ACALA-R In Predominantly Demyelinating IgM Mediated Neuropathy

Inclusion Criteria:

• Participants must meet the following criteria on screening examination to beeligible to participate. Screening evaluations including consent, physical exam, andlaboratory assessments will be done within 30 days prior to Cycle 1 Day 1. Bonemarrow biopsy &aspirate, skin (fat) biopsy, EMG, and CT C/A/P will be done within 90days prior to Cycle1 Day 1.

• Presence of an IgM monoclonal paraprotein on serum immunofixation electrophoresis

• Diagnosis of IgM MGUS or Waldenstrӧm macroglobulinemia using the criteria from OwenRG, Treon SP, Al-Katib A, Fonseca R, Greipp PR, McMaster ML, etal.Clinicopathological definition of Waldenstrom's macroglobulinemia: consensuspanel recommendations from the Second International Workshop on Waldenstrom'sMacroglobulinemia. Semin Oncol. 2003. 30(2): 110-5.

• WM diagnostic criteria

• IgM monoclonal gammopathy of any concentration

• Bone marrow infiltration by small lymphocytes showing plasmacytoid/plasmacell differentiation

• Intertrabecular pattern of bone marrow infiltration

• Surface IgM+, CD5 +/-, CD10-, CD19+, CD20+, CD22+, CD23-, CD25+, CD27+, FMC7+,CD103-, CD138- immunophenotype* --- Variations from this immunophenotypicprofile can occur. However, care should be taken to satisfactorily excludeother lymphoproliferative disorders. This is most relevant in CD5+ cases, forwhich chronic lymphocytic leukemia and mantle cell lymphoma require specificexclusion before a diagnosis of WM can be made.

• IgM MGUS diagnostic criteria

• IgM monoclonal gammopathy of any concentration

• No bone marrow infiltration

• Presence of predominantly sensory neuropathy with predominant demyelinating featureson nerve conduction studies.

• Modified Rankin Scale score of ≥1 with progressing symptoms or a score ≥2

• ECOG ≤2

• Age > 18 years

• Participants may not be on any active therapy for other malignancies with theexception of topical therapies for basal cell or squamous cell cancers of the skin

• At the time of screening, participants must have acceptable organ and marrowfunction as defined below:

• Absolute neutrophil count≥1,000/uL (no growth factor permitted within previous 7 days)

• Platelets ≥100,000/uL (no platelet transfusions permitted within previous 7days); patients may enroll below this threshold if not attributable to IgM MGUSor WM after consultation with Sponsor-Investigator.

• For participants with platelets <100,000 uL deemed to be attributable to othercauses than IgM MGUS or WM, platelets must be ≥50,000 uL (no platelettransfusions permitted)

• Hemoglobin ≥ 10 g/dL (transfusions permitted); patients may enroll below thisthreshold if not attributable to IgM MGUS or WM after consultation withSponsor-Investigator.

-- For participants with hemoglobin <10 g/dL deemed to be attributable to othercauses than IgM MGUS or WM, hemoglobin must be ≥7 g/dL(transfusions permitted)

• Total bilirubin < 1.5 x institutional ULN

• AST(SGOT)/ALT(SGPT) ≤2.5 × institutional ULN

• Estimated GFR ≥30 mL/min

• International normalized ratio (INR) ≤ 2 x ULN and activated partial thromboplastintime (aPTT) ≤ 2 x ULN. Patients with INR and/or aPTT >2 x ULN who have lupusanticoagulant may be enrolled.

• Females of childbearing potential (FCBP) must use highly effective contraception (see Appendix D) or have complete abstinence from heterosexual intercourse duringthe following time periods related to this study: 1) while participating in thestudy; and 2) for at least 1 week after last dose of acalabrutinib and 12 monthsfrom last dose of rituximab/biosimilar. FCBP must be referred to a qualifiedprovider of contraceptive methods if needed. FCBP must have a negative serumpregnancy test at screening.

• Men must agree to use a latex condom during treatment and for up to 1 week after thelast dose of acalabrutinib and 12 months after the last dose of rituximab duringsexual contact with a FCBP

• Ability to adhere to the study visit schedule and other protocol requirements

• Ability to understand and the willingness to sign a written informed consentdocument

Exclusion Criteria:

• Participants who exhibit any of the following conditions at screening will not beeligible for admission into the study:

• Serum IgM ≥4,000 mg/dL

• Waldenstrӧm macroglobulinemia meeting criteria for treatment using consensus panelcriteria from the Second International Workshop on WM besides symptomatic peripheralneuropathy.

• Prior exposure to chemotherapy, BTK inhibitors or other therapies used for WMtreatment, except steroids, IVIG, or anti-CD20 antibodies that were administered >90days prior to first dose of study drug

• Concurrent participation in another therapeutic clinical trial.

• Participants with marginal zone lymphoma (MZL), chronic lymphocytic leukemia (CLL),mantle cell lymphoma (MCL), IgM Myeloma or AL amyloidosis are excluded (Diagnosisbased on WHO Classification of Tumours of Hematopoietic and Lymphoid Tissues, S.H.Swerdlow, et al., Editors. 2017, IARC)

• Uncontrolled autoimmune hemolytic anemia (AIHA) or idiopathic thrombocytopenicpurpura (ITP)

• Presence of a gastrointestinal ulcer diagnosed by endoscopy within 3 months prior toscreening

• Prior hypersensitivity, anaphylaxis, or intolerance to rituximab/biosimilar andofatumumab, or acalabrutinib, including active product or excipient components

• Vaccination with a live vaccine within 4 weeks prior to first dose of rituximab.

• Prior or concurrent active malignancy within the past 2 years, except for curativelytreated basal or squamous cell skin cancer, carcinoma in situ of the cervix orbreast, or localized prostate cancer.

• Any condition, including the presence of laboratory abnormalities, which places theparticipant at unacceptable risk if he/she were to participate in the study

• Known history of neuropathy attributed to an etiology other than IgM-mediatedneuropathy

• Concurrent administration of medications that are moderate or strong inhibitors orinducers of CYP3A within 7 days prior to first dose of study drug

• Current, ongoing daily use of a proton pump inhibitor. Participants who switch toH2- receptor antagonists or antacids are eligible.

• Participants with chronic liver disease and hepatic impairment meeting Child-Pughclass C

• Requires or receiving anticoagulation with warfarin or equivalent vitamin Kantagonists

• Peripheral neuropathy symptoms that have been present for >5 years

• Known central nervous system lymphoma

• Active bleeding or history of bleeding diathesis (e.g., congenital von Willebrand'sdisease or hemophilia)

• History of significant cerebrovascular disease/event, including stroke orintracranial hemorrhage, within 6 months prior to the first dose of study drug

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

• Malabsorption syndrome or other condition that precludes enteral route ofadministration

• Female participants who are pregnant, breastfeeding, or planning to become pregnantwhile enrolled in this study or within 1 week of last dose of study drugacalabrutinib, or 12 months of last dose of rituximab/biosimilar.

• Male participants who plan to father a child while enrolled in this study or within 90 days after the last dose of study drug

• Significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias,congestive heart failure, or myocardial infarction within 6 months of screening

• New York Heart Association classification III or IV heart failure

• No active Human Immunodeficiency Virus (HIV) infection

• Active infection with Hepatitis B virus (HBV) or viral hepatitis C (HCV) as follows:

• Presence of hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb). Note: Patients with presence of HBcAb, but absence of HBsAg, areeligible if HBV DNA is undetectable and if they are willing to undergomonitoring for HBV reactivation throughout the study.

• Patients with presence of HCV antibody are eligible if HCV RNA is undetectableand if they are willing to undergo monitoring for HCV reactivation.

• No significant infection (eg bacterial, viral, or fungal) at study entry

• Inability to swallow pills

• Uncontrolled intercurrent illness including, but not limited to, ongoing or activeinfection, symptomatic congestive heart failure, unstable angina pectoris, cardiacarrhythmia, or psychiatric illness/social situations that would limit compliancewith study requirements

• Unwillingness or inability to comply with the protocol