Daratumumab Plus Ibrutinib in Patients With Waldenstrӧm's Macroglobulinemia

This is a multi-center, two cohort Phase 2 clinical trial investigating the effectiveness of
adding daratumumab to ibrutinib in WM patients. Cohort A will consist of patients who are
ibrutinib naïve and appropriate for ibrutinib based treatment. Cohort B will consist of
patients who have achieved a response plateau less than a complete remission (CR) on single
agent ibrutinib. Subjects in Cohort A will be identified by their treating physician and
eligible for enrollment if they are treatment naïve or relapsed after 1 prior therapy for WM
and eligible for ibrutinib based treatment.

Subjects in Cohort B will be identified by their treating physician and eligible for
enrollment if they have had at least 6 months of exposure to single agent ibrutinib and
demonstrate an IgM response plateau defined by two IgM measurements, at least 8 weeks apart
that have changed <15% from the previous mark. In Cohort B response assessment will be
measured from initial IgM level prior to ibrutinib initiation.

Enrolled subjects will be prescribed commercial ibrutinib, 420mg PO daily. The
investigational agent, daratumumab will be administered based on FDA approved dosing in
multiple myeloma (16mg/kg) with 8 weekly induction treatments during Cycles 1 and 2, followed
by every other week dosing for Cycles 3-6, then monthly dosing from Cycle 7 until Cycle 25 at
which point subjects will continue with ibrutinib as monotherapy until Cycle 52 (4 years
total) which is the predefined study completion for enrolled subjects at which point they
will complete follow-up. Study visits and response assessments with IgM measurements will
occur with each cycle for the first year then every three cycles after cycle 13. Subjects
with measureable extramedullary disease will have CT scans every 6 cycles until radiographic
CR. Patients will be considered evaluable for response if they completed the initial 8 weeks
of daratumumab induction therapy and evaluable for toxicity if receiving one dose of
daratumumab. Patients will continue on combination therapy for 2 years or until disease
progression or unacceptable toxicities at which point subjects will come off trial. Patients
achieving a CR after two years of combination therapy will be given an option to continue
with single agent commercial ibrutinib.

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 1.

2. Subjects entering cohort 2 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 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.

- 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.

- 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.

- Known history of human immunodeficiency virus (HIV) or hepatitis C virus or active
hepatitis B virus infection defined as hep B DNA PCR+ or any uncontrolled active
systemic infection. Subjects with hepatitis B core antibody positivity must have a
negative PCR performed and start on prophylaxis and or have monthly hep B DNA PCR
performed while on study.

- 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.