ACALA-R In Predominantly Demyelinating IgM Mediated Neuropathy

NCT05065554 | Active Not Recruiting Phase 2 DMC FDA Drug

• 1 other identifier: 21-439
• Study Type: interventional
• Target: 12
• Locations: 1 country
• Sites: 2

Brief Summary

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

Conditions

IgM MGUS; Waldenstrom Macroglobulinemia; Neuropathy;Peripheral

Keywords

IgM MGUS; Waldenstrom Macroglobulinemia

Outcome Measures

Primary Outcomes (1)

• Overall hematologic response rate

  defined as ≥25% reduction in serum IgM) during treatment compared to baseline in patients with IgM mediated symptomatic neuropathy treated with the combination acalabrutinib + rituximab (or biosimilar

  baseline to 6 years

Secondary Outcomes (18)

• Progression Free Survival

  Duration of time from start of treatment to time of objective disease progression (including initiation of new therapy or death) up to 6 years

• Time to next treatment

  Duration of time from start of treatment to next therapy or last follow-up up to 72 months

• Overall Survival

  Duration of time from start of treatment to time of death or last follow-up up to 72 months

• Complete Response Rate

  Duration of time from start of treatment to last follow-up up to 72 months.

• Bone marrow response

  Cycle 12, yearly up to 4 years

Study Arms (1)

ACALABRUTINIB + RITUXIMAB/BIOSIMILAR

EXPERIMENTAL

Acalabrutinib and rituximab (or biosimilar) with be contained in the treatment regimen. Acalabrutinib will be administered twice daily, with 28 consecutive days defined as a treatment cycle. Acalabrutinib will be administered for 48 cycles or until disease progression or unacceptable toxicity. Rituximab will be administered on Days 1, 8, 15, and 22 of Cycles 1 and 4. Participants will have study visits every cycle for cycles 1-6, then every 3 cycles, with the next visit at Cycle 9, then C12, C15, etc. Participants will continue acalabrutinib until disease progression or intolerable adverse effect develops. They will be followed for up to 2 years after completion of 48 cycles of treatment or until death

Drug: Acalabrutinib; Drug: Rituximab

Interventions

Acalabrutinib DRUG

Dose per protocol, oral twice daily per cycle

Also known as: Calquence

ACALABRUTINIB + RITUXIMAB/BIOSIMILAR

Rituximab DRUG

Premedications (including acetaminophen, an antihistamine, and a steroid) will be given per institutional guideline Dosage determined per protocol and cycle timepoint, Route IV or SQ per protocol and cycle timepoint, schedule per protocol and cycle timepoint

Also known as: Rituxan

ACALABRUTINIB + RITUXIMAB/BIOSIMILAR

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• 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
• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• Shayna Sarosiek, MD: lead
• AstraZeneca: collaborator

Study Sites (2)

Massachusetts General Hospital

Boston, Massachusetts, 02214, United States

Location

Dana Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

Related Publications (1)

• Nardin J, Dittus C, Traub R. Clinical and Electrodiagnostic Findings in Anti-myelin-Associated Glycoprotein Antibody Polyneuropathy: A Single Center Review. J Clin Neuromuscul Dis. 2025 Jun 2;26(4):200-205. doi: 10.1097/CND.0000000000000525.

  PMID: 40513035 DERIVED

MeSH Terms

Conditions

Waldenstrom Macroglobulinemia; Neuritis

Interventions

acalabrutinib; Rituximab

Condition Hierarchy (Ancestors)

Neoplasms, Plasma Cell; Neoplasms by Histologic Type; Neoplasms; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemorrhagic Disorders; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Peripheral Nervous System Diseases; Neuromuscular Diseases; Nervous System Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Shayna R. Sarosiek, MD

  Dana-Farber Cancer Institute

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Sponsor Investigator

Study Record Dates

• First Submitted: September 20, 2021
• First Posted: October 4, 2021
• Study Start: November 16, 2021
• Primary Completion (Estimated): December 1, 2026
• Study Completion (Estimated): October 1, 2028
• Last Updated: December 5, 2025

Record last verified: 2025-12

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP
• Time Frame: Data can be shared no earlier than 1 year following the date of publication
• Access Criteria: Contact the Belfer Office for Dana-Farber Innovations (BODFI) at innovation@dfci.harvard.edu

Locations

US (2)