Clinical Trials /

Bendamustine, Rituximab and Acalabrutinib in Waldenstrom's Macroglobulinemia

NCT04624906

Description:

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, partcipants will receive 100 mg of the investigational product, acalabrutinib, orally for 1 year (365 days) at 100 mg BID.

Related Conditions:
  • Waldenstrom Macroglobulinemia
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Bendamustine, Rituximab and Acalabrutinib in Waldenstrom's Macroglobulinemia
  • 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

Clinical Trial IDs

  • ORG STUDY ID: 3242
  • NCT ID: NCT04624906

Conditions

  • Waldenstrom Macroglobulinemia

Interventions

DrugSynonymsArms
AcalabrutinibCalquenceSingle arm intervention
BendamustineTreandaSingle arm intervention
RituximabRituxanSingle arm intervention

Purpose

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, partcipants will receive 100 mg of the investigational product, acalabrutinib, orally for 1 year (365 days) at 100 mg BID.

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), immunofixations (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.
    

Trial Arms

NameTypeDescriptionInterventions
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).
  • Acalabrutinib
  • Bendamustine
  • Rituximab

Eligibility 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

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)
Safety Issue:
Description: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

Measure:Overall objective response and partial response
Time Frame:6 and 12 months
Safety Issue:
Description:using criteria from 6th international workshop on WM
Measure:Documentation of minimal residual disease (MRD) rate
Time Frame:through study completion, an average of 18 months cycle 7, 12 and 18
Safety Issue:
Description: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.
Measure:Documentation of overall survival
Time Frame:Up to 6 years post first dose
Safety Issue:
Description: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.
Measure:Documentation of progression free survival
Time Frame:Up to 6 years post first dose
Safety Issue:
Description: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.
Measure: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
Safety Issue:
Description: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.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Sunnybrook Health Sciences Centre

Trial Keywords

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

Last Updated

November 5, 2020