Daratumumab Plus Ibrutinib in Patients With Waldenstrӧm's Macroglobulinemia
Condition: Waldenstrom Macroglobulinemia; Waldenstrom's Disease; Waldenström; Hypergammaglobulinemia; Waldenstrom's Macroglobulinemia Recurrent; Waldenstrom's Macroglobulinemia of Lymph Nodes; Waldenstrom's Macroglobulinaemia, Without Mention of Remission; Waldenstrom's Macroglobulinemia Refractory
MeSH terms: Waldenstrom Macroglobulinemia; Hypergammaglobulinemia
Intervention: Ibrutinib; Daratumumab
Intervention description: Ibrutinib, 420mg orally, once daily; Daratumumab, 16 mg/kg intravenously, weekly for 8 weeks, bi weekly for 16 weeks, then monthly for up to 19 months.
Intervention MeSH terms: Daratumumab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 1.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: treatment naive; relapsed; frontline; refractory; daratumumab; ibrutinib

Summary:

      This study evaluates the safety and efficacy of daratumumab in combination with ibrutinib in
      patients with Waldenstrӧm's macroglobulinemia (WM). The study will evaluate this combination
      in two cohorts. Cohort A will comprise of ibrutinib naïve WM patients. Patients in this
      cohort may be treatment naïve or relapsed but who remain ibrutinib naïve. Cohort B will
      comprise of patients who are currently receiving ibrutinib but whose response to treatment
      has plateaued. In this cohort, daratumumab will be added on to ibrutinib in an attempt to
      deepen response.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Subjects must have a diagnosis of WM and meet the requirements for active therapy as
             defined by the 2nd International Workshop on Waldenstrom's Macroglobulinemia

          -  Age ≥18 years of age

          -  Ibrutinib naïve or previously treated patients currently on ibrutinib with a plateau
             in disease response are eligible to participate.

               1. Ibrutinib naïve subjects may be either treatment naïve or previously treated but
                  ibrutinib naïve to enter cohort A.

               2. Subjects entering cohort B must have a plateau response on ibrutinib defined as ≥
                  6 months of ibrutinib treatment with 2 IgM measurements at least 2 months apart
                  with ≤ 15% change from the previous measurement. Subjects with IgM level < 0.7
                  g/dL will be eligible if their IgM level increases < 0.15 g/dL over two
                  subsequent IgM measurements as defined above.

          -  Subjects must have measurable disease defined by a serum IgM level ≥0.5g/dL

          -  Eastern Cooperative Oncology Group performance status of 0-2

          -  Hematology values must be within the following limits:

               1. Absolute neutrophil count (ANC) ≥ 1000/mm3 independent of growth factor support
                  for 7 days of study entry if cytopenias are due to marrow involvement.

               2. Platelets ≥ 50,000/mm3 independent of transfusion support within 7 days of study
                  entry. TPO mimetics are not allowed to meet eligibility criteria.

               3. Hemoglobin ≥ 8g/dL, independent of transfusion support within 7 days of study
                  entry

          -  Biochemical values within the following limits:

             d. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 x upper
             limit of normal (ULN)

             e. Total bilirubin ≤ 2 x ULN unless bilirubin rise is due to Gilbert's syndrome or of
             non-hepatic origin

             f. Creatinine clearance (CLcr) > 25 ml/min

          -  Women of childbearing potential and men who are sexually active must be practicing a
             highly effective method of birth control during and after the study consistent with
             local regulations regarding the use of birth control methods for subjects
             participating in clinical trials. Men must agree to not donate sperm during and after
             the study. For females, these restrictions apply for 1 month after the last dose of
             study drug. For males, these restrictions apply for 3 months after the last dose of
             study drug.

          -  Women of childbearing potential must have a negative serum (beta-human chorionic
             gonadotropin (beta-hCG) or urine beta hCG pregnancy test at Screening. Women who are
             pregnant or breastfeeding are ineligible for this study.

          -  Subjects must be able to sign (or their legally-acceptable representatives must sign)
             an informed consent indicating that they understand the rational of the study and can
             participate in all study procedures.

        Exclusion Criteria:

          -  Subject does not have a recorded IgM level recorded within 3 months prior to ibrutinib
             initiation.

          -  Subject meeting definition of disease progression while on ibrutinib. Subjects with
             IgM levels < 0.7gdL are given special consideration. Please see inclusion criteria for
             2b.

          -  Subjects in cohort B experiencing ongoing non hematologic toxicities attributable to
             ibrutinib > Grade 1 will be excluded from study entry.

          -  Major surgery or a wound that has not fully healed within 4 weeks of enrollment.

          -  Evidence of disease transformation at time of enrollment.

          -  Waldenstrom's complicated by amyloidosis

          -  Known central nervous system lymphoma.

          -  History of stroke or intracranial hemorrhage within 6 months prior to randomization.

          -  Requires anticoagulation with warfarin or equivalent vitamin K antagonists (eg,
             phenprocoumon).

          -  Requires chronic treatment with strong CYP3A inhibitors. Subjects that required strong
             CYP3A inhibitors but completed a course of treatment can be considered for enrollment
             after a washout period of 14 days prior to study drug administration.

          -  Requires strong CYP3A inducers. Subjects that required strong CYP3A inducers but
             completed a course of treatment can be considered for enrollment after a washout
             period of 14 days prior to study drug administration.

          -  Patients with history of Chronic Obstructive Pulmonary Disease or Reactive Airway
             disease must have PFTs with FEV1 calculated. Patients with a FEV1 ≤ 50% of predicted
             normal will be excluded.

          -  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 (moderate) or Class 4 (severe) cardiac disease as defined by
             the New York Heart Association Functional Classification.

          -  Vaccinated with live, attenuated vaccines within 4 weeks of randomization.

          -  Seropositive for human immunodeficiency virus (HIV).

          -  Seropositive for hepatitis B (defined by a positive test for hepatitis B surface
             antigen [HBsAg]). Subjects with resolved infection (i.e., subjects who are HBsAg
             negative but positive for antibodies to hepatitis B core antigen [anti-HBc] and/or
             antibodies to hepatitis B surface antigen [anti-HBs]) must be screened using real-time
             polymerase chain reaction (PCR) measurement of hepatitis B virus (HBV) DNA levels.
             Those who are PCR positive will be excluded. EXCEPTION: Subjects with serologic
             findings suggestive of HBV vaccination (anti-HBs positivity as the only serologic
             marker) AND a known history of prior HBV vaccination, do not need to be tested for HBV
             DNA by PCR.

          -  Seropositive for hepatitis C (except in the setting of a sustained virologic response
             [SVR], defined as aviremia at least 12 weeks after completion of antiviral therapy).

          -  Any 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 ibrutinib capsules, or put the study outcomes at undue
             risk.

          -  Active malignancy not treated with curative intent within 2 years of study entry.
             Nonmelanotic skin cancers and cervical carcinoma in situ are excluded from this
             criteria.