A Study of Ulocuplumab And Ibrutinib in Symptomatic Patients With Mutated CXCR4 Waldenstrom's Macroglobulinemia

Inclusion Criteria:

* Clinicopathological diagnosis of Waldenstrom's Macroglobulinemia and meeting criteria for treatment using consensus panel criteria from the Second International Workshop on Waldenstrom's macroglobulinemia (Kyle et al, 2003) or have high risk disease with an serum IgM level of 6,000 mg or higher (Gustine et al, 2016).
* MYD88 and CXCR4 mutated disease (determined by Treon laboratory or molecular diagnostics laboratory).
* Measurable disease, defined as presence of serum immunoglobulin M (IgM) with a minimum IgM level of \>2 times the upper limit of normal of each institution is required.
* Age ≥ 18 years
* ECOG performance status \< or = 2 (see Appendix A.).
* To establish eligibility, participants must have adequate organ and marrow function as defined below:

  * Absolute neutrophil count ≥ 1,000/uL
  * Platelets ≥ 75,000/uL
  * Hemoglobin ≥ 8 g/dL
  * Total bilirubin ≤ 1.5 mg/dL or \< 2 mg/dL if attributable to hepatic infiltration by neoplastic disease or Gilbert's syndrome
  * AST(SGOT)/ALT(SGPT) ≤ 2.5 × institutional upper limit of normal
  * Creatinine ≤ 2 mg/dL
* Not on any active therapy for other malignancies with the exception of topical therapies for basal cell or squamous cell cancers of the skin.
* Females of childbearing potential (FCBP) must agree to use two reliable forms of contraception simultaneously or have or will have complete abstinence from heterosexual intercourse during the following time periods related to this study: 1) while participating in the study; and 2) for at least 28 days after discontinuation from the study. Men must agree to use a latex condom during sexual contact with a FCBP even if the participants have had a successful vasectomy. FCBP must be referred to a qualified provider of contraceptive methods if needed. FCBP must have a negative serum pregnancy test at screening.
* Able to adhere to the study visit schedule and other protocol requirements.
* Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

* Any serious medical condition, laboratory abnormality, uncontrolled intercurrent illness, or psychiatric illness/social condition that would prevent study participation.
* Concurrent use of any other anti-cancer agents or treatments or any other investigational agents.
* Treatment with strong CYP3A4/5 and/or CYP2D6 inhibitors
* Prior exposure to ibrutinib or ulocuplumab
* With the exception of low-dose aspirin, subjects enrolled in this study should not take concomitant medications that durably inhibit platelet function including marine oil tablets. For such medications a wash-out period of ≥ 7 days is required prior to starting treatment. Agents which inhibit platelet function transiently or inhibit coagulation by other mechanisms are restricted (e.g. use with caution). Medications that directly and durably inhibit platelet function include aspirin containing combinations, clopidogrel, dipyridamole, tirofiban, epoprostenol, eptifibatide, cilostazol, abciximab, ticlopidine, cilostazol.
* Participants should not take drugs that directly and durably inhibit coagulation with the exception of warfarin (coumadin) and heparin including low-molecular-weight heparin (LMWH), including enoxaparin, tinzaparin, etc.
* Any condition, including the presence of laboratory abnormalities, which places the participant at unacceptable risk if he/she were to participate in the study or confounds the ability to interpret data from the study.
* Known CNS lymphoma.
* New York Heart Association classification III or IV heart failure.
* Known history of Human Immunodeficiency Virus (HIV), active infection with Hepatitis B Virus (HBV), and/or Hepatitis C Virus (HCV).
* Lactating or pregnant women.
* Grade \> 2 toxicity (other than alopecia) continuing from prior anti-cancer therapy.
* Inability to swallow capsules
* History of non-compliance to medical regimens.