Bendamustine, Rituximab and Acalabrutinib in Waldenstrom's Macroglobulinemia

NCT04624906 | Active Not Recruiting Phase 2 DMC

• 1 other identifier: 3242
• Study Type: interventional
• Target: 63
• Locations: 1 country
• Sites: 9

Brief 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. 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.

Conditions

Waldenstrom Macroglobulinemia

Keywords

Waldenstrom Macroglobulinemia; WM; Acalabrutinib; Waldenstrom; Macroglobulinemia; BTK inhibitor; BTK; Bruton's Tyrosine Kinase; First line treatment; BRAWM

Outcome Measures

Primary Outcomes (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).

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

Secondary Outcomes (7)

• Overall objective response and partial response

  6 and 12 months

• Documentation of minimal residual disease (MRD) rate

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

• Documentation of overall survival

  Up to 6 years post first dose

• Documentation of progression free survival

  Up to 6 years post first dose

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

  Up to 30 days following last dose

Study Arms (1)

Single arm intervention

EXPERIMENTAL

100 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).

Drug: Acalabrutinib; Drug: Bendamustine; Drug: Rituximab

Interventions

Acalabrutinib DRUG

100 mg oral capsules twice daily for 1 year

Also known as: Calquence

Single arm intervention

Bendamustine DRUG

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

Also known as: Treanda

Single arm intervention

Rituximab DRUG

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).

Also known as: Rituxan

Single arm intervention

Eligibility Criteria

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

You may qualify if:

• 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.
• 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.

You may not qualify if:

• 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.
• \. 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.
• \. 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.
• \. 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).
• \. 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.
• \. 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.
• \. 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.
• \. Has known history of, or any evidence of active, non-infectious pneumonitis that has required treatment in the last five years.
• \. 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.
• \. 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.
• \. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
• \. 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.

Sponsors & Collaborators

• AstraZeneca: collaborator
• Sunnybrook Health Sciences Centre: lead

Study Sites (9)

Tom Baker Cancer Centre

Calgary, Alberta, Canada

Location

Cross Cancer Institute

Edmonton, Alberta, Canada

Location

Vancouver General Hospital

Vancouver, British Columbia, Canada

Location

QEII Health Sciences Centre

Halifax, Nova Scotia, Canada

Location

Hamilton Health Sciences Centre - Juravinksi

Hamilton, Ontario, Canada

Location

The Ottawa Hospital

Ottawa, Ontario, Canada

Location

Sunnybrook Health Sciences Centre

Toronto, Ontario, M4N 3M5, Canada

Location

CHU de Quebec - University Laval

Laval, Quebec, Canada

Location

McGill University Health Centre

Montreal, Quebec, Canada

Location

MeSH Terms

Conditions

Waldenstrom Macroglobulinemia

Interventions

acalabrutinib; Bendamustine Hydrochloride; 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

Intervention Hierarchy (Ancestors)

Butyrates; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Benzimidazoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Neil L Berinstein, MD

  Sunnybrook Research 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

Model Details: Bendamustine, Rituximab and Acalabrutinib

Study Record Dates

• First Submitted: October 23, 2020
• First Posted: November 12, 2020
• Study Start: March 2, 2021
• Primary Completion: December 31, 2025
• Study Completion (Estimated): March 1, 2030
• Last Updated: February 4, 2026

Record last verified: 2026-01

Data Sharing

• IPD Sharing: Will not share

Locations

CA (9)