Ibrutinib After Intensive Induction in Treating Patients With Previously Untreated Mantle Cell Lymphoma

Study Overview
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Brief Summary
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This study is being done to see whether or not a drug called ibrutinib can be given to patients with mantle cell lymphoma (MCL) as maintenance therapy after induction chemotherapy. This drug blocks an enzyme that affects how the lymphocytes grow and survive. The investigators hope to learn how safe and effective ibrutinib is for treating patients with MCL after responding to induction chemotherapy.

Detailed Description
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PRIMARY OBJECTIVES: I. To determine the progression-free survival (PFS) rate after 2 years. SECONDARY OBJECTIVES: I. Assess toxicity. II. Determine rates of conversion from partial response (PR) to complete response (CR). III. Determine median overall survival (OS) after 4 years. TERTIARY OBJECTIVES: I. Compare minimal residual disease (MRD) results overtime by polymerase chain reaction (PCR) and correlate these with PFS and OS. OUTLINE: Patients receive ibrutinib orally (PO) once daily (QD) on days 1-28. Courses repeat every 28 days for up to 4 years in the absence of disease progression, unacceptable toxicity or patient preference. After completion of study treatment, patients who completed 4 years of treatment are followed up at 30 days. Patients who did not complete 4 years of treatment are followed up for up to 4 years post-first dose of treatment (every 3 months for 2 years and then every 6 months for 4 years).

Official Title
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A Phase II Clinical Trial Evaluating Ibrutinib Maintenance Following Intensive Induction for Patients With Previously Untreated Mantle Cell Lymphoma (MCL)

Conditions
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Contiguous Stage II Mantle Cell Lymphoma, Noncontiguous Stage II Mantle Cell Lymphoma, Stage I Mantle Cell Lymphoma, Stage III Mantle Cell Lymphoma, Stage IV Mantle Cell Lymphoma

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: Patients must have histologically confirmed mantle cell lymphoma (MCL) Please note: Measurable disease is not required, but will be followed if it exists Patients must have received 4 or more cycles of one of the following prior systemic induction chemotherapy regimens: Rituximab, cyclophosphamide, doxorubicin hydrochloride (hydroxydaunomycin), vincristine sulfate (Oncovin), prednisone (R-CHOP) (with or without alternating rituximab, dexamethasone, cytarabine [ara-c], cisplatin [platinum] [R-DHAP]) with or without autologous (auto) stem cell transplant (SCT) Hyper-cyclophosphamide, vincristine sulfate, doxorubicin hydrochloride (adriamycin), dexamethasone (CVAD) with or without auto SCT Bendamustine + rituximab with or without auto SCT Please note: Patients who received combinations of the above regimens are not eligible for enrollment At the time of registration, patients must be at least 14 days out from last dose of cytotoxic chemotherapy, but no more than 90 days; if a patient underwent auto SCT, he/she must demonstrate engraftment (per treating investigator's discretion) and must meet all other hematological requirements as outlined below Patients must have achieved a response to induction chemotherapy (either CR or PR by Cheson 2007 criteria) and be without known progression Patients may have received prior radiotherapy Patients must exhibit an Eastern Cooperative Oncology Group (ECOG) performance status =< 2 Absolute neutrophil count (ANC) >= 1000/mm^3, independent of growth factor support Platelets >= 100,000/mm^3, or >= 50,000 in cases of ongoing bone marrow involvement (in either case, these must be independent of transfusion support) Total bilirubin =< 1.5 x upper limit of normal (ULN) Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SPGT]) =< 3 x ULN Creatinine clearance >= 25 ml/min Please note: Patients who do not meet the above criteria because of Gilbert's Syndrome are still eligible Women of child-bearing potential (WOCBP) and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation (see timelines below for women and men); in addition, men must agree not to donate sperm during and after study participation; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately NOTE: For female patients, these restrictions apply for 1 month after the last dose of study drug; for male patients, these restrictions apply for 3 months after the last dose of study drug NOTE: A female of child-bearing potential is any woman (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria: Has not undergone a hysterectomy or bilateral oophorectomy; or Has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months) Female patients must have a negative pregnancy test (blood or urine) within 28 days prior to registration Patients must be willing and able to avoid consuming food and beverages containing grapefruit or Seville oranges while on ibrutinib study therapy Patients must have the ability to understand and the willingness to sign a written informed consent prior to registration on study Exclusion Criteria: Patients who have received >= 7 days of prior ibrutinib or any prior treatment with another Bruton tyrosine kinase (BTK) inhibitor are not eligible Patients receiving ongoing treatment with any other investigational agents are not eligible Patients receiving live/attenuated vaccinations within 4 weeks prior to registration are not eligible Patients with a known central nervous system (CNS) involvement of lymphoma are not eligible (CNS staging not required) Patients who have undergone major surgery within 4 weeks prior to registration are not eligible Patients diagnosed or treated for malignancy other than MCL are not eligible unless they meet one of the following exceptions: Malignancy treated with curative intent and with no known active disease present for >= 3 years before registration and felt to be at low risk for recurrence by the treating physician Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease Adequately treated cervical carcinoma in situ without evidence of disease Patients with a history of stroke or intracranial hemorrhage within 6 months prior to registration are not eligible Patients who require anticoagulation with warfarin or equivalent vitamin K antagonists are not eligible Patients who require chronic treatment with strong cytochrome P450, family 3, subfamily A, polypeptide 4/5 (CYP3A4/5) inhibitors are not eligible NOTE: Patients who are currently on treatment with strong CYP3A4/5 inhibitors may be eligible if they are able to be switched to an alternative therapy that is not a strong CYP3A4/5 inhibitor prior to registration on study Patients with a history of allergic reactions attributed to compounds of similar chemical or biologic composition to ibrutinib are not eligible Patients with uncontrolled intercurrent illness including, but not limited to, any of the following are not eligible: Ongoing or active systemic infection Symptomatic congestive heart failure Myocardial infarction within 6 months prior to registration Unstable angina pectoris Uncontrolled or symptomatic cardiac arrhythmias Any class 3 (moderate) or class 4 (severe) cardiac disease as defined by the New York Heart Association Functional Classification Psychiatric illness/social situations that would limit compliance with study requirements Patients who have 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 ibrutinib capsules, or put the study outcomes at risk are not eligible Patients with a known human immunodeficiency virus (HIV) infection are not eligible (HIV testing not required) Patients with a known John Cunningham (JC) virus infection and/or progressive multifocal leukoencephalopathy (PML) are not eligible Patients with clinically active hepatitis A, B, or C infections are not eligible Female patients who are pregnant and/or lactating are not eligible

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 orally PO QD on days 1-28. Courses repeat every 28 days for up to 4 years in the absence of disease progression, unacceptable toxicity, or patient preference. | 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 |
| --- | --- | --- |
| Determine the progression-free survival (PFS) rate after 2 years | PFS will be measured from start of treatment to time of progression. Evidence of clinical progression will be documented by imaging (CT scan) for patients who have measurable disease. | Assessed at 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of adverse events, defined according to the National Cancer Institute's Common Terminology Criteria for Adverse Events version 4.0 | To assess toxicity, all adverse events will be summarized as to type, severity, frequency, timing and attribution. | Up to 30 days after completion of study treatment, maximum 4 years post-first dose | 
| Rate of conversion from Partial Response (PR) to Complete Response (CR) | Progression will be evaluated using Cheson 2007 criteria, only patients who had a PR at the time of registration and who complete ≥ 1 complete cycle of ibrutinib maintenance therapy will be evaluable for this endpoint. | Up to 4 years | 
| Determine median Overall Survival (OS) after 4 years | Patients will be evaluated monthly for the first 6 months on treatment, then every 3 months thereafter. Patients who go off treatment will continue to be followed for up to 4 years post-first dose. Follow-up will occur every 3 months (up to 2 years after the first dose of treatment) and then every 6 months thereafter (up to 4 years post-first dose). Median OS after 4 years will be calculated. | Up to 4 years post-first dose |