Phase II study on Acalabrutinib and anti-CD20 antibody in Patients with Anti-MAG Mediated Neuropathy

Protocol # :
Waldenstrom Macroglobulinemia
Disease Sites
Other Hematopoietic
Multiple Myeloma
Principal Investigator
Castillo, Jorge, J
Site Research Nurses
Gammon, Marilyn
Lively, Kathleen, J.
Packer, Lisette, A.

Trial Description

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:

- Acalabrutinib

- Rituximab or similar CD20 antibody

Eligibility Requirements

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

- 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 anti-MAG antibodies

- 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:

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

- 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.

- 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

-- 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

- 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

- 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

- Presence of a gastrointestinal ulcer diagnosed by endoscopy within 3 months prior to

- 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

- 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

- 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

- 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:

- 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 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 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