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Waldenstrom MacroglobulinemiaPhase 2BRAWMNCT04624906

Bendamustine, Rituximab and Acalabrutinib in Waldenstrom's Macroglobulinemia

A Phase 2 study testing Acalabrutinib, Bendamustine and Rituximab in people with Waldenstrom Macroglobulinemia, run by Sunnybrook Health Sciences Centre at 9 sites in Canada.

Active, not recruiting

Under way, not looking for participants. Everyone needed has enrolled. The study is still running.

Official record
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Trial summary

This is a multi-centre, open label, single-arm, phase II clinical trial in untreated patients with Waldenstrom's Macroglobulinemia. Symptomatic, previously untreated patients will receive SOC bendamustine and rituximab for 6 28-day cycles. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Waldenstrom Macroglobulinemia
What is being tested?
Acalabrutinib, Bendamustine and Rituximab
Could I receive a placebo?
No, everyone receives an active treatment
How many people
63 participants
Where
9 sitesCanada
Study dates
2 Mar 2021to Mar 2030
Phase
Phase 2
Are there results?
Not yet: the study is under way

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Have biopsy proven Waldenstrom's macroglobulinemia, (biopsy from within 3 months (+/- 7 days) prior to Day 1).
  • Have not received any systemic treatment for the disease (plasmapheresis, involved field radiation or corticosteroids (for contrast enhanced studies and to acutely control disease-related symptoms or as chemotherapy premedication)) are allowed.
  • Be willing and able to provide written informed consent for the trial.
  • Male or female >=18 years of age on day of signing informed consent and of any racial or ethnic group.
  • Have at least one measurable site of disease based on Cheson Criteria (Appendix C) using standard CT imaging or a quantifiable IgM paraprotein that is two times the upper limit of normal.
  • Have symptomatic or impending symptomatic disease or evidence of hematologic or biochemical compromise related to the lymphoma.
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  • Have a performance status of 0-2 on the ECOG Performance Scale.
  • Demonstrate adequate organ function as defined in Table 2. Adequate organ function must be confirmed within 72 hours prior to start of treatment. Patients with abnormal liver enzymes of up to 5 times the upper limit of normal and/or reduced glomerular filtration rate (GFR) or estimated glomerular filtration rate (eGRF) of ≥ 30 mL/min/1.73 m2can be considered for enrolment.
  • A life expectancy > 6 months in the opinion of the investigator.
  • Female subject of childbearing potential should have a negative serum pregnancy test within 72 hours prior to receiving the first dose of study medication (day 1).
  • Female subjects of childbearing potential should be willing to use 2 highly effective methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study until 2 days post-last dose of acalabrutinib, 4 weeks post-last dose of bendamustine, and 12 months post-last dose of rituximab. Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year.
  • Male subjects should agree to use a highly-effective method of contraception starting with the first dose of study therapy until 2 days post-last dose of acalabrutinib, 6 months post-last dose of bendamustine, and 12 months post-last dose of rituximab.
  • Ability to comply with protocol requirements.

Who cannot join

  • Previous systemic therapy for WM (other than described in the inclusion criteria).
  • Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 21 days of the first dose of treatment (SD1).
  • Patient is being planned for consolidative autologous stem cell transplant (ASCT).
  • Is on warfarin anti-coagulation
  • Requires treatment with proton pump inhibitors (eg, omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole). Subjects receiving proton pump inhibitors who switch to H2-receptor antagonists or antacids 7 days prior to the start of treatment are eligible.
  • 5. Has clinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of screening, or any Class 3 or 4 cardiac diseases as defined by the New York Heart Association Functional Classification, or corrected QT interval (QTc) > 480 msec at screening. Subjects with controlled, asymptomatic atrial fibrillation during screening can enroll on study.
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  • 6. Has clinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of screening, or any Class 3 or 4 cardiac diseases as defined by the New York Heart Association Functional Classification, or corrected QT interval (QTc) > 480 msec at screening. Subjects with controlled, asymptomatic atrial fibrillation during screening can enroll on study.
  • 7. Has hypertension that cannot be controlled with anti-hypertensives. 8. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 35 days prior to the first dose of trial treatment (SD1), except that used as pre-medication for chemotherapy or contrast-enhanced studies are eligible. Subjects may be on physiologic doses of replacement prednisone or equivalent doses of corticosteroid (<10 mg daily).
  • 9. Has a known history of active TB (Bacillus Tuberculosis). 10. Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer.
  • 11. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for their CNS disease for at least 35 days prior to trial treatment.
  • 12. Has history of active autoimmune disease that has required systemic immune suppressive treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is allowed.
  • 13. Has known history of, or any evidence of active, non-infectious pneumonitis that has required treatment in the last five years.
  • 14. Has an active infection requiring systemic therapy. Note: Subjects completing a course of antibiotic for acute infection 7 days prior to SD1 and who do not experience a recurrence of symptoms or fever are eligible.
  • 15. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
  • 16. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
  • 17. Is breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with screening visit to 2 days post last dose of acalabrutinib, 4 weeks post last dose of bendamustine and 12 months post last dose of rituximab.
  • 18. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
  • 19. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., Hepatitis C Virus (HCV) RNA [qualitative] is detected). Evidence of Hepatitis B surface antigen or Hepatitis B DNA are exclusion criteria. Participants with positive hepatitis B core antibody (HBcAb) can be enrolled only if confirmatory negative Hepatitis B Virus (HBV) DNA levels is obtained by polymerase chain reaction (PCR) AND the patient is on Hepatitis B prophylaxis before the first dose of study drug.
  • 20. Serious intercurrent chronic or acute illness, such as hepatic disease, or other illness considered by the investigator as an unwarranted high risk for an investigational product.
  • 21. History of stroke or intracranial hemorrhage within 6 months before first dose of study drug.
  • 22. History of bleeding diathesis (e.g., hemophilia, von Willebrand disease). 23. Requires treatment with a strong cytochrome P450 3A (CYP3A) inhibitor or within 1 week or a strong CYP3A inducer within 3 weeks of the first dose of study drug is prohibited. boceprevir, clarithromycin, conivaptin, indinavir, itraconazole, ketoconazole, lopin/ritonavir combination, fluconazole, izavuconazole, mibefradil, nefazodone, nelfinavir, saquinavir, posaconazole, ritonavir, telaprevir, telithromycin, voriconazole, carbamazepine, phenytoin, rifampin or St. John's wort.
  • 24. Received a live virus vaccination within 28 days of first dose of study drug.
  • 25. Major surgical procedure within 30 days before the first dose of study drug. Note: if a subject had major surgery, they must have recovered adequately from any toxicity and/or complications from the intervention before the first dose of study drug.
  • 26. Refractory nausea and vomiting, inability to swallow the formulated product, or malabsorption syndrome; chronic gastrointestinal disease, gastric restrictions, or bariatric surgery such as gastric bypass partial or complete bowel obstruction, or previous significant bowel resection that would preclude adequate absorption, distribution, metabolism, or excretion of study treatment.

Trial locations and contacts

9 sites in 1 country.

9 sites in 1 country

Canada9 sites

  • Tom Baker Cancer Centre

    Calgary, Alberta

  • Cross Cancer Institute

    Edmonton, Alberta

  • QEII Health Sciences Centre

    Halifax, Nova Scotia

  • Hamilton Health Sciences Centre - Juravinksi

    Hamilton, Ontario

  • CHU de Quebec - University Laval

    Laval, Quebec

  • McGill University Health Centre

    Montreal, Quebec

  • The Ottawa Hospital

    Ottawa, Ontario

  • Sunnybrook Health Sciences Centre

    Toronto, Ontario, M4N 3M5

  • Vancouver General Hospital

    Vancouver, British Columbia

Other trials in Canada

About this study

Official title: A Multi-Center, Open-Label, Single-Arm Phase II Trial of Bendamustine, Rituximab and the Second Generation BTK Inhibitor Acalabrutinib in Previously Untreated Waldenstrom's Macroglobulinemia

This is a multi-centre, open label, single-arm, phase II clinical trial in untreated patients with Waldenstrom's Macroglobulinemia. Symptomatic, previously untreated patients will receive SOC bendamustine and rituximab for 6 28-day cycles. Bendamustine will be given intravenously at 90 mg/m2 on days 1 and 2 of each cycle. Rituximab will be given on day 1 of each cycle (375 mg/m2 intravenously for the first cycle and 1400 mg subcutaneously OR 375 mg/m2 intravenously for subsequent cycles (as per institutional procedures)). Concomitantly, participants will receive 100 mg of the investigational product, Acalabrutinib, orally for 1 year (365 days) at 100 mg BID.

Read the detailed description

This is a multi-centre, open label, single-arm, phase II clinical trial in untreated patients with WM. Patients will require a biopsy to confirm the pathology and molecular testing for MYD88, CXCR4 and P53 mutations. A bone marrow aspiration and biopsy will be performed to document WM and MRD. Participants will be classified into clinical risk categories based on the International Prognostic Scoring (IPS) System for WM. Symptomatic, previously untreated patients will receive SOC bendamustine and rituximab for 6 28-day cycles. Bendamustine will be given intravenously at 90 mg/m2 on days 1 and 2 of each cycle. Rituximab will be given on day 1 of each cycle (375 mg/m2 intravenously for the first cycle and 1400 mg subcutaneously OR 375 mg/m2 intravenously for subsequent cycles (as per institutional procedures)).

Concomitantly, participants will receive 100 mg of the investigational product, Acalabrutinib, orally for 1 year (365 days) at 100 mg BID. Patients will have pre-treatment computed tomography (CT) scans, and CT scans at 7, 12 and 18 months. Best objective response will be documented using the criteria from the Sixth International Workshop on Waldenstrom's Macroglobulinemia. Assessment of metabolic uptake by positron emission tomography (PET) scan is not considered appropriate for WM as WM usually do not take up fluorodeoxyglucose (FDG). Patients with WM will also have disease assessed using measurements of serum IgM, serum protein electrophoresis (SPE), immunofixation (IFA), and viscosity assessments measured serially. A bone marrow aspiration and biopsy will be done before treatment and at response assessment at cycle 6 and will be repeated if positive. Durability of response will also be assessed at 18 months.

Participants will be followed by extended follow-up by telephone for up to 6 years to obtain data on the secondary endpoints.

Being tested
Acalabrutinib, Bendamustine, Rituximab
Keywords
Waldenstrom Macroglobulinemia, WM, Acalabrutinib, Waldenstrom, Macroglobulinemia, BTK inhibitor, BTK, Bruton's Tyrosine Kinase, First line treatment, BRAWM
Medical subject headings
Waldenstrom Macroglobulinemia

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • AcalabrutinibDrug

    Also called Calquence

    100 mg oral capsules twice daily for 1 year

  • BendamustineDrug

    Also called Treanda

    90 mg/m2 on days 1 and 2 of each cycle.

  • RituximabDrug

    Also called Rituxan

    day 1 of each cycle (375 mg/m2 intravenously for the first cycle and 1400 mg subcutaneously OR 375 mg/m2 intravenously for subsequent cycles (as per institutional procedures).

Study groups in NCT04624906
Study groupRoleWhat they receive
Single arm interventionExperimental100 mg Acalabrutinib (ACP-196) oral capsules twice daily for 1 year Bendamustine and rituximab will be given for 6 x 28-day cycles. Bendamustine will be given intravenously at 90 mg/m2 on days 1 and 2 of each cycle. Rituximab will be given on day 1 of each cycle (375 mg/m2 intravenously for the first cycle and 1400 mg subcutaneously OR 375 mg/m2 intravenously for subsequent cycles (as per institutional procedures).
Receives: Drug: Acalabrutinib; Drug: Bendamustine; Drug: Rituximab

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Best combined complete response (CR) and very good partial response (VGPR)

    To document the best combined CR and VGPR rate of first-line treatment with bendamustine and rituximab plus acalabrutinib in patients with WM using response criteria from the Sixth International Workshop on Waldenstrom's Macroglobulinemia9. Response will be documented at cycle 7, 12 and 18 (durable CR).

    Measured: through study completion, an average of 1 year - cycle 7, 12 (day 1 of 28 day cycle) up to 18 months

Secondary outcomes (7)

  1. Overall objective response and partial response

    using criteria from 6th international workshop on WM

    Measured: 6 and 12 months

  2. Documentation of minimal residual disease (MRD) rate

    MRD will be assessed at three on treatment timepoints (before start of cycles 7, 12, 18) as well as extended follow-up vistis. MRD will be measured from two body compartments-peripheral blood and bone marrow. MRD will be recorded and will be reported based on the limit of detection of the assay (to be determined). Results will be pooled and rates of MRD negativity for the assay will be recorded at each time point for the pooled patients and for each of the two body compartments that are being assessed.

    Measured: through study completion, an average of 18 months cycle 7, 12 and 18 (each cycle is 28 days)

  3. Documentation of overall survival

    OS will be determined using the time from first day of study treatment to death for each patients. Results for each patient will be pooled to derive an overall survival rate.

    Measured: Up to 6 years post first dose

  4. Documentation of progression free survival

    PFS will be defined as the time from first dose of study treatment to the first objective documentation of progressive disease (PD), the start of an alternative anticancer therapy, or death from any cause during study. Results for each patient will be pooled to derive an overall progressive free survival rate. Participants not meeting criteria for PD will be followed by telephone every 6 months for up to six years from the time of first dose.

    Measured: Up to 6 years post first dose

  5. Toxicities graded according to the NCI Common Terminology Criteria for Adverse Events, version 5.0 (NCI CTCAE, v5.0)]

    A descriptive analysis of safety will be performed with descriptions of frequency and grade of the adverse events including adverse events of special interest such as hypertension, cardiac arrhythmias and bleeding events. The common toxicities described in the NCK common terminology criteriae for adverse events (NC CTAE v5.0) will be documented and grade in each patient at each visit throughout the trial. Rates and severity of all of these toxicity will be collected and reported.

    Measured: Up to 30 days following last dose

  6. Duration of Response

    Defined as the length of time a participant is identified as CR or VGPR until they progress. Different from PFS

    Measured: Up to 6 years post first dose

  7. Time to Next Treatment

    Defined as the amount of time from the start of trial until the patient requires a new form of treatment to treat their WM

    Measured: Up to 6 year post first dose

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted12 Nov 2020
  2. Study start2 Mar 2021
  3. Primary completion31 Dec 2025
  4. Study completionMar 2030 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Model description
Bendamustine, Rituximab and Acalabrutinib
Masking
None (open label)
Enrolment
63 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04624906
Sponsor's protocol ID
3242
Acronym
BRAWM
Status last verified
Jan 2026
First submitted
23 Oct 2020
Last updated
3 Sep 2026
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
Yes: Aggregate data may be shared. Individual patient data will be de-identified.

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Acalabrutinib, Bendamustine and Rituximab in people with Waldenstrom Macroglobulinemia, run by Sunnybrook Health Sciences Centre at 9 sites in Canada.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 13 inclusion and 24 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: under way, not looking for participants, as of the sponsor's last update on 3 Sep 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 9 sites in Canada. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

This study is still under way. Results are not available in the source record yet.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Best combined complete response (CR) and very good partial response (VGPR) (time frame: through study completion, an average of 1 year - cycle 7, 12 (day 1 of 28 day cycle) up to 18 months). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04624906.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 3 Sep 2026.

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