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
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.
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.
Study Phase
Phase 2
Study Type
Interventional
Primary Outcome
Best combined complete response (CR) and very good partial response (VGPR)
Secondary Outcome
Overall objective response and partial response
Condition
Waldenstrom Macroglobulinemia
Intervention
Acalabrutinib
Study Arms / Comparison Groups
Single arm intervention
Description: 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).
Publications
* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.
Recruitment Information
Recruitment Status
Drug
Estimated Enrollment
59
Start Date
March 2, 2021
Completion Date
March 2030
Primary Completion Date
December 2024
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.
Gender
All
Ages
18 Years - N/A
Accepts Healthy Volunteers
No
Contacts
Neil L Berinstein, MD, 416-480-5248, [email protected]
Location Countries
Canada
Location Countries
Canada
Administrative Informations
NCT ID
NCT04624906
Organization ID
3242
Responsible Party
Sponsor
Study Sponsor
Sunnybrook Health Sciences Centre
Collaborators
AstraZeneca
Study Sponsor
Neil L Berinstein, MD, Principal Investigator, Sunnybrook Research Institute
Verification Date
July 2021