Lenalidomide, Ibrutinib, and Rituximab in Treating Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma That Is Metastatic or Cannot Be Removed by Surgery
Lenalidomide, Ibrutinib, and Rituximab in Treating Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma That Is Metastatic or Cannot Be Removed by Surgery
This phase I trial studies the side effects and best dose of lenalidomide when given together
 with ibrutinib and rituximab in treating patients with chronic lymphocytic leukemia or small
 lymphocytic lymphoma that has come back (relapsed), has not responded well to prior
 treatments (refractory), has spread to other parts of the body (metastatic), or cannot be
 removed by surgery. Biological therapies, such as lenalidomide, use substances made from
 living organisms that may stimulate or suppress the immune system in different ways and stop
 cancer cells from growing. Ibrutinib may stop the growth of cancer cells by blocking some of
 the enzymes needed for cell growth. Rituximab is a monoclonal antibody that may interfere
 with the ability of tumor cells to grow and spread. Giving lenalidomide together with
 ibrutinib and rituximab may kill more cancer cells.
PRIMARY OBJECTIVE:

 I. To determine the recommended phase II doses of lenalidomide and ibrutinib for combination
 with rituximab in previously treated chronic lymphocytic leukemia and small lymphocytic
 lymphoma.

 SECONDARY OBJECTIVES:

 I. To determine the safety and tolerability of the combination of lenalidomide, ibrutinib and
 rituximab in previously treated chronic lymphocytic leukemia and small lymphocytic lymphoma.

 II. To describe any preliminary evidence of antitumor activity of the combination of
 lenalidomide, rituximab and ibrutinib in previously treated chronic lymphocytic leukemia and
 small lymphocytic lymphoma as defined by response rate, duration of response, and
 progression-free survival.

 III. To observe and record anti-tumor activity.

 OUTLINE: This is a dose-escalation study of lenalidomide.

 Patients receive rituximab intravenously (IV) on day 1 (up to 6 cycles), lenalidomide orally
 (PO) once daily (QD) on days 1-21 (up to 12 cycles), and ibrutinib PO QD on days 1-28. Cycles
 repeat every 28 days in the absence of disease progression or unacceptable toxicity.

 After completion of study treatment, patients are followed up at 30 days and every 6 months
 for 10 years.
Inclusion Criteria:

 -  Patients must have histologically confirmed malignancy that is metastatic or
 unresectable and for which standard curative or palliative measures do not exist or
 are no longer effective; previously treated, pathologically confirmed chronic
 lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) that requires as per
 the National Cancer Institute (NCI) Working Group Guidelines for the treatment of CLL;
 the diagnosis of CLL is defined by the presence of 5 x 10^9 clonal B-lymphocytes/L in
 the peripheral blood; clonality of the lymphocyte population is established with flow
 cytometry and the demonstration of the following surface markers: CD5, CD23, CD19,
 CD20 and the presence of either kappa or lambda immunoglobulins; the diagnosis of SLL
 may be made with the demonstration of < 5 x 10^9 clonal B-lymphocytes/L in the
 peripheral blood, with the clinical or radiographic features of enlarged lymph nodes
 or organomegaly, and the demonstration of SLL cells in the lymph node biopsy;
 institutional flow cytometry or immunohistochemistry must confirm CD20 antigen
 expression; patients may not have had a history of Richter's transformation

 -  No prior systemic therapy for CLL or SLL including chemotherapy or immunotherapy
 (e.g., monoclonal antibody-based therapy), radiation therapy, within 4 weeks of
 enrollment; no prior carmustine (BCNU) or mitomycin C within 6 weeks of enrollment; no
 radioimmunotherapy within a year of enrollment; no corticosteroids administered within
 2 weeks prior to study entry, except for maintenance therapy (=< prednisone 20 mg
 daily or equivalent) for a non-malignant disease

 -  Patients may have had a prior autologous stem cell transplant; no prior history of
 allogeneic stem cell transplant

 -  Patients may have received prior lenalidomide as long as it has been at least two
 years since exposure and the patient may not have experienced a progression while
 receiving lenalidomide previously

 -  No Bruton's tyrosine kinase inhibitor at any point prior to enrollment

 -  No history of allergic reactions attributed to compounds of similar chemical or
 biologic composition to ibrutinib, lenalidomide or rituximab or hypersensitivity to
 murine proteins or to any component of rituximab

 -  Measurable disease must be present either on physical examination or imaging studies;
 non-measurable disease alone is not acceptable; any tumor mass > 1 cm is acceptable;
 lesions that are considered non-measurable include the following:

 -  Bone lesions (lesions if present should be noted)

 -  Ascites

 -  Pleural/pericardial effusion

 -  Lymphangitis cutis/pulmonis

 -  Bone marrow (involvement by SLL or CLL should be noted)

 -  No concomitant approved anti-cancer therapies or any investigational agents

 -  Patients with active or uncontrolled autoimmune hemolytic anemia or idiopathic
 thrombocytopenic purpura (ITP) are excluded; patients who have transfusion-dependent
 thrombocytopenia or bleeding/coagulation disorders that may increase the risk of
 life-threatening bleeding are excluded

 -  Eastern Cooperative Oncology Group (ECOG) performance status must be < 2

 -  Patients with human immunodeficiency virus (HIV) infection are eligible, provided they
 meet the following:

 -  No evidence of co-infection with hepatitis B or C

 -  CD4+ cell count >= 400/mm^3

 -  No evidence of resistant strains of HIV

 -  Patients with a prior diagnosis of CLL/SLL in central nervous system (CNS) are
 eligible only if the CNS disease has been treated; patients must be neurologically
 stable, without progressive symptoms while off of steroids and anti-convulsants; at
 least 28 days must have elapsed since CNS treatment, and the patient must have
 recovered from all associated toxicities of treatment; patients who have
 transfusion-dependent thrombocytopenia or bleeding/coagulation disorders that may
 increase the risk of life-threatening bleeding are excluded

 -  No evidence of active hepatitis B or C infections (hepatitis B surface antigen
 positive [HBsAg +], hepatitis B deoxyribonucleic acid [DNA] positive by polymerase
 chain reaction [PCR], or anti-hepatitis C virus [HCV] antibodies); hepatitis core
 antibody (HBcAb) seropositive patients that are HBsAg negative are eligible if they
 are closely monitored for evidence of active hepatitis B virus (HBV) infection by HBV
 DNA testing and receive suppressive therapy with lamivudine or other HBV suppressive
 therapy until 6 months after the last rituximab dose

 -  Patients must be non-pregnant and non-nursing; the effects of ibrutinib on the
 developing human fetus are unknown; for this reason and because B- cell receptor
 kinase inhibitors agents as well as other therapeutic agents used in this trial are
 known to be teratogenic, women of child-bearing potential and men must agree to use
 two forms of contraception (hormonal or barrier method of birth control; abstinence)
 prior to study entry and for the duration of study participation

 -  Should a woman become pregnant or suspect she is pregnant while she or her partner is
 participating in this study, she should inform her treating physician immediately; men
 treated or enrolled on this protocol must also agree to use adequate contraception
 prior to the study, for the duration of study participation, and for at least 3 days
 after discontinuation of ibrutinib, 28 days after discontinuation of lenalidomide, and
 12 months after discontinuation of rituximab

 -  Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy
 test with a sensitivity of at least 25 mIU/mL within 10-14 days and again within 24
 hours prior to starting cycle 1 of lenalidomide; further, they must either commit to
 continued abstinence from heterosexual intercourse or begin TWO acceptable methods of
 birth control: one highly effective method and one additional effective method AT THE
 SAME TIME, at least 28 days before starting lenalidomide; FCBP must also agree to
 ongoing pregnancy testing; men must agree to use a latex condom during sexual contact
 with a FCBP, even if they have had a successful vasectomy; a FCBP is a sexually mature
 woman who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has
 not been naturally postmenopausal for at least 24 consecutive months (i.e., has had
 menses at any time in the preceding 24 consecutive months); all patients must be
 counseled by a trained counselor every 28 days about pregnancy precautions and risks
 of fetal exposure

 -  Contraception is recommended for 28 days prior to starting therapy, while
 participating in this study, during dose interruptions, and for at least 3 days after
 discontinuation of ibrutinib, 28 days after discontinuation of lenalidomide, and 12
 months after discontinuation of rituximab

 -  No history of known human anti-chimeric antibody (HACA) positivity; this does not have
 to be checked prior to enrollment unless clinically indicated

 -  Life expectancy must be greater than 60 days

 -  No history of erythema multiforme, toxic epidermal necrolysis or Stevens-Johnson
 syndrome

 -  No history of uncontrolled seizures

 -  No autoimmune disorder that requires active immunosuppression

 -  No stroke or intracranial hemorrhage within the last 6 months

 -  No major surgery within 28 days prior to treatment; no minor surgery within 5 days
 prior to treatment

 -  No history of a congestive heart failure, myocardial infarction, unstable angina,
 uncontrolled arrhythmia, or any class 3 or 4 cardiac disease as defined by the New
 York Heart Association Functional Classification in the last 6 months

 -  No uncontrolled intercurrent illness including, but not limited to: ongoing or active
 infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
 arrhythmia, or psychiatric illness/social situations that would limit compliance with
 study requirements

 -  No prior malignancy with the exceptions listed below:

 -  Malignancy treated with curative intent and with no evidence of active disease
 for more than 3 years prior to screening and felt to be at low risk (< 30%) for
 recurrence by the treating physician

 -  Adequately treated non-melanomatous skin cancer or lentigo maligna melanoma
 without current evidence of disease

 -  Adequately treated cervical carcinoma in situ without current evidence of disease

 -  No use of warfarin or similar vitamin K antagonists

 -  No oral or intravenous corticosteroid use within 2 weeks prior to study entry

 -  Inhaled steroids are permitted

 -  Patients unable to swallow capsules, or disease significantly affecting
 gastrointestinal function and/or inhibiting small intestine absorption, such as
 malabsorption syndrome, resection of the small bowel, or poorly controlled
 inflammatory bowel disease affecting the small intestine are ineligible

 -  Patients should not receive growth factors or transfusions for at least 7 days prior
 to first dose of study drug, with the exception of pegylated G-CSF (pegfilgrastim) and
 darbopoeitin which require at least 14 days prior to screening and randomization

 -  Absolute neutrophil count > 750 cells/mcL (0.75 x 10^9/L)

 -  Platelet count > 50,000 cells/mcL (50 x 10^9/L)

 -  Hemoglobin > 8.0 g/dL

 -  Total bilirubin =< 1.5 x upper limit of normal (ULN) (unless Gilbert's syndrome or
 disease infiltration of the liver is present)

 -  Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
 [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
 =< 3.0 x institutional ULN

 -  Creatinine clearance estimated (est.) glomerular filtration rate (GFR) >= 30
 mL/min/1.73 m^2 (Cockcroft-Gault)

 -  Prothrombin time (PT)/international normalized ratio (INR) =< 1.5 x ULN and partial
 thromboplastin time (PTT) (activated partial thromboplastin time [aPTT]) < 1.5 x ULN

 -  A minimum organ function requirement may be waived if the malignancy being treated has
 involvement of the relevant organ

 Exclusion Criteria:

 -  Chemotherapy =< 21 days prior to first administration of study treatment and/or
 monoclonal antibody =< 6 weeks prior to first administration of study treatment

 -  Prior exposure to a Bruton's tyrosine kinase (BTK) inhibitor

 -  Patients with known brain metastases should be excluded from this clinical trial
 because of their poor prognosis and because they often develop progressive neurologic
 dysfunction that would confound the evaluation of neurologic and other adverse events

 -  History of allergic reactions attributed to compounds of similar chemical or biologic
 composition to ibrutinib

 -  Patients who received a strong cytochrome P450 (CYP) 3A inhibitor within 7 days prior
 to the first dose of ibrutinib or patients who require continuous treatment with a
 strong CYP3A inhibitor

 -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active
 infection or an infection requiring systemic antibiotics, symptomatic congestive heart
 failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social
 situations that would limit compliance with study requirements; recent infections
 requiring systemic treatment need to have completed therapy > 14 days before the first
 dose of study drug

 -  Pregnant and breastfeeding women are excluded from this study; pregnant women are
 excluded in this study because ibrutinib is a tyrosine kinase inhibitor with the
 potential for teratogenic or abortifacient effects; because there is an unknown but
 potential risk for adverse events in nursing infants secondary to treatment of the
 mother with ibrutinib, breastfeeding should be discontinued if the mother is treated
 with ibrutinib

 -  Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral
 therapy are eligible; unless the patient's CD4 count is below the institutional lower
 limit of normal

 -  Uncontrolled autoimmune hemolytic anemia or idiopathic thrombocytopenic purpura (ITP)
 resulting in (or as evidenced by) declining platelet or hemoglobin (Hgb) levels within
 the 4 weeks prior to first dose of study drug

 -  Presence of transfusion-dependent thrombocytopenia

 -  Patients requiring daily corticosteroids at a prednisone equivalent of >= 20 mg daily
 should not be enrolled; if corticosteroids can be discontinued (or reduced to < 20 mg
 per day of prednisone or equivalent), the discontinuation or dose reduction should be
 done at least 7 days prior to first dose

 -  History of prior malignancy, with the exception of the following:

 -  Malignancy treated with curative intent and with no evidence of active disease
 present for more than 3 years prior to screening and felt to be at low risk for
 recurrence by treating physician

 -  Adequately treated non-melanomatous skin cancer or lentigo maligna melanoma
 without current evidence of disease

 -  Adequately treated cervical carcinoma in situ without current evidence of disease

 -  Currently active clinically significant cardiovascular disease such as uncontrolled
 arrhythmia, congestive heart failure, or class 3 or 4 congestive heart failure as
 defined by the New York Heart Association Functional Classification, or history of
 myocardial infarction, unstable angina, or acute coronary syndrome within 6 months
 prior to randomization

 -  Unable to swallow capsules, or disease significantly affecting gastrointestinal
 function, or resection of the stomach or small bowel, symptomatic inflammatory bowel
 disease or ulcerative colitis, or partial or complete bowel obstruction

 -  Serologic status reflecting active hepatitis B or C infection; patients that are
 positive for hepatitis B core antibody, hepatitis B surface antigen (HBsAg), or
 hepatitis C antibody must have a negative polymerase chain reaction (PCR) prior to
 enrollment; (PCR positive patients will be excluded)

 -  History of stroke or intracranial hemorrhage within 6 months prior to enrollment

 -  Any life-threatening illness, medical condition, or organ system dysfunction that, in
 the investigator's opinion, could compromise the patient's safety, or put the study at
 undue risk

 -  Concomitant use of warfarin or other vitamin K antagonists

 -  Concurrent systemic immunosuppressant therapy other than corticosteroids (e.g.,
 cyclosporine A, tacrolimus, etc.) within 28 days of the first dose of study drug

 -  Vaccinated with live, attenuated vaccines within 4 weeks of first dose of study drug

 -  Unresolved toxicities from prior anti-cancer therapy, defined as having not resolved
 to Common Terminology Criteria for Adverse Event (CTCAE, version 4), grade =< 1, or to
 the levels dictated in the inclusion/exclusion criteria with the exception of alopecia

 -  Known bleeding disorders (e.g., von Willebrand's disease) or hemophilia

 -  Major surgery within 4 weeks of first dose of study drug

 -  Unwilling or unable to participate in all required study evaluations and procedures

 -  Currently active, clinically significant hepatic impairment (>= moderate hepatic
 impairment according to the NCI/Child Pugh classification)