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Bendamustine, Rituximab and Acalabrutinib in Waldenstrom's Macroglobulinemia (BRAWM)

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ClinicalTrials.gov Identifier: NCT04624906
Recruitment Status : Recruiting
First Posted : November 12, 2020
Last Update Posted : July 26, 2021
Sponsor:
Collaborator:
AstraZeneca
Information provided by (Responsible Party):
Sunnybrook Health Sciences Centre

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.

Condition or disease Intervention/treatment Phase
Waldenstrom Macroglobulinemia Drug: Acalabrutinib Drug: Bendamustine Drug: Rituximab Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 59 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description: Bendamustine, Rituximab and Acalabrutinib
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : March 2, 2021
Estimated Primary Completion Date : December 2024
Estimated Study Completion Date : March 2030


Arm Intervention/treatment
Experimental: Single arm intervention

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
100 mg oral capsules twice daily for 1 year
Other Name: Calquence

Drug: Bendamustine
90 mg/m2 on days 1 and 2 of each cycle.
Other Name: Treanda

Drug: Rituximab
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).
Other Name: Rituxan




Primary Outcome Measures :
  1. 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) ]
    To document the best combined CR and VGPR rate of first line treatment with bendamustine & rituximab plus Acalabrutinib in patients with Waldenstrom's macroglobulinemia using the criteria from the Sixth International Workshop on Waldenstrom's Macroglobulinemia. Best response will be recorded within the first twelve months of treatment. These include assessments at the beginning treatment cycles; 2,3,4,5,6 , 7,10, and 12. For each participant, the best response will be selected at any of these timepoints to be used as the best objective response for that participant. The results from each participant will be pooled and participants whose best response at any of these time points is either CR or VGPR will be added together to derive the overall best CR/VGPR rate for the study population.


Secondary Outcome Measures :
  1. Overall objective response and partial response [ Time Frame: 6 and 12 months ]
    using criteria from 6th international workshop on WM

  2. Documentation of minimal residual disease (MRD) rate [ Time Frame: through study completion, an average of 18 months cycle 7, 12 and 18 (each cycle is 28 days) ]
    MRD will be assessed at three on treatment timepoints (before start of cycles 7, 12, 18). 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.

  3. Documentation of overall survival [ Time Frame: Up to 6 years post first dose ]
    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.

  4. Documentation of progression free survival [ Time Frame: Up to 6 years post first dose ]
    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.

  5. Toxicities graded according to the NCI Common Terminology Criteria for Adverse Events, version 5.0 (NCI CTCAE, v5.0)] [ Time Frame: Up to 30 days following last dose ]
    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.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Have biopsy proven Waldenstrom's macroglobulinemia (biopsy from within 3 months (+/- 7 days) prior to Day 1).
  2. Have not received any systemic treatment for the disease (plasmapheresis, involved field radiation or corticosteroids are allowed (as premedication or for contrast enhanced studies)).
  3. Be willing and able to provide written informed consent for the trial.
  4. Male or female greater than 18 years of age on day of signing informed consent and of any racial or ethnic group.
  5. Have at least one measurable site of disease based on Cheson Criteria using standard CT imaging or a quantifiable IgM paraprotein that is two times the upper limit of normal.
  6. Have symptomatic or impending symptomatic disease or evidence of hematologic or biochemical compromise related to the lymphoma.
  7. Pathology sample must be available for molecular testing or otherwise be willing to provide tissue from a core biopsy prior to starting treatment.
  8. Have a performance status of 0-1 on the ECOG Performance Scale.
  9. Demonstrate adequate organ function as defined in Table 2 below. Adequate organ function should be confirmed within 48 hours prior to enrollment. 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.
  10. A life expectancy > 6 months.
  11. 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 0).
  12. 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.
  13. 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. study medication.
  14. Ability to comply with protocol requirements.

Exclusion Criteria:

  1. Previous systemic therapy for WM (other than described in the inclusion criteria).
  2. 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 (SD0).
  3. Patient is being planned for consolidative autologous stem cell transplant (ASCT).
  4. Is on warfarin anti-coagulation or a proton pump inhibitor.
  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.
  6. Has difficult to control hypertension.
  7. 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 (SD0), 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).
  8. Has a known history of active TB (Bacillus Tuberculosis).
  9. 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.
  10. 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.
  11. 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.
  12. Has known history of, or any evidence of active, non-infectious pneumonitis that has required treatment in the last five years.
  13. Thyroiditis within the past 5 years.
  14. Has an active infection requiring systemic therapy. Note: Subjects completing a course of antibiotic for acute infection 7 days prior to SD0 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 pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with screening visit to 120 days post completion of study
  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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04624906


Contacts
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Contact: Neil L Berinstein, MD 416-480-5248 BRAWM@sunnybrook.ca

Locations
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Canada, British Columbia
Vancouver General Hospital Recruiting
Vancouver, British Columbia, Canada
Contact       BRAWM@sunnybrook.ca   
Canada, Nova Scotia
QEII Health Sciences Centre Recruiting
Halifax, Nova Scotia, Canada
Contact       BRAWM@sunnybrook.ca   
Canada, Ontario
The Ottawa Hospital Recruiting
Ottawa, Ontario, Canada
Contact       BRAWM@sunnybrook.ca   
Sunnybrook Health Sciences Centre Recruiting
Toronto, Ontario, Canada, M4N 3M5
Contact: Neil Berinstein       neil.berinstein@sunnybrook.ca   
Sponsors and Collaborators
Sunnybrook Health Sciences Centre
AstraZeneca
Investigators
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Principal Investigator: Neil L Berinstein, MD Sunnybrook Research Institute
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Responsible Party: Sunnybrook Health Sciences Centre
ClinicalTrials.gov Identifier: NCT04624906    
Other Study ID Numbers: 3242
First Posted: November 12, 2020    Key Record Dates
Last Update Posted: July 26, 2021
Last Verified: July 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: Aggregate data may be shared

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Sunnybrook Health Sciences Centre:
Waldenstrom Macroglobulinemia
WM
Acalabrutinib
Waldenstrom
Macroglobulinemia
BTK inhibitor
BTK
Bruton's Tyrosine Kinase
First line treatment
BRAWM
Additional relevant MeSH terms:
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Waldenstrom Macroglobulinemia
Neoplasms, Plasma Cell
Neoplasms by Histologic Type
Neoplasms
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Rituximab
Bendamustine Hydrochloride
Antineoplastic Agents, Immunological
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action