An Open-label, Phase 2 Study of ACP-196 in Subjects With Waldenström Macroglobulinemia
Condition: Waldenström Macroglobulinemia (WM)
MeSH terms: Waldenstrom Macroglobulinemia
Intervention: Acalabrutinib (ACP-196); Acalabrutinib (ACP-196)
Intervention MeSH terms: Acalabrutinib
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 107.0
Sex: All
Minimum age: 18 Years
Maximum age: 130 Years
Healthy volunteers: No
Keywords: Bruton tyrosine kinase inhibitor; Btk; Waldenström Macroglobulinemia; WM; Waldenström; Macroglobulinemia

Summary:

      The purpose of this study is to evaluate the safety, pharmacokinetics, pharmacodynamics, and
      activity of acalabrutinib in treating subjects with WM.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Men and women ≥18 years of age.

          2. Previously treated cohort only: A confirmed diagnosis of WM, which has relapsed after,
             or been refractory to ≥1prior therapy for WM and which requires treatment.

          3. Previously untreated cohort only: A confirmed diagnosis of previously untreated WM in
             subjects who require treatment and do not want to receive chemoimmunotherapy or have
             comorbidities that would preclude chemoimmunotherapy such as:

               -  Symptomatic hyperviscosity with an IgM ≥5,000mg/dL

               -  Disease-related neuropathy

          4. Serum concentration of IgM, as measured by SPEP and IFE, that exceeds the upper limits
             of normal or measurable nodal WM (defined as the presence of ≥1lymph node that
             measures ≥2.0 cm in the longest diameter and ≥1.0cm in the longest perpendicular
             diameter).

          5. ECOG performance status of ≤2.

          6. Women who are sexually active and can bear children must agree to use highly effective
             forms of contraception during the study and for 2 days after the last dose of
             acalabrutinib.

          7. Willing and able to participate in all required evaluations and procedures in this
             study protocol including swallowing capsules without difficulty.

          8. Ability to understand the purpose and risks of the study and provide signed and dated
             informed consent and authorization to use protected health information (in accordance
             with national and local patient privacy regulations).

        Exclusion Criteria:

          1. Prior malignancy, except for adequately treated basal cell or squamous cell skin
             cancer, in situ cervical cancer, or other cancer from which the subject has been
             disease free for ≥2 years or which will not limit survival to <2 years. Note: These
             cases must be discussed with the medical monitor.

          2. A life-threatening illness, medical condition, or organ system dysfunction which, in
             the investigator's opinion, could compromise the subject's safety, interfere with the
             absorption or metabolism of acalabrutinib, or put the study outcomes at undue risk.

          3. 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 disease as defined by the New York Heart Association
             Functional Classification, or QTc >480 msec.

          4. Malabsorption syndrome, disease significantly affecting gastrointestinal function, or
             resection of the stomach or small bowel or gastric bypass, symptomatic inflammatory
             bowel disease, or partial or complete bowel obstruction.

          5. Any immunotherapy within 4 weeks of first dose of study drug.

          6. For subjects with recent chemotherapy or experimental therapy, the first dose of study
             drug must occur after 5 times the half-life of the agent(s).

          7. Prior exposure to a BCR inhibitor (e.g., BTK,PI3K, or SYK inhibitors) or BCL-2
             inhibitors (e.g., ABT-199).

          8. Ongoing immunosuppressive therapy, including systemic or enteric corticosteroids for
             treatment of WM or other conditions. Note: Subjects may use topical or inhaled
             corticosteroids or low-dose steroids (≤10 mg of prednisone or equivalent per day) as
             therapy for comorbid conditions. During study participation, subjects may also receive
             systemic or enteric corticosteroids as needed for treatment-emergent comorbid
             conditions.

          9. Grade ≥2 toxicity (other than alopecia) continuing from prior anticancer therapy
             including radiation.

         10. Known history of HIV or active infection with HCV or hepatitis B virus (HBV) or any
             uncontrolled active systemic infection.

         11. Major surgery within 4 weeks before first dose of study drug.

         12. Uncontrolled autoimmune hemolytic anemia or idiopathic thrombocytopenia purpura.

         13. History of a bleeding diathesis (e.g., hemophilia, von Willebrand disease).

         14. History of stroke or intracranial hemorrhage within 6 months before the first dose of
             acalabrutinib.

         15. Requires or receiving anticoagulation with warfarin or equivalent vitamin K
             antagonists (e.g., phenprocoumon) within 28 days of first dose of study drug.

         16. Requires treatment with proton-pump inhibitors (e.g., omeprazole, esomeprazole,
             lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole).

         17. ANC <0.75 x 109/L or platelet count <50 x 109/L. For subjects with disease involvement
             in the bone marrow, ANC <0.50 x 109/L or platelet count <30x109/L.

         18. Creatinine >2.5 x institutional ULN; total bilirubin >2.5 x ULN; or AST or ALT >3.0 x
             ULN.

         19. Lactating or pregnant.

         20. Concurrent participation in another therapeutic clinical trial.