Clinical trial NCT02160015 (phase 1, status: active, not recruiting)
Conditions: ann arbor stage iii small lymphocytic lymphoma, ann arbor stage iv small lymphocytic lymphoma, recurrent chronic lymphocytic leukemia, recurrent small lymphocytic lymphoma, refractory chronic lymphocytic leukemia, refractory small lymphocytic lymphoma, stage iii chronic lymphocytic leukemia, stage iv chronic lymphocytic leukemia
ICD codes: A87.2, K52.832, D72.111, C91.11, C91.12, C91.10, S33.110S, S33.111S, S33.120S, S33.121S, S33.130S, S33.131S, S33.140S, A87.2, K52.832, D72.111, C91.11, C91.12, C91.10, C91.11, C91.12, C91.10, C91.11, C91.12, C91.10
Drugs: ibrutinib, lenalidomide
SMILES: NC1=NC=NC2=C1C(=NN2[C@@H]1CCCN(C1)C(=O)C=C)C1=CC=C(OC2=CC=CC=C2)C=C1, NC1=CC=CC2=C1CN(C1CCC(=O)NC1=O)C2=O
Eligibility criteria:

        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)