Acalabrutinib and Rituximab for the Treatment of IgM Monoclonal Gammopathy of Undetermined Significance or Waldenstrom Macroglobulinemia Related Neuropathy

Inclusion Criteria

• Presence of an IgM monoclonal paraprotein on serum immunofixation electrophoresis
• Diagnosis of IgM monoclonal gammopathy of undetermined significance (MGUS) or Waldenstrom macroglobulinemia * Waldenstrom macroglobulinemia (WM) diagnostic criteria ** IgM monoclonal gammopathy of any concentration ** Bone marrow infiltration by small lymphocytes showing plasmacytoid/plasma cell differentiation ** Intertrabecular pattern of bone marrow infiltration ** Surface IgM+, CD5 +/-, CD10-, CD19+, CD20+, CD22+, CD23-, CD25+, CD27+, FMC7+, CD103-, CD138-immunophenotype *** Variations from this immunophenotypic profile can occur. However, care should be taken to satisfactorily exclude other lymphoproliferative disorders. This is most relevant in CD5+ cases, for which chronic lymphocytic leukemia and mantle cell lymphoma require specific exclusion 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 features on nerve conduction studies
• Modified Rankin Scale score of >= 1 with progressing symptoms or a score >= 2
• Eastern Cooperative Oncology Group (ECOG) =< 2
• Age >= 18 years
• Participants may not be on any active therapy for other malignancies with the exception of topical therapies for basal cell or squamous cell cancers of the skin
• Absolute neutrophil count >= 1,000/uL (no growth factor permitted within previous 7 days) (within 30 days prior to cycle 1 day 1)
• Platelets >= 100,000/uL (no platelet transfusions permitted within previous 7 days); patients may enroll below this threshold if not attributable to IgM MGUS or WM after consultation with Sponsor-Investigator. (within 30 days prior to cycle 1 day 1) * For participants with platelets < 100,000 uL deemed to be attributable to other causes than IgM MGUS or WM, platelets must be >= 50,000 uL (no platelet transfusions permitted)
• Hemoglobin >= 10 g/dL (transfusions permitted); patients may enroll below this threshold if not attributable to IgM MGUS or WM after consultation with Sponsor-Investigator. (within 30 days prior to cycle 1 day 1) * For participants with hemoglobin < 10 g/dL deemed to be attributable to other causes than IgM MGUS or WM, hemoglobin must be >= 7 g/dL (transfusions permitted)
• Total bilirubin < 1.5 x institutional upper limit of normal (ULN) unless directly attributable to Gilbert's syndrome (within 30 days prior to cycle 1 day 1)
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 × institutional ULN (within 30 days prior to cycle 1 day 1)
• Estimated glomerular filtration rate (GFR) >= 30 mL/min (within 30 days prior to cycle 1 day 1)
• International normalized ratio (INR) =< 2 x ULN and activated partial thromboplastin time (aPTT) =< 2 x ULN. Patients with INR and/or aPTT > 2 x ULN who have lupus anticoagulant may be enrolled (within 30 days prior to cycle 1 day 1)
• Females of childbearing potential (FCBP) must use highly effective contraception or 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 1 week after last dose of acalabrutinib and 12 months from last dose of rituximab/biosimilar or ofatumumab. FCBP must be referred to a qualified provider of contraceptive methods if needed. FCBP must have a negative serum pregnancy test at screening.
• Men must agree to use a latex condom during treatment and for up to 1 week after the last dose of acalabrutinib and 12 months after the last dose of rituximab/anti-CD20 antibody during sexual 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 consent document

Exclusion Criteria

• Serum IgM >= 4,000 mg/dL
• Waldenstrom macroglobulinemia meeting criteria for treatment using consensus panel criteria from the Second International Workshop on WM besides symptomatic peripheral neuropathy
• Prior exposure to chemotherapy, bruton tyrosine kinase (BTK) inhibitors or other therapies used for WM treatment, except steroids, intravenous immune globulin (IVIG), or anti-CD20 antibodies that were administered > 90 days prior to first dose of study drug
• Concurrent participation in another therapeutic clinical trial
• History of or ongoing confirmed progressive multifocal leukoencephalopathy (PML)
• Participants with marginal zone lymphoma (MZL), chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), IgM Myeloma or amyloid light-chain (AL) amyloidosis are excluded
• Uncontrolled autoimmune hemolytic anemia (AIHA) or idiopathic thrombocytopenic purpura (ITP)
• Presence of a gastrointestinal ulcer diagnosed by endoscopy within 3 months prior to screening
• Prior hypersensitivity, anaphylaxis, or intolerance to rituximab/biosimilar and ofatumumab, or acalabrutinib, including active product or excipient components
• Vaccination with a live vaccine within 4 weeks prior to first dose of rituximab and acalabrutinib
• Prior or concurrent active malignancy within the past 2 years, except for curatively treated basal or squamous cell skin cancer, carcinoma in situ of the cervix or breast, or localized prostate cancer
• Any condition, including the presence of laboratory abnormalities, which places the participant at unacceptable risk if he/she were to participate in the study
• Known history of neuropathy attributed to an etiology other than IgM-mediated neuropathy
• The use of strong CYP3A inhibitors within 1 week or strong CYP3A inducers within 3 weeks of the first dose of study drug is prohibited
• Participants with chronic liver disease and hepatic impairment meeting Child-Pugh class C
• Requires or receiving anticoagulation with warfarin or equivalent vitamin K antagonists
• 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’s disease or hemophilia)
• History of significant cerebrovascular disease/event, including stroke or intracranial hemorrhage, within 6 months prior to the first dose of study drug
• Major surgery within 4 weeks of first dose of study drug * Note: If a participant had major surgery, they must have recovered adequately from any toxicity and/or complications from the intervention before the first dose of study drug
• Malabsorption syndrome or other condition that precludes enteral route of administration
• Female participants who are pregnant, breastfeeding, or planning to become pregnant while enrolled in this study or within 1 week of last dose of study drug acalabrutinib, or 12 months of last dose of rituximab/biosimilar or ofatumumab
• 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 * Note: participants with controlled, asymptomatic atrial fibrillation are allowed to enroll on study
• 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, are eligible if HBV deoxyribonucleic acid (DNA) is undetectable and if they are willing to undergo monitoring for HBV reactivation throughout the study * Patients with presence of HCV antibody are eligible if HCV ribonucleic acid (RNA) is undetectable and 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 active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
• Unwillingness or inability to comply with the protocol