucleic acid (DNA) samples for correlative research purposes Diagnosis of B-cell chronic lymphocytic leukemia (B-CLL), confirmed by flow cytometry and as per the criteria outlined by the IWCLL/Hallek December 2008 Prior frontline therapy for B-CLL must have been discontinued >= 56 days but =< 365 days prior to registration; NOTE: Patients on supportive care therapy due to use of specific induction regimen such as antibiotics may continue on those treatments at the discretion of the treating physician Patient must have completed a frontline induction therapy (minimum of 2 treatment cycles); NOTE: Standard therapies/therapeutic agents are defined as those listed in the National Comprehensive Cancer Network (NCCN) guidelines for treatment of CLL; also, patients who received induction regimen as part of a clinical trial and is not necessarily mentioned in the NCCN guidelines, will also be eligible as long as the patient has completed at least 2 treatment cycles of induction regimen, achieved a clinical response (PR or CR) and is able to meet all other criteria for the study; however, patients who have previously received ibrutinib or have been randomized to ibrutinib containing arms in a clinical trial will not be eligible for this study Patients must have a sustained clinical response (PR, nodular PR [nPR], complete clinical response [CCR], CR with incomplete marrow recovery [CRi], CR) with documented residual disease (>= 1 CLL cell per 10,000 leukocytes or >= 0.01% MRD) either in the blood, bone marrow or a lymph node >= 3.5 cm by any available techniques Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2 at registration Absolute neutrophil count >= 1000/mm^3 Platelet count >= 30,000/mm^3 Serum creatinine =< 1.5 x upper limit of normal (ULN) Total bilirubin =< 1.5 mg/dL or direct bilirubin =< 1.0 mg/dL for patients with Gilbert's syndrome Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) and serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 3.5 x ULN Negative pregnancy test done =< 7 days prior to registration, for women of childbearing potential only Exclusion Criteria: Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from signing the informed consent form Since this study involves an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown, any of the following will deem the subject ineligible for the study: Pregnant women Nursing women Men or women of childbearing potential who are unwilling to employ adequate contraception Any condition, including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study or confounds the ability to interpret data from the study Use of any other experimental drug or therapy =< 28 days prior to registration on this study; NOTE: Patients on low dose prednisone (=< 10 mg) for treatment of conditions other than CLL are eligible Patients who have received more than 1 prior therapy; NOTE: Prior therapy is defined as any single agent or combination regimen that is included as treatment for symptomatic CLL; treatment(s) given prior to the symptomatic phase of the disease (preventive strategy) will not be considered as prior induction therapy; for the purpose of a particular therapy/regimen to be counted towards the number of prior treatments a patient must have received at least 2 cycles of the induction regimen e.g., a patient who change their treatment regimen after only 1 cycle (due to toxicity or any other reason) will not be considered to have 2 prior therapies Patients who have progressive disease or relapse (as defined by the IWCLL criteria) at or any time before registration on this study Patients with history of any other cancer (except non-melanoma skin cancer or carcinoma in-situ of the cervix, unless in complete remission and off therapy for that disease for > 3 years) Patients who are already MRD- (both in the blood and the bone marrow) after frontline therapy and have lymph nodes < 3.5 cm Concomitant use of warfarin or other vitamin K antagonists Requires treatment with a strong cytochrome P450 modulators (cytochrome P450, family 3, subfamily A [CYP3A] inhibitor and/or CYP3A inducers) Currently active, clinically significant hepatic impairment Child-Pugh class B or C according to the Child Pugh classification Major surgery =< 4 weeks prior to registration Patients who have active infectious hepatitis Patients with other diseases that in the opinion of the treating physician pose a higher risk for treatment with ibrutinib therapy including active human immunodeficiency virus (HIV) infection and bleeding disorders

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 receive ibrutinib PO QD on days 1-28. Treatment repeats every 4 weeks* for up to 36 courses in the absence of disease progression or unacceptable toxicity. Note: *The last course may last up to 56 days to accommodate the study drug discontinuation visit. | Drug: Ibrutinib<br>* Given PO<br>* Other names: PCI-32765;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of confirmed MRD-negative response | A confirmed MRD-negative response is defined as an achievement of MRD-negative status in both the blood and the bone marrow on two consecutive evaluations at least 3 months apart. The proportion of successes will be estimated by the number of successes divided by the total number of evaluable patients. Ninety-five percent exact binomial confidence intervals for the true success proportion will be calculated. | Up to 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of MRD-negative response | The distribution of duration of MRD-negative response will be estimated using the method of Kaplan-Meier. | From the earliest date that the patient was noted as having MRD-negative response in both the blood and bone marrow until the first notation of MRD positive disease in the blood or the bone marrow, assessed up to 5 years | 
| Improvement in Clinical Response | The percentage of patients with improvement in clinical response will be calculated as the number of patients with an improvement in IWCLL response at any time during treatment compared to baseline divided by the number of evaluable patients with an objective status of PR or CR (MRD+) at baseline. Exact binomial 95% confidence intervals for the true percentage of patients with improvement in clinical response will be calculated. | Baseline to up to 5 years | 
| Incidence of adverse events | Platelets and hemoglobin will be graded according to the Grading Scale for Hematologic Adverse Events in CLL Studies. The maximum grade for each type of adverse event, regardless of causality, will be recorded and reported for each patient, and frequency tables will be reviewed to determine adverse event patterns. | Up to 30 days after the last day of study drug treatment | 
| Progression-free survival | A landmark analysis will be conducted to evaluate progression-free survival for patients who achieve a confirmed MRD-negative response in both the blood and bone marrow vs. those who remain MRD-positive, as assessed at 48 weeks (end of 12 cycles; +/- 4 weeks). Patients who discontinue treatment before 48 weeks are excluded from this analysis. The distribution of progression-free survival will be estimated using the Kaplan-Meier method and log-rank statistics will be utilized to evaluate differences between the two groups. | From the 48 week MRD evaluation until the time of disease progression per the IWCLL criteria or death due to any cause, assessed up to 5 years | 
| Time to MRD-negative response | Time to MRD-negative response will be summarized descriptively (median, range). | From the date of registration to the earliest date that the patient was noted as having MRD-negative response in both the blood and bone marrow, assessed up to 5 years | 
| Time to requirement of next therapy | A landmark analysis will be conducted to evaluate time to requirement of next therapy for patients who achieve a confirmed MRD-negative response in both the blood and bone marrow vs. those who remain MRD-positive, as assessed at 48 weeks (end of 12 courses; +/- 4 weeks). The distribution of time to requirement of next therapy will be estimated using the Kaplan-Meier method and log-rank statistics will be utilized to evaluate differences between the two groups. | From the 48 week MRD evaluation until the time of initiation of subsequent treatment for progressive CLL, assessed up to 5 years |