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Criteria for inclusion |
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Patients must meet all of the following inclusion criteria to be eligible for participation |
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in this study |
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Local confirmed clinicopathological diagnosis of WM in accordance with the consensus |
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panel of the Second International Workshop on WM (Owen 2003) |
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WM patients with symptomatic and measurable disease (defined as presence of serum |
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For Arm B only: Previously untreated WM |
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immunoglobulin M (IgM)>0.5g/dL), requiring treatment as per mSMART guidelines (Kyle |
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For Arm C only: Have received at least one prior therapy, relapsed or refractory WM |
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): with B symptoms (fever, night sweats, fatigue, night sweats weight loss) |
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Adequate hematologic function defined as |
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progressive lymphadenopathy or splenomegaly, anemia (hemoglobin value of <10 g/dL) or |
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platelet count <100109/L due to marrow infiltration. Complications such as |
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hyperviscosity syndrome, symptomatic sensorimotor peripheral neuropathy due to WM |
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systemic amyloidosis related to WM, renal insufficiency related to WM, or symptomatic |
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Adequate hepatic and renal function defined as |
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cryoglobulinemia may also be indications for therapy |
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AST and ALT < 2.5 x ULN (upper limit of normal) |
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For Arm A only: Have received at least one prior therapy for WM. Patient must have |
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Glomerular filtration rate (GFR) >30mL/min |
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either failed (defined as progressing while on or within 6 months of treatment with |
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Bilirubin< 1.5 x ULN |
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ibrutinib treatment) or intolerant to ibrutinib |
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ANC ≥1.0 x 109/L independent of growth factor support within 7 days of the first |
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dose with study drug |
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Hemoglobin ≥9 g/dL without transfusion or growth factor support within 7 days of |
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the first dose of study drug |
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Platelet count ≥ 75 x 109/L without transfusion support within 7 days of the |
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first dose of study drug |
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Clinically relevant fatigue which is not relieved by rest due to WM |
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PT/INR ≤1.5 x ULN and PTT (aPTT) ≤1.5 x ULN |
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Symptomatic hyperviscosity or serum viscosity levels greater than 4.0 centipoises |
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≥18 years of age |
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Eastern Cooperative Oncology Group (ECOG) ≤1 |
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Symptomatic hepatomegaly and/or splenomegaly and/or organ tissue infiltration |
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Life expectancy≥3 months |
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Peripheral neuropathy due to WM |
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Female subjects who are of non-reproductive potential (i.e., post-menopausal by |
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Symptomatic cryoglobulinemia |
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history-no menses for ≥2 year; OR history of hysterectomy; OR history of bilateral |
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Cold agglutinin anemia |
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tubal ligation; OR history of bilateral oophorectomy). Female subjects of childbearing |
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IgM related immune hemolytic anemia and/or thrombocytopenia |
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potential must have a negative serum pregnancy test upon study entry |
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Nephropathy related to WM |
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Male and female subjects who agree to use highly effective methods of birth control |
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Amyloidosis related to WM |
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(e.g.,condoms, implants, injectables, combined oral contraceptives, some intrauterine |
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devices[IUDs], sexual abstinence, or sterilized partner) during the period of therapy |
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Platelet count <100 x109/L |
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and for 30 days after the last dose of study drug and 90 days (males) after the last |
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Serum monoclonal protein >5g/dL, with or without overt clinical symptoms |
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dose of study drug |
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Symptomatic disease meeting at least 1 of the recommendations from the Second International |
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Workshop on Waldenström Macroglobulinemia for requiring treatment (Kyle 2003) |
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Constitutional symptoms documented in the subject's chart with supportive objective |
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measures, as appropriate, defined as one or more of the following disease-related |
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symptoms or signs |
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Unintentional weight loss ≥10% within the previous 6 months prior to Screening |
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Fevers higher than 100.5°F or 38.0°C for 2 or more weeks prior to Screening |
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without evidence of infection |
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Night sweats for more than 1 month prior to Screening without evidence of |
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infection |
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Lymphadenopathy which is either symptomatic or bulky (≥5cm in maximum diameter) |
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Hemoglobin ≤10g/dL |
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Any other condition or circumstance that would, in the opinion of the investigator |
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make the patient unsuitable for participation in the study |
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Criteria for exclusion
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study
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For Arm A only: Patients who have never been treated with ibrutinib
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For Arm B only: Patients who have previously received any treatment for WM
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For Arm C only
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Patients who have previously been treated with ibrutinib or other BTK inhibitor
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Any uncontrolled active systemic infection
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Any concurrent malignancy
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Concomitant use of warfarin or other Vitamin K antagonists (eg. phenoprocoumon)
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Requires treatment with a strong cytochrome P450 (CYP) 3A inhibitor
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Known bleeding disorders (eg, von Willebrand's disease) or hemophilia
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History of stroke or intracranial hemorrhage within 12 months prior to enrollment
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Patients who meet any of the following exclusion criteria are not to be enrolled in this
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Disease that is refractory to the last prior rituximab based-therapy defined as
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either Relapse after the last rituximab-based therapy (<12 months since last dose
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of rituximab), OR Failure to achieve at least a MR after the last rituximab-based
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therapy
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Rituximab treatment within the last 12 months before the first dose of study
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drug
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Known anaphylaxis or IgE-mediated hypersensitivity to murine proteins or to any
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component of rituximab
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Patients with central nervous system involvement (Bing-Neel syndrome), active
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infection (including active hepatitis B or C virus infection, known human
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immunodeficiency virus (HIV) positive) or any other serious (unresolved) medical
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condition
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Plasmapheresis <35 days prior to the initiation of study drug. (Note: Subjects with
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high IgM values or hyper-viscosity symptoms during screening may receive
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plasmapheresis prior to initiating study drug if the previous plasmapheresis was
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performed >35 days before the plasmapheresis performed during screening (in order to
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obtain a true baseline IgM value for efficacy evaluations)
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Failure to have fully recovered (i.e., ≤Grade 1 toxicity) from the reversible effects
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of prior treatment for WM
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Significant screening electrocardiogram (ECG) abnormalities including left bundle
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branch block, 2nd degree atrioventricular (AV) block type II, 3rd degree block, or
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corrected QT interval (QTc) ≥470 msec
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Unable to swallow tablets or malabsorption syndrome, disease significantly affecting
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gastrointestinal function, or resection of the stomach or small bowel, symptomatic
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inflammatory bowel disease or ulcerative colitis, or partial or complete bowel
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obstruction
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History of active or chronic infection with hepatitis C virus (HCV) or hepatitis B
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virus (HBV) defined by positive polymerase chain reaction (PCR)
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Currently active, clinically significant cardiovascular disease, such as uncontrolled
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arrhythmia or Class 3 or 4 congestive heart failure as defined by the New York Heart
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Association Functional Classification; or a history of myocardial infarction, unstable
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angina, or acute coronary syndrome within 6 months prior to randomization
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Major surgical procedure within ≤14 days prior to initiating study treatment, or
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anticipation of the need for major surgery during the course of the study treatment
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radiotherapy ≤14 days prior to initiating study treatment, systemic treatment within
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days before the first dose of APG-2575
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Recent infection requiring systemic treatment that was completed≤14 days before the
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first dose of study drug
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