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In this research study, is combining a new treatment acalabrutinib with a standard treatment, rituximab or other CD20 antibody, to determine whether this combination is safe and effective for participants with Immunoglobulin (Ig) M monoclonal gammopathy of undetermined significance ( IgM MGUS) or Waldenström macroglobulinemia WM related neuropathies.
The names of the study drugs involved in this study are/is:
Full description
This research study involves an experimental drug combination of a targeted therapy and a CD20 antibody.
The names of the study drugs involved in this study are/is:
The research study procedures include screening for eligibility and study treatment including evaluations and follow up visits.
The study treatment for up to 4 years and will be followed for 2 years after completion of study treatment.
It is expected that about 33 people will take part in this research study.
This research study is a Phase II clinical trial. Phase II clinical trials test the safety and effectiveness of an investigational drug to learn whether the drug works in treating a specific disease. "Investigational" means that the drug is being studied.
The U.S. Food and Drug Administration (FDA) has not approved acalabrutinib for this specific disease but it has been approved for other uses.
The U.S. Food and Drug Administration (FDA) has not approved rituximab or similar CD20 antibody for this specific disease but it has been approved for other uses.
Enrollment
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Inclusion criteria
Participants must meet the following criteria on screening examination to be eligible to participate. Screening evaluations including consent, physical exam, and laboratory assessments will be done within 30 days prior to Cycle 1 Day 1. Bone marrow biopsy &aspirate, skin (fat) biopsy, EMG, and CT C/A/P will be done within 90 days 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 Owen RG, Treon SP, Al-Katib A, Fonseca R, Greipp PR, McMaster ML, et al.Clinicopathological definition of Waldenstrom's macroglobulinemia: consensus panel recommendations from the Second International Workshop on Waldenstrom's Macroglobulinemia. Semin Oncol. 2003. 30(2): 110-5.
WM diagnostic criteria
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
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
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
At the time of screening, participants must have acceptable organ and marrow function as defined below:
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.
-- 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 ULN
AST(SGOT)/ALT(SGPT) ≤2.5 × institutional ULN
Estimated GFR ≥30 mL/min
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.
Females of childbearing potential (FCBP) must use highly effective contraception (see Appendix D) 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. 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 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
Participants who exhibit any of the following conditions at screening will not be eligible for admission into the study:
Serum IgM ≥4,000 mg/dL
Waldenstrӧm macroglobulinemia meeting criteria for treatment using consensus panel criteria from the Second International Workshop on WM besides symptomatic peripheral neuropathy.
Prior exposure to chemotherapy, BTK inhibitors or other therapies used for WM treatment, except steroids, IVIG, or anti-CD20 antibodies that were administered >90 days 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 (Diagnosis based 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 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.
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
Concurrent administration of medications that are moderate or strong inhibitors or inducers of CYP3A within 7 days prior to first dose of study drug
Current, ongoing daily use of a proton pump inhibitor. Participants who switch to H2- receptor antagonists or antacids are eligible.
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
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.
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:
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
Primary purpose
Allocation
Interventional model
Masking
12 participants in 1 patient group
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Central trial contact
Shayna R. Sarosiek, MD
Data sourced from clinicaltrials.gov
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