Conditions: 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
Keywords: treatment naive relapsed frontline refractory daratumumab ibrutinib
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 1
Healthy volunteers: no

Brief 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.

Detailed description:
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.

Arms:
arm 1: Cohort A will consist of subjects who are ibrutinib naïve and appropriate for ibrutinib based treatment. Treatment naïve subjects will be eligible to enroll in this cohort. All subjects in this cohort will receive ibrutinib plus daratumumab arm 2: Cohort B will consist of subjects who have had at least 6 months of exposure to single agent ibrutinib and who have demonstrated an IgM response plateau defined by two IgM measurements, at least 8 weeks apart that have changed \<15% from the previous mark. All subjects in this cohort will receive ibrutinib plus daratumumab

Interventions: intervention 1: Ibrutinib intervention 2: Daratumumab
Intervention descriptions: intervention 1: Ibrutinib, 420mg orally, once daily intervention 2: Daratumumab, 16 mg/kg intravenously, weekly for 8 weeks, bi weekly for 16 weeks, then monthly for up to 19 months.

Protocol document:
Prot_SAP_000.pdf: 
TITLE:  A Phase II Study of Daratumumab plus Ibrutinib in Patients with Waldenstrӧm’s 
Macroglobulinemia.  
IRB Protocol #: 1708018494 IND/ IDE 
#: 141558 , NCT #: NCT03679624
Version Date: March 13, 2020 
Principal Investigator: 
John Allan MD 
1305 York Avenue 7th Floor 
646-962-2064
646-962-1617
joa9069@med.cornell.edu
Co-Investigators: 
Richard Furman MD 
John Leonard MD 
Peter Martin MD 
Sarah Rutherford MD 
Jia Ruan MD, PhD 
Ruben Niesvizky MD 
Adriana Rossi MD 
Roger Pearse MD 
Orel Agami PA 
 Melanie Bernstein PA 
Sandra Stewart PA 
Stephanie Prezioso PA 
Leslie Rudolph PA 
Melissa Lapinta PA 
 Cara Rosenbaum MD 
Lisa Roth MD 
Alexandra Kaiser PA 
Janiece Francis NP 
Grace Chan NP 
Karen Pekle NP 
Statistician: 
 Paul Christos Ph.D 
Sponsor: 
Weill Cornell Medicine 
Drug and Funding Support: 
Janssen Scientific Affairs 


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Confidentiality Statement 
 
This document is confidential and is to be distributed for review only to investigators, potential 
investigators, consultants, study staff, and applicable independent ethics committees or 
institutional review boards. The contents of this document shall not be disclosed to others without 
written authorization from WCM. 
 


 
 
  
 
Protocol Synopsis: 
 
Title: A Phase II Study of Daratumumab plus Ibrutinib in Patients with Waldenstrom’s 
Macroglobulinemia 
Study Drugs: 
Daratumumab and Ibrutinib 
Indication: 
Waldenstrom’s Macroglobulinemia  
Study Phase: 
Phase II 
Background and Rationale: 
While many treatment options are available for Waldenstrom’s macroglobulinemia (WM), ibrutinib 
remains the only approved therapy in both upfront and salvage settings. Data for effective therapies is 
derived from published Phase 2 studies utilizing rituximab in combination with alkylating agents, purine 
analogs or proteasome inhibitors with overall response rates (ORR) ~80-95% 1.  
Ibrutinib has demonstrated impressive results as a single agent in previously treated rituximab refractory 
WM patients with an ORR of 91%, a major response rate of 73%, and a 2 year PFS of 69% 2. Despite 
the impressive response rates, the majority of patients only achieve partial responses with the median 
IgM levels plateauing around 800mg/dL at time of best response. Mutations in genes such as MYD88, 
CXCR4 and BTK, affect response and in the case of CXCR4 and BTK, resistance to ibrutinib 3,4. When 
ibrutinib is held for side effects, surgery or other reasons there is a rapid rise in IgM off of the drug, 
suggesting ibrutinib is having more of an effect on inhibition of IgM secretion than cell death. These 
observations provide an opportunity to use novel targeted approaches in combination with ibrutinib to 
further deepen these response rates in hopes to improve both PFS and OS.  
Increasing evidence suggests the cell of origin for WM is an activated memory B cell with ~50-70% of 
cases demonstrating some level of CD38 expression 5-7. Daratumumab is a monoclonal antibody 
targeting CD38 currently approved for use in multiple myeloma but not approved to treat WM 8,9. Using 
daratumumab in combination with ibrutinib, we seek to target CD38 expression in WM patients both in 
combination as upfront therapy and as an additive therapy to patients currently on ibrutinib who have 
reached a response plateau. 
Objectives: 
Primary Objective: 
 To evaluate the safety and toxicity of combination daratumumab and ibrutinib 
Secondary Objectives:  
 To assess overall response rate in Cohort A 
 To evaluate the deepening of response in cohort B.  
 To evaluate duration of response (DoR) 
 To evaluate time to progression (TTP) 
 To assess progression free survival (PFS) 
 To assess overall survival (OS) 


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Exploratory Objectives: 
 Specimens will be collected for future unknown use. Anticipated studies will be determined at a 
future date. Janssen will retain the right to approve the use of samples for exploratory analysis. 
Methodology: 
We propose a multi-center, two cohort Phase II clinical trial to investigate 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 ibrutinib naïve after prior therapy 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 24 at which point they 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 patients 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. 
 
Subjects to be enrolled  
24 total subjects, 12 in Cohort A and 12 in Cohort B 
Study Duration 
6 years 
Accrual period 
2 years 
Inclusion Criteria: 
1. Age ≥18 years of age 
2. Ibrutinib naïve or previously treated patients currently on ibrutinib with a plateau in disease 


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response are eligible to participate: 
a. Ibrutinib naïve subjects may be either treatment naïve or previously treated but ibrutinib 
naive to enter cohort A.  
b. 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. 
3. Subjects must have measurable disease defined by a serum IgM level ≥0.5g/dL 
4. Eastern Cooperative Oncology Group performance status of 0-2 
5. Hematology values must be within the following limits:  
a. Absolute neutrophil count (ANC) ≥ 1000 mm3 independent of growth factor support for 7 
days prior to study entry. 
b. Platelets ≥ 50,000/mm3 independent of transfusion support within 7 days of study entry. TPO 
mimetics are not allowed to meet criteria. 
c. Hemoglobin ≥ 8g/dL, independent of transfusion support within 7 days of study entry 
6. Biochemical values within the following limits: 
a. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 x upper limit 
of normal (ULN) 
b. Total bilirubin ≤ 2 x ULN unless bilirubin rise is due to Gilbert’s syndrome or of non-
hepatic origin 
c. Creatinine clearance (CLcr) ≥ 25 ml/min 
7. 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. 
8. Women of childbearing potential must have a negative serum (beta-human chorionic 
gonadotropin [β-hCG]) or urine pregnancy test at Screening. Women who are pregnant or 
breastfeeding are ineligible for this study. 
9. Subjects must 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 


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procedures. 
Exclusion Criteria:  
1. Subject does not have a recorded IgM level recorded within 3 months prior to ibrutinib initiation. 
2. 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. 
3. Subjects in cohort B experiencing ongoing non hematologic toxicities attributable to ibrutinib > 
Grade 1 will be excluded from study entry.     
4. Major surgery or a wound that has not fully healed within 4 weeks of enrollment. 
5. Evidence of disease transformation at time of enrollment.  
6. Evidence of or known central nervous system involvement. 
7. Evidence of or known amyloidosis.  
8. History of stroke or intracranial hemorrhage within 6 months prior to enrollment. 
9. Requires anticoagulation with warfarin or equivalent vitamin K antagonists. 
10. Requires chronic treatment with strong CYP3A inhibitors. Subjects that required strong CYP3A 
inhibitors can be considered for enrollment after a washout period of 14 days prior to study drug 
administration. 
11. 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. 
12. Patients with history of Chronic Obstructive Pulmonary Disease or Reactive Airway disease must 
have pulmonary function tests. If the subject has a FEV1 ≤ 50% of predicted normal they will be 
excluded. 
13. 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. 
14. Vaccinated with live, attenuated vaccines within 4 weeks of randomization. 
15. Seropositive for human immunodeficiency virus (HIV) 
16. 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 


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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. 
 
17. 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). 
18. 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. 
19. Active malignancy not treated with curative intent within 2 years of study entry with exception of 
nonmelanomatous skin cancers and cervical carcinoma in situ. 
Treatment Phases: 
Treatment will consist of induction, continuation, and maintenance phases. Induction will be defined as 
the first 2 cycles of combination treatment. The consolidation phase will include treatment with 
daratumumab on day 1 and day 15 of each cycle starting with cycle 3 through cycle 6. Starting at cycle 7 
subjects will enter the maintenance phase with monthly daratumumab infusions until Cycle 24 day 1 
(two years) at which point they will complete their combination treatment with daratumumab. Cycle 25 
and beyond patients will continue on ibrutinib monotherapy.   
Subjects will have doctor visits on each day of treatment with daratumumab but required study visits will 
only occur monthly for the first year followed by every 3 cycles for the remainder of the study.  On non-
study visits during induction, subjects will have baseline labwork considered to be standard of care 
obtained at the discretion of the investigator followed by daratumumab infusions. Subjects will take 
three, 140mg capsules of ibrutinib orally, daily starting on the same day as infusion and continue daily 
through all cycles. 
Treatment Administration:  
Treatment will be administered on an outpatient basis.  
 
Ibrutinib will be administered as a single dose 420mg tablet daily for a total daily dose of 420mg. 
Ibrutinib naïve subjects, will have a one month lead-in Cycle -1, with ibrutinib monotherapy prior to 
initiating combination induction. Subjects in Cohort A who experience any Grade 3 or greater toxicity 
must have that toxicity resolve to Grade 1 or less prior to daratumumab combination therapy. Subjects 
will be asked to take a single tablet of ibrutinib orally with or without food. Subjects will take the tab on 
a continuous daily basis with one cycle of treatment consisting of 28 days. Subjects enrolled on the 
ibrutinib naïve Cohort A, will take their first dose of ibrutinib before or after their daratumumab 
infusion. On days in which they do not receive a daratumumab infusion they will be asked to take their 
ibrutinib tablet at the same time each day. Subjects will continue daily dosing of ibrutinib until disease 
progression, toxicities, or study completion whichever comes first.  
 


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Daratumumab will be administered per the current package insert. Subjects will receive 16mg/kg weekly 
for 8 total doses during induction. They will then receive 16mg/kg of daratumumab on day 1 and day 15 
starting on cycle 3 through cycle 6. Starting with Cycle 7 through cycle 24 subjects will receive 
daratumumab 16mg/kg on day 1 until disease progression, toxicities or study completion whichever 
comes first.  
 
Subjects will be premedicated with 100mg of methylprednisolone intravenously (IV), 650mg of 
acetaminophen PO, and 25-50mg of diphenhydramine IV all given 30 minutes prior to infusions with 
daratumumab. Methylprednisolone dosing may be reduced to 60mg IV with subsequent doses after the 
first infusion if no adverse events are recorded. Subjects will be asked to take 20mg of 
methylprednisolone PO for two days after each infusion and this can be eliminated at the discretion of 
the investigator after completion of the first cycle.  
Evaluation of Efficacy and Safety 
Response will be assessed by the investigator, based on laboratory values, physical examinations, CT 
scans (or MRI if CT scan is medically contraindicated), bone marrow examinations.  
All measurable disease must be documented at screening by physical examination, laboratory testing, 
CT scan (or MRI if CT is medically contraindicated), and bone marrow. During the study, each study 
visit by a physical examination and laboratory testing. Clinical disease assessments will take place at 
baseline, monthly for the first 12 months and then every 3 months until disease progression, death or 
study removal for any other reason. Additional radiographic studies will be performed every 6 months 
on study for patients with baseline extramedullary disease. For consistency, the same method of imaging 
should be performed for a subject throughout the study.  
Safety Assessment: 
Safety will be assessed by physical examinations, Eastern Cooperative Oncology Group (ECOG) criteria 
for performance status, laboratory tests, adverse events, and concomitant medication usage. The 
following adverse events (including laboratory abnormalities reported as adverse events) that occur 
between the first dose of either study drug through 30 days after the last dose of either study drug will be 
collected: 
• Treatment-emergent serious adverse events 
• Grade ≥3 adverse events 
• Adverse events of special interest, and any adverse event resulting in ibrutinib or daratumumab dose 
interruption, reduction or discontinuation 
Any laboratory assessments associated with the above adverse events should be collected in the CRF. 
The severity of adverse events will be assessed using National Cancer Institute Common Terminology 
Criteria for Adverse Events Version 4.03. 
 


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Schema 
 
 
 
 
 
 
 


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Table of Contents 
1. STUDY OBJECTIVES  ...................................................................................................... 11 
1.1 PRIMARY OBJECTIVES ............................................................................................... 12 
    1.2 SECONDARY OBJECTIVES ......................................................................................... 12 
    1.3 EXPLORATORY OBJECTIVES .................................................................................... 12 
2. WALDENSTRӦM’S MACROGLOBULINEMIA DISEASE BACKGROUND ............. 12 
3. RATIONALE ...................................................................................................................... 13 
4. RISK BENEFIT RATIO ..................................................................................................... 14 
5. CORRELATIVE STUDIES................................................................................................ 14 
6. INVESTIGATIONAL AGENTS ........................................................................................ 15 
 6.1 IBRUTINIB .................................................................................................................... 15 
    6.1.1 MECHANISM OF ACTION ..................................................................................... 15 
    6.1.2 NONCLINICAL STUDIES ...................................................................................... 15 
    6.1.3 NONCLINICAL PHARMACOKINETICS AND METABOLISM ........................... 15 
    6.1.4 TOXICOLOGY ........................................................................................................ 16 
6.1.5 CLINICAL STUDIES ............................................................................................... 16 
6.1.6 CLINICAL PHARMACOKINETICS AND METABOLISM .................................... 17 
6.1.7 CLINICAL SAFETY ................................................................................................ 17 
6.2 DARATUMUMAB ......................................................................................................... 17 
6.2.1 MECHANISM OF ACTION ..................................................................................... 17 
6.2.2 NONCLINICAL STUDIES ....................................................................................... 17 
6.2.3 NONCLINICAL PHARMACOKINETICS AND METABOLISM ........................... 18 
6.2.4 TOXICOLOGY ........................................................................................................ 18 
6.2.5 CLINICAL STUDIES ............................................................................................... 18 
6.2.6 CLINICAL PHARMACOKINETICS AND METABOLISM .................................... 18 
6.2.7 CLINICAL SAFETY ................................................................................................ 19 
7. SUBJECT SELECTION ..................................................................................................... 19 
7.1 STUDY POPULATION  ................................................................................................. 19 
7.2 INCLUSION CRITERIA ................................................................................................. 19 
7.3 EXCLUSION CRITERIA ................................................................................................ 20 
8. REGISTRATION PROCEDURES .................................................................................... 21 
8.1 PATIENT REGISTRATION ........................................................................................... 21 
9. STUDY PROCEDURES ..................................................................................................... 22 
9.1 STUDY SCHEDULE ...................................................................................................... 23 
9.2 SCREENING PROCEDURES ......................................................................................... 26 
9.3 TREATMENT PHASES .................................................................................................. 26 
9.3.1 IBRUTINIB LEAD-IN AND INDUCTION PHASE ................................................. 28 


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9.3.2 CONSOLIDATION PHASE ..................................................................................... 28 
9.3.3 MAINTENANCE PHASE ........................................................................................ 29 
9.3.4 IBRUTINIB MONOTHERAPY PHASE ................................................................... 30 
9.3.5 END OF TREATMENT OR PROGRESSION .......................................................... 31 
10. TREATMENT ADMINISTRATION  .............................................................................. 31 
10.1 GENERAL CONCOMITANT MEDICATIONS AND SUPPORTIVE CARE 
GUIDELINES ....................................................................................................................... 32 
10.2 MEDICATIONS TO BE USED WITH CAUTION WITH IBRUTINIB ........................ 32 
10.2.1 ANTIPLATELET AGENTS AND ANTICOAGULATION .................................... 33 
10.2.2 MANAGEMENT OF MINOR SURGICAL PROCEDURES .................................. 33 
10.2.3 MANAGEMENT OF MAJOR SURGICAL PROCEDURES .................................. 33 
10.2.4 PROHIBITED CONCOMITANT MEDICATIONS ON STUDY ............................ 34 
11. DURATION OF THERAPY AND CRITERIA FOR REMOVAL FROM STUDY ...... 34 
11.1 DURATION OF FOLLOWUP ...................................................................................... 34 
12. DOSAGE AND ADMINISTRATION OF STUDY DRUGS ........................................... 34 
12.1 STUDY DRUG ADMINISTRATION OVERVIEW ...................................................... 34 
12.1.1 DARATUMUMAB ADMINISTRATION .............................................................. 35 
12.1.2 DARATUMUMAB PREINFUSION MEDICATIONS ........................................... 35 
12.1.3 DARATUMUMAB POSTINFUSION MEDICATIONS ......................................... 35 
12.2 MANAGEMENT OF INFUSION-RELATED REACTIONS ........................................ 35 
12.2.1 INFUSION-RELATED EVENTS OF GRADE 1 OR GRADE 2 ............................. 36 
12.2.2 INFUSION-RELATED EVENTS OF GRADE 3 OR GRADE 4 ............................. 36 
12.3 IBRUTINIB ADMINISTRATION ................................................................................. 36 
12.3.1 IBRUTINIB OVERDOSE ....................................................................................... 37 
12.4 DOSE DELAYS AND DOSE MODIFICATIONS......................................................... 37 
12.4.1 DARATUMUMAB DOSE DELAY MANAGEMENT ........................................... 38 
12.4.2 IBRUTINIB TOXICITY MANAGEMENT ............................................................ 38 
13. PHARMACEUTICAL INFORMATION......................................................................... 38 
13.1 INVESTIGATIONAL AGENT DARATUMUMAB...................................................... 38 
13.2 AVAILABILITY ........................................................................................................... 39 
13.3 DARATUMUMAB ACCOUNTABILITY .................................................................... 39 
14. MEASUREMENT OF EFFECT ...................................................................................... 39 
14.1 RESPONSE CRITERIA ................................................................................................ 39 
14.2 TIME TO EVENT DEFINITIONS ................................................................................ 40 
15. DATA MONITORING ..................................................................................................... 40 
15.1 DATA COLLECTION................................................................................................... 41 
15.2 REDCAP ....................................................................................................................... 41 
15.3 REGULATORY CONSIDERATIONS .......................................................................... 41 


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16. STATISTICAL CONSIDERATIONS .............................................................................. 41 
17. REPORTING AND EXCLUSIONS ................................................................................. 42 
17.1 ADVERSE EVENT AND REPORTING REQUIREMENTS......................................... 42 
17.2 ADVERSE EVENT DEFINITION ................................................................................ 42 
17.3 ADVERSE EVENTS OF SPECIAL INTEREST FOR DARATUMUMAB ................... 42 
17.4 ADVERSE EVENTS OF SPECIAL INTEREST FOR IBRUTINIB .............................. 42 
17.5 INDIVIDUAL CASE SAFETY REPORT…………………............. .............................. 43 
17.6 PRODUCT QUALITY COMPLAINT ........................................................................... 44 
17.7 SERIOUS ADVERSE EVENT DEFINITION ............................................................... 44 
17.7.1 HOSPITALIZATION.............................................................................................. 44 
17.7.2 LIFE THREATENING CONDITIONS ................................................................... 45 
17.8 UNEXPECTED ADVERSE EVENT ............................................................................. 45 
18. SPECIAL REPORTING SITUATIONS .......................................................................... 45 
18.1 PREGNANCY ............................................................................................................... 46 
19. MAINTENANCE OF SAFETY INFORMATION .......................................................... 47 
20. PROCEDURES OF REPORTING SAFETY DATA AND PRODUCT QUALITY 
COMPLAINTS FOR JANSSEN MEDICINAL PRODUCTS .............................................. 47 
20.1 SERIOUS ADVERSE EVENTS AND SPECIAL REPORTING SITUATIONS ............ 47 
20.2 NON-SERIOUS ADVERSE EVENTS .......................................................................... 48 
20.3 PQC REPORTING ........................................................................................................ 48 
21. TRANSMISSION METHODS ......................................................................................... 48 
22. DATA SAFETY MONITORING PLAN .......................................................................... 49 
REFERENCES ........................................................................................................................ 51 
APPENDICES ......................................................................................................................... 53 
 
 
 
 
 
 
 
 
 
 
 
 
 


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1. Study Objectives 
 
Ibrutinib is an effective treatment strategy for Waldenstrӧm’s macroglobulinemia (WM) 
achieving major response rates of approximately 70% in rituximab refractory patients. 
Unfortunately these responses are generally partial responses (PR) and rapid elevations of IgM 
occur when the drug is held. This suggests an inability of ibrutinib to address the source of the 
disease. It is not yet clear whether long-term health risks of persistently elevated IgMs exist and 
thus we hypothesize we can deepen response rates and increase durability by adding 
daratumumab to ibrutinib in both treatment naïve and previously treated WM patients who have 
achieved a disease response plateau on ibrutinib.  
 
We propose a multi-center, two cohort, Phase II clinical trial to investigate the effectiveness of 
adding daratumumab to ibrutinib in WM patients. 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 but remain naïve to ibrutinib or BTK inhibitors and appropriate 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. 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, followed by every other week dosing for cycles 3-6, then monthly dosing, 
cycle 7-24. Cycle 25 and beyond subjects will continue on single agent ibrutinib. Patients will be 
premedicated with 100mg of methylprednisolone, 650mg of acetaminophen and 25-50mg IV of 
diphenhydramine 30 minutes prior to all infusions of daratumumab. Methylprednisolone dosing 
may be reduced to 60mg with subsequent doses after the first infusion. Subjects will be asked to 
take 20mg of methylprednisolone for two days after each infusion which can be eliminated after 
the first cycle at the discretion of the investigator.  
 
Study visits and response assessments with IgM measurements will occur day 1 of each cycle 
through cycle 13 then day of 1 every three cycles after the first year on treatment. Subjects with 
measureable extramedullary disease will have CT scans every 6 months while on study or until 
radiographic CR at which point they will occur at the discretion of the investigator. Patients will 
be considered evaluable for response if they completed the initial 8 weeks of daratumumab 
induction therapy. Response assessment in Cohort B will be measured from the IgM level 
recorded prior to ibrutinib initiation. Subjects will continue on combination therapy for 2 years 
until disease progression or unacceptable toxicities at which point patients will stop 
daratumumab therapy and come off study. All subjects will be followed for 1 year after 
completing combination therapy unless they come off study early for other reasons. Subjects 
achieving a CR will be given an option to continue with single agent commercial ibrutinib or 
stop all therapy. 
 
 


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1.1. Primary Objectives 
 To evaluate safety and toxicity of combination daratumumab and ibrutinib.  
 
1.2. Secondary Objectives 
 
 To assess major response rate with combination daratumumab and ibrutinib 
cohort A 
 To evaluate deepening response rates in Cohort B after daratumumab addition 
 To evaluate duration of response (DoR) 
 To evaluate time to progression (TTP) 
 To assess progression free survival (PFS) 
 To assess overall survival (OS) 
 
1.3. Exploratory Objectives 
There are no prespecified exploratory studies planned. However, samples will be collected at 
specifi time points as outlined in Section 9 and will be available for future unknown use. Janssen 
will retain the right to approve the use of banked specimens for correlative analysis even if not 
the primary scientific collaborator performing the analysis.  
 
 
 
 
2. Waldenstrӧm’s Macroglobulinemia Background 
 
Waldenstrӧm’s Macroglobulinemia is defined as a IgM producing lymphoplasmacytic 
lymphoma (LPL) characterized by small B lymphocytes, plasmacytoid lymphocytes and 
differentiated plasma cells usually infiltrating the bone marrow10. It is considered a rare indolent 
lymphoma with affecting 3 out of 1 million people in the United States yearly with median 
survival of approximately 8-9 years 11,12. 
 
Upon diagnosis, patients are commonly observed until development of IgM related 
complications such as peripheral neuropathy, cold agglutinins, or cryoglobulinemia and 
constitutional symptoms, bulky extramedullary disease or cytopenias due to infiltration of bone 
marrow by tumor cells 1. 
 
Historically upfront management for fit patients with WM has been with chemo-immunotherapy 
(CIT) regimens when treatment was indicated. Phase 3 data comparing bendamustine/rituximab 
(BR) to rituximab/cyclophosphamide/doxorubicin/prednisone (RCHOP) for indolent lymphomas 
included 41 patients with WM 13. Overall response rates were high in both groups but there was 
less toxicity with improved progression free survival (PFS) was noted in subjects receiving BR. 
Additionally, dexamethasone/rituximab/cyclophosphamide (DRC) has been studied 
demonstrating it was safe and effective with 83% of patients responding 14.   
 
Novel agent containing therapies have since been established as safe, effective, and 
chemotherapy free options for older unfit patients with comparable response rates and durability 
compared to standard the CIT regimens previously published. Outcomes with 
bortezomib/dexamethasone/rituximab (BDR) has recently been updated with 6 year minimum 


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follow-up of 59 previously untreated patients demonstrating 85% ORR with median PFS of 43 
months and median duration of response (DoR) of 64.5 months 15.  
 
Anti-CD20 therapy has been a mainstay as an initial treatment for unfit low tumor burden 
patients with both rituximab and ofatumumab demonstrating impressive response rates 16-18. 
While anti-CD20 therapy is a great option for moderately symptomatic patients it should be used 
with caution in patients with elevated IgM levels or symptoms of hyperviscosity as an IgM flare 
has been noted which can cause an exacerbation of the patient’s symptoms 19.  
 
Ibrutinib has now garnered approval in both upfront and salvage settings for previously treated 
patients with WM after it demonstrated impressive response rates in rituximab refractory patients 
with an ORR of 90.5% with a major response rate of 73% 2. 2 year PFS and overall survivals 
(OS) were 69.1% and 95.2% respectively in which it received accelerated approval. 
 
Genomic alterations leading to WM development have been identified and can impact on clinical 
presentation and response to novel therapies. In 2012, Treon et al identified MYD88 L265P 
mutations in 91% of LPL samples with subsequent downstream activation of NF kappa B 
signaling. These studies also identified WHIM-like CXCR4 mutations as impaciting on 
lymphomagenesis and response to ibrutinib 20,21. Since those seminal publications, a host of other 
relevant genes have been identified as recurrently mutated and playing a role in pathogenesis 
including genes such as ARID1A, ARIDA1B, CD79B, MLL2, TP53, MYBBP1A, HIVEP2, and 
LYN 3.  
 
In 2015, Treon et al published response rates to ibrutinib based on mutational status of these two 
genes 2. The authors showed that patients with mutated MYD88 and wild type (wt) CXCR4 had 
the best response compared to those with both mutated MYD88 and CXCR4, major response 
rates of 91.7% vs. 61.9% respectively. The patients who were wt for both mutations had the 
worst response rates demonstrating a major response rate of only 28.2%. While responses for 
ibrutinib can be durable22, most remain as only partial responses (PR) and resistance to ibrutinib 
has been documented requiring novel therapeutic combinations to overcome or prevent disease 
resistance and deepen responses.   
 
3. Rationale 
 
Ibrutinib a potent inhibitor of Bruton’s tyrosine kinase (BTK) has been approved by the Federal 
Drug Administration (FDA) for patients with untreated and relapsed WM 2. Despite an 
impressive ORR of 90.5%, the majority of patients only achieve partial responses (PRs) with the 
median IgM nadir at approximately 800mg/dL at time of best response demonstrating a 2 year 
progression free survival (PFS) of 69.1% 2. Additionally, when ibrutinib dosing is interrupted 
there is a rapid rise in IgM off of the drug suggesting ibrutinib’s dominant impact is upon the 
inhibition of IgM secretion rather than elimination of the malignant clone. 
 
As long as the malignant clone persists, the patient remains at risk for rapid return of the disease 
with any interruption of treatment or upon developing resistance to ibrutinib. In addition, given 


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the current paradigm of continuous therapy patients remain at risk to developing toxicities 
related to long term treatment. As a result, additional therapeutic options are required. As WM is 
a disease characterized by intra-clonal differentiation, any therapy to be highly effective has to 
be able to attack lymphocytes, plasmacytoid lymphocytes, and plasma cells. Ibrutinib’s efficacy 
in other low grade B cell malignancies and lack of efficacy in myeloma would suggest its 
greatest effect is on the lymphocyte population and not on the plasmacytoid or plasma cell 
populations.   
 
Increasing evidence suggests the cell of origin for WM is an activated memory B cell with ~50-
70% of cases demonstrating some level of CD38 expression 5-7. Cell lines models of WM also 
have demonstrated to have high expression of CD38 23. Daratumumab is a monoclonal antibody 
targeting CD38 and is currently FDA approved for use in multiple myeloma 8,9. Importantly, 
there is recent evidence that by targeting CD38 with daratumumab, B cell receptor signaling can 
be attenuated enhancing the activity of ibrutinib in preclinical models (Paulus ASH 2017).  
 
The hypothesis of the study is that combination therapy with ibrutinib and daratumumab in 
patients with WM will be safe, effective, and result in deeper responses with improved durability 
over that seen historically with ibrutinib monotherapy. This study will provide the scientific 
community with preliminary evidence of activity of this novel combination in WM and provide a 
platform for future studies investigating this combination. 
 
4. Risk/Benefit Assessment  
 
 
The benefits of treatment and knowledge gained from this study outweigh risk of combination 
therapy to subjects. Daratumumab is currently an FDA approved therapy for multiple myeloma 
that has been safely combined with multi-modality treatments with good safety profile with 
outstanding effects on disease control. Ibrutinib is a well tolerated and effective FDA approved 
therapy for WM and has been safely combined with rituximab and CIT regimens in other 
histologies such as CLL.  
 
5. Correlative Studies 
 
 
Samples will be collected at prespecified time points as outlined in Section 9. All baseline 
correlative samples will be collected during screening upon a subject’s signing of informed 
consent. Samples will be collected for study specific use and will be retained for future unknown 
testing. Samples will be protected from patient identifiers and coded with subject ID numbers 
that will be generated upon consenting to the protocol. Only qualified researchers who have been 
approved and deemed collaborators by the principal investigator will be allowed access to 
deidentifed patient samples to perform correlative assays. Samples will be collected and shipped 
within 1 business day and stored in collaboration with laboratories at Mayo Clinic-Jacksonville. 
All specimens collected for future use will be shipped to: 
 
 
 


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Aneel Paulus, M.D. 
Mayo Clinic 
4500 San Pablo Rd. 
Griffin Building Room 132 
Jacksonville, FL 32224 
 
6. Investigational Agents 
 
6.1. Ibrutinib 
 
Ibrutinib is a first-in-class, potent, orally administered covalently binding small-molecule 
inhibitor of Bruton’s tyrosine kinase (BTK) currently under investigation as an anti-cancer agent 
in various B-cell malignancies, AML and in solid tumors. It has garnered FDA approvals in 
mantle cell lymphoma, chronic lymphocytic lymphoma, Waldenstrom’s macroglobulinemia and 
most recently marginal zone lymphoma and chronic GVHD. 
 
6.1.1. Mechanism of Action 
 
Bruton’s tyrosine kinase is an integral protein that mediates downstream signaling of the B cell 
receptor (BCR). In WM, BTK is constitutively activated and directly interacts with MYD88 
L265P mutants resulting in robust BTK activity. Inhibition of BTK with ibrutinib decreases 
MYD88 L265P mediated complexing, resulting in decreased Nf Kappa B activation and 
increased apoptotic activity and cell death after exposure to ibrutinib24.   
 
6.1.2. Nonclinical Studies-Ibrutinb 
 
Ibrutinib has been evaluated in vitro for its ability to inhibit purified BTK and other members of 
Tec family kinases. B cell receptor signaling has been demonstrated to be inhibited via inhibition 
of BTK autophosphorylation at an inhibitory concentration (IC50) of 11nM 25. Ibrutinib inhibited 
the proliferation of cell lines derived from patients with DLBCL at concentrations of 1-2nM. 
Studies performed with primary CLL cells, ibrutinib reduced proliferation at concentrations of 
500-1000nM. In Waldenstrom’s cell lines, ibrutinib reduced cell growth but only at 1uM and 
was dose dependent. Exposure to ibrutinib did not affect cellular proliferation or viability. 
Ibrutinib was able to completely abrogate BTK autophosphorylation but that phosphorylation by 
upstream LYN/SYK was actually augmented. In WM cell lines ibrutinib was able to inhibit ERK 
phosphorylation but AKT activation was not abrogated which is not the case in CLL or MCL cell 
lines. Lastly it was demonstrated that the BCR signalosome is not critical for CXCL12 induced 
responses in WM and only affect BCR controlled integrin adhesion thus mobilizing malignant 
cells from the protective niches of the lymphoid organs 26. 
 
6.1.3. Nonclinical Pharmacokinetics and Metabolism-Ibrutinib 
 
Ibrutinib is metabolized by CYP3A. In both animals and humans, ibrutinib was metabolized 
primarily by hydroxylation of the phenyl moiety, opening of the piperidine with reduction to a 


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primary alcohol or carboxylic acid, and epoxidation of the acrolein moiety. In vitro studies 
indicate ibrutinib is a weak inhibitor of CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and 
CYP3A4/5. Both ibrutinib and its main metabolite are at most weak inducers of CYP450 thus it 
is unlikely to involve drug-drug interactions with other drugs involving CYP450 enzymes.  
 
In rats, dogs and humans excretion of ibrutinib-related radioactivity occurred principally via 
feces with less than 3.3% of administered radioactivity recovered in the urine of rats and dogs. 
Biliary excretion was confirmed as the major route of elimination in rats. 
 
6.1.4. Toxicology-Ibrutinib 
 
The maximum nonlethal dose of ibrutinib following administration by oral gavage was 
2000mg/kg for mice, 400mg/kg for female rats and 1000mg/kg for male rats. The no observed 
adverse effect level (NOAEL) was found to be 100mg/kg/day for males and 50mg/kg/day for 
female rats. Clinical histologic signs of toxicity included adverse effects on body weight (weight 
gain), diarrhea, lymphoid depletion, intestinal inflammation and acinar atrophy of the pancreas. 
With recovery periods up to 6 weeks partial or complete resolution of all histopathologic changes 
occurred in the specific tissues. There was no evidence of genotoxicity in any of the assays used 
to assess this parameter.   
 
6.1.5. Clinical Studies-Ibrutinib 
 
In WM, 2 pivotal trials have been completed and reported. In 2015, Treon et al reported on the 
initial efficacy in a Phase II study enrolling 63 rituximab refractory WM subjects 2. In this report 
the median serum IgM level decreased from 3520mg/dL to 880 mg/dL at time of best response. 
An overall response rate (ORR) 90.5% with major responses defined as, partial response (PR), 
very good partial response (VGPR) or complete response (CR), of 73%. Mutational genotypes 
were associated with responses with mutated MYD88 L265P only subjects with 91.2% achieving 
a major response. Subjects with mutated MYD88 and mutated CXCR4 had a major response rate 
of 61.9% and those with wt sequences had a major response rate of only 28.6%. At 24 months 
the estimated rate of PFS was 69.1% and the OS was estimated at 95.2% 
 
Safety analysis revealed 15% of patients experienced grade 3 or greater neutropenia, 13% 
experienced grade 3 or greater thrombocytopenia. Grade 3 or greater nonhematologic toxicity 
was rare with the vast majority of toxicities considered Grade 2 or less. The most common Grade 
2 toxicities were related to gastrointestinal disorders and infections with up to 6% of patients 
experiencing grade 2 reflux or pneumonias. Grade 2 or greater atrial fibrillation was noted in 5% 
of patients with only 2% of patients experiencing post procedural bleeding.   
 
In 2017, the iNNOVATE investigators published a sub study analysis reporting on the efficacy 
and safety of single agent ibrutinib in relapsed refractory WM patients. The study is a currently 
ongoing international randomized Phase 3 study accruing patients with relapsed rituximab 
refractory disease. The study randomized patients to 3 arms; rituximab plus ibrutinib, rituximab 
plus placebo, or ibrutinib alone. The published data focused on the results from the ibrutinib only 


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arm. In total 31 patients were accrued to the ibrutinib only arm between August 2014 and 
February 2015. Thirteen (42%) of the 31 patients had high-risk disease per the International 
Prognostic Scoring System Waldenstrӧm Macroglobulinemia. At a median follow-up of 18.1 
months, the overall response rate was 90% with 71% of patients attaining a major response. The 
estimated 18 month PFS was 86% and the 18 month OS was 97%. Baseline hemoglobin of 10.3 
g/dL increased to 11.4 g/dL after 4 weeks of treatment. Grade 3 or greater adverse events were 
neutropenia (13%), hypertension (10%), and anemia, thrombocytopenia, and diarrhea (6%) each. 
Serious adverse events occurred in 10 patients (32%) and most often related to infections. Five 
patients discontinued ibrutinib; 3 due to progression and 2 due to adverse events. 
 
Given the results of the Phase II data the Federal Drug Administration (FDA) gave accelerated 
approval for the treatment of patients in both treatment naïve and relapsed refractory settings. 
 
6.1.6. Clinical Pharmacokinetics and Metabolism-Ibrutinib 
 
The absolute bioavailability of ibrutinib administered in capsule formulation after 560mg oral 
dose was found to be 2.9%. Ibrutinib absorption from the GI tract is complete as there is minimal 
fecal excretion of unchanged ibrutinib in combination with high levels of oxidative metabolites. 
Plasma protein binding of ibrutinib in human plasma is 97.3% and 91.0% respectively with a 
volume of distribution of 683L after an IV dose of 100ug of ibrutinib. 
 
The drug is extensively metabolized by CYP3A mediated metabolic pathways mainly 
epoxidation of the acryloyl moiety and hydroloysis to form the dihydrodiol. Excretion is 
predominantly via the feces with approximately 80% recovered mostly within 2 days with only 
8% excreted in the urine. The half-life of ibrutinib is 4 to 6 hours.  
 
6.1.7. Clinical Safety-Ibrutinib 
 
Based on available data, ibrutinib has an acceptable safety profile as both monotherapy and when 
combined with chemo immunotherapy among the B cell malignancies studied. The most 
frequently treatment emergent adverse events in > 10% of patients were diarrhea, fatigue and 
nausea. The most common serious treatment adverse events in >1% of subjects were pneumonia 
and atrial fibrillation.  
 
6.2. Daratumumab 
Daratumumab is a human immunoglobulin G1 kappa monoclonal antibody that binds CD38 
expressing cells with high affinity in several hematologic malignancies.  
 
6.2.1. Mechanism of Action-Daratumumab 
 
Daratumumab is a human IgG mAb immunotherapy with high binding affinity to CD38 which 
induces cell death through multiple mechanisms of action. Complement-dependent cytotoxicity 
(CDC), antibody dependent cellular cytotoxicity (ADCC) and antibody dependent cellular 
phagocytosis as well as direct cytotoxicity by induction of apoptosis Fc gamma receptor 


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crosslinking. Daratumumab eliminates Tregs, B regs and leads to expansion of both CD4 and 
CD8 helper T cells.  
 
6.2.2. Nonclinical Studies-Daratumumab 
In mouse xenograft models, daratumumab reduced tumor growth in both preventative and 
therapeutic settings. In vitro studies using bone marrow mononuclear cells from patients with 
multiple myeloma demonstrated increased killing of tumor cells when combined with 
lenalidomide or bortezomib. In WM daratumumab can exert direct lethal effect on cell lines and 
ADCC not CDC appears to be the dominant mechanism of action. ADCC mediated toxicity was 
contingent on CD38 expression and that ibrutinib resistant clones can down regulate CD38 
expression 27. 
 
6.2.3. Nonclinical Pharmacokinetics and Metabolism-Daratumumab 
 
The half-life increased from 36 to 132 hours over the course of 6 weekly at 5mg/kg and 
increased from 103 to 586 hours at 25mg/kg. Dosing gave rise to a more than dose proportional 
exposure suggestive of target mediated disposition.  
 
6.2.4. Nonclinical Toxicology-Daratumumab 
 
Two primary toxicities observed in primate studies were infusion related reactions and 
thrombocytopenia. Infusion reactions occurred during the first but not subsequent infusions. The 
thrombocytopenia was reversible upon clearance of the drug and the drug has a 15 fold increased 
affinity for chimpanzee platelets over human platelets.  
 
6.2.5. Clinical Studies-Daratumumab 
 
Daratumumab currently has 3 FDA approved indications to treat patients with multiple 
myeloma. Daratumumab is indicated as monotherapy in patients who have received at least three 
prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory agent 
(IMiD) or who are double refractory to a PI and IMiD, in combination with pomolidamide and 
dexamethasone in patients who have received at least two prior therapies including lenalidomide 
and a PI, and in in combination with lenalidomide and dexamethasone who have received at least 
one prior therapy. No clinical studies with daratumumab have been performed today in patients 
with WM.   
 
6.2.6. Clinical Pharmocokinetics and Metabolism-Daratumumab 
 
The half-life of daratumumab is both concentration and time dependent. After the first dose of 
16mg/kg of daratumumab the half-life was 9 days and is expected to be 18 days with repeated 
dosing. Exposure efficacy analyses on the data from combination therapies suggest that 
maximum clinical benefit on progression free survival, duration of response and overall response 
rate has been attained for the majority of the subjects with an acceptable safety profile at the 
recommended dose, 16mg/kg. Despite decreasing concentration of daratumumab over time the 


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current dosing schedule was adequate to produce the concentration level that can maintain the 
level of target saturation at Q4W dosing interval. Daratumumab peak and trough concentrations 
at similar timepoints across monotherapy and combination studies have had no impact on the 
concentration of daratumumab.  
 
6.2.7. Clinical Safety-Daratumumab 
 
Grade 3 or 4 treatment emergent adverse events (TEAE) were reported in 56% of sujects treated 
with 16mg/kg. The most frequently reported Grade 3 or 4 TEAE were anemia (17%), 
neutropenia (12%), lymphopenia (6%), leukopenia, pneumonia and hypertension (5% each). 
Serious adverse events were reported in 33% of subjects treated with 16mg/kg. Most frequently 
noted were pneumonia (6%), pyrexia, general health debilitation, hypercalcemia (3%). In the 
16mg/kg group, 14 subjects (9%) died 11 dying from progressive disease the remaining due to 
TEAE though none were felt related to daratumumab.  
 
7. Subject Selection 
 
7.1 Study Population 
 
Subjects with a diagnosis of WM and meeting requirements for active therapy as defined by the 
2nd International Workshop on Waldenstrom’s Macroglobulinemia 28 and meet the inclusion and 
exclusion criteria will be eligible for participation in this study. See Appendix A for indications 
for therapy.   
 
7.2. Inclusion Criteria 
 
 
 
 
1) 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 (see Appendix A 
for indications for therapy).  
2) Age ≥18 years of age 
3) Ibrutinib naïve or previously treated patients currently on ibrutinib with a plateau in disease 
response are eligible to participate. 
a) Ibrutinib naïve subjects may be either treatment naïve or previously treated but ibrutinib 
naïve to enter cohort A.  
b) 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 IgM measurements as defined above. 
4) Subjects must have measurable disease defined by a serum IgM level ≥0.5g/dL 
5) Eastern Cooperative Oncology Group performance status of 0-2 
6) Hematology values must be within the following limits:   


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a. 
Absolute neutrophil count (ANC)  1000/mm3 independent of growth factor support 
for 7 days of study entry if cytopenias are due to marrow involvement. 
b. Platelets  50,000/mm3 independent of transfusion support within 7 days of study 
entry. TPO mimetics are not allowed to meet eligibility criteria. 
c. 
Hemoglobin ≥ 8g/dL, independent of transfusion support within 7 days of study 
entry 
7) 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 
8) 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. 
9) Women of childbearing potential must have a negative serum (beta-human chorionic 
gonadotropin [-hCG]) or urine pregnancy test at Screening. Women who are pregnant or 
breastfeeding are ineligible for this study. 
Subjects must 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.  
 
7.3. Exclusion Criteria  
 
 
 
1) Subject does not have a recorded IgM level recorded within 3 months prior to ibrutinib 
initiation. 
2) 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. 
3) Subjects in cohort B experiencing ongoing non hematologic toxicities attributable to ibrutinib 
> Grade 1 will be excluded from study entry.    
4) Major surgery or a wound that has not fully healed within 4 weeks of enrollment. 
5) Evidence of disease transformation at time of enrollment.  
6) Waldenstrom’s complicated by amyloidosis 
7) Known central nervous system lymphoma.  


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8) History of stroke or intracranial hemorrhage within 6 months prior to randomization. 
9) Requires 
anticoagulation 
with 
warfarin 
or 
equivalent 
vitamin 
K 
antagonists 
(eg, phenprocoumon). 
10) 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. 
11) 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. 
12) 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. 
13) 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. 
14) Vaccinated with live, attenuated vaccines within 4 weeks of randomization. 
15) Seropositive for human immunodeficiency virus (HIV) 
16) 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. 
 
17) 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). 
18) 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. 
19) Active malignancy not treated with curative intent within 2 years of study entry. 
Nonmelanomatous skin cancers and cervical carcinoma in situ are excluded.  
 
8. Registration Procedures 
 
8.1. Patient Registration 
 


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Patients will be centrally registered with the Weill Cornell Medicine (WCM), Division of 
Hematology and Medical Oncology, Joint Clinical Trials Office.  To register a patient, email the 
following documents to your assigned registration contact: 
 
 WCM Patient registration form 
 First and last page of the fully executed informed consent form, plus additional 
pages if checkboxes for correlative studies are required. 
 Fully executed HIPAA research authorization form (if separate from the consent 
document) 
 Eligibility checklist signed and dated by investigator and research nurse 
 Documentation of any eligibility waivers granted  
 Redacted source documentation to verify eligibility 
 
Central registration documents should be scanned/emailed Monday to Friday from 9:00 AM to 
4:00 PM EST to study investigators and jctoiit@med.cornell.edu, along with all other assigned 
registration contacts for this study. Central registration information is reviewed and entered into 
the REDCap database by the Coordinating Center.  Patients will be assigned a sequence number 
for the protocol.  The registering institution will then be emailed a copy of the sequence number 
as confirmation of a completed registration.  Subjects should NOT receive any study medication 
prior to receipt of registration confirmation.  Note that attachments larger than 4.5 MB are not 
accepted, so larger attachments should be split into more than one email. 
 
Registration of patients cannot occur until the Coordinating Center has received proper 
documentation from the registering institution of IRB approval, including a copy of the current 
approval letter, stamped consent and signed FDA Form 1572, along with other required regulatory 
documents.  These documents will be requested at site activation and may be scanned/emailed to 
the Coordinating Center.   
 
9. Study Procedures 
 
Eligible subjects will be identified by the treating investigator and be recommended for the study 
based on potential to meet eligibility criteria. Identified subjects will be brought to clinic to 
initiate the informed consenting process. Once a subject agrees to participate they will be 
provided an informed consent form detailing the study design, investigational agents, risks, 
benefits and subject and investigator responsibilities prior to obtaining their signature.  
 
Once consented, subjects will enter the screening phase which will last up to 28 days, during 
which time confirmation of eligibility and baseline evaluations will take place. Subjects meeting 
eligibility will then be assigned to one of two cohorts depending on their treatment history. 
Cohort A subjects will be ibrutinib naïve patients and cohort B will be subjects currently on 
ibrutinib who have reached a response plateau. Twelve patients will be enrolled into each cohort.  
 
Subjects will then enter the treatment phase with initial induction followed by the maintenance 


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phase as defined by the protocol. Subjects will be followed by clinical exams, laboratory 
investigations and imaging until disease progression unacceptable toxicity or completion of 2 
years of therapy. After completion of combination therapy, subjects will be followed for an 
additional year on single agent ibrutinib.  
 
9.1. Schedule of Evaluations 
Table 1. Schedule of events 
 
 
Study Procedure 
Screening 
Cycle -1  
Day -28 
(Cohort A only 
prior to 
daratumumab 
dosing) 
Cycle 1 
Cycle 2 
Week 
1 
Week 
2 
Week 
3 
Week 
4 
Week 
5 
Week 
6 
Week 
7 
Week 
8 
Day  
1 
Day  
8 
Day 
15 
Day 
22 
Day   
1 
Day   
8 
Day 
15 
Day 
22 
Daratumumab 
Administrationk 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
Medical history 
X 
X 
X 
 
 
 
X 
 
 
 
Concurrent meds 
X 
X 
X 
 
 
 
X 
 
 
 
Physical exam 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs, height, weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CBC w/differential 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum chemistrya 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SIFE+b 
X 
 
 
 
 
 
 
 
 
 
Immunoglobulin M  
 
X 
X 
 
 
 
X 
 
 
 
Bone marrow 
biopsy/aspiratec 
X 
 
 
 
 
 
 
 
 
 
HIV and Hepatitis Ab 
screeningd 
X 
 
 
 
 
 
 
 
 
 
EKG 
X 
 
 
 
 
 
 
 
 
 
Pulmonary Function 
Testing (FEV1 calculation) 
X 
 
 
 
 
 
 
 
 
 
Blood Type and Screen 
X 
 
X 
 
 
 
 
 
 
 
Research sample  
(aspirate)c 
X 
 
 
 
 
 
 
 
 
 
Research sample 
(peripheral blood)j 
X 
 
 
 
 
 
 
 
 
 
Adverse event evaluation 
 
Continuously and at each treatment or study visit 
Radiologic evaluatione 
X 
Radiologic measurements should be performed on Day 1 Cycle 7, 13, 19, 25, 31, 37 
day 1 evaluation (+15 day window after Day 1 is allowed) 
B-HCG 
Xf 
 
 
 
 
 
 
 
 
 


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Study Procedure 
Cycles 3-6 
Cycles 
7-13 
Day 1 
Cycles 
14, 15, 
17, 18, 
20, 21, 
23, 24 
Day 1 
(non-
study 
visits) 
Cycles 
16, 19, 
22 Day 
1 
(study 
visits) 
Cycles 
25, 28, 
31, 34 
Day 1 
(study 
visits) 
EOT Cycle 
37 Day 1 
visit or 28 
days after 
coming 
off-study  
Day 1 
Day 15 
Daratumumab Administrationk 
X 
X 
X 
X 
X 
  
  
Informed consent 
  
  
  
  
  
  
  
Demographics 
  
  
  
  
  
  
  
Medical history 
X 
  
X 
X 
X 
X 
X 
Concurrent meds 
X 
  
X 
X 
X 
X 
X 
Physical exam 
X 
  
X 
X 
X 
X 
X 
Vital signs, height, weight 
X 
X 
X 
X 
X 
X 
X 
CBC w/differential 
X 
X 
X 
X 
X 
X 
X 
Serum chemistrya 
X 
X 
X 
X 
X 
X 
X 
SIFE+b 
Xg 
  
Xh 
  
X 
X 
  
Immunoglobulin M  
X 
X 
X 
X 
  
  
X 
Bone marrow biopsy/aspiratec 
Xi 
  
  
  
  
  
Xi 
HIV and Hepatitis Ab screeningd 
Xd  
  
Xd   
  
Xd   
Xd   
  Xd  
EKG 
  
  
  
  
  
  
  
Pulmonary Function Testing 
(FEV1 calculation) 
  
  
  
  
  
  
  
Blood Type and Screen 
  
  
  
  
  
  
  
Research sample  (aspirate)c 
Xi 
  
  
  
  
  
Xi 
Research sample (peripheral 
blood)j 
  
  
Xj 
  
  
  
Xj 
Adverse event evaluation 
Continuously and at each treatment or study visit 
Radiologic evaluatione 
Radiologic measurements should be performed on Day 1 Cycle 7, 13, 19, 
25, 31, 37 day 1 evaluation (+15 day window after Day 1 is allowed) 
B-HCG 
  
  
  
  
  
  
  


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a. Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, 
phosphorus, potassium, total protein, SGOT[AST], SGPT[ALT], sodium. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
b. SIFE+ should include serum protein electrophoresis, immunofixation, serum immunoglobulin G, A, M levels, 
free kappa light chains, free lambda light chains. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c. Bone marrow biopsy will be performed at baseline and then to confirm complete remission as is standard of care. 
At baseline, 1 green top tube and 1 lavender top tube will be collected for research.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
d. Hepatitis ab screening should include Hepatitis A IgG with reflex to IgM, Hepatitis B surface Ag, Hepatitis B 
surface ab, Hepatitis B core ab, Hepatitis C ab. If Hepatitis B surface or core ab, or Hepatitis C ab are positive, 
reflex testing with PCR for either HBV DNA or HCV RNA should be performed. HBV serology testing does not 
need to be repeated if performed within three months prior to first dose. 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. Subjects with a history of HBV infection will be 
monitored for reactivation by HBV DNA by PCR every 3 cycles during treatment (e.g. Cycle 4, 7, 10, etc.), at end 
of daratumumab treatment (e.g. Cycle 25), and for up to 6 months post-daratumumab therapy (e.g. Cycle 28 and 31). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
e. Radiologic evaluation is defined as CT chest, abdomen and pelvis with contrast. For patients ineligible for 
contrast CT chest non con with MRI abdomen and pelvis is default. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
f. Serum pregnancy test (women of childbearing potential). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
g. SIFE+ will only be required Cycle 4 D1, the remaining cycles serum IgM will be recorded only.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
h. SIFE+ will only be required for Cycle 7 D1, Cycle 13 D1, the remaining cycles serum IgM will be recorded only. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
i. Research biopsy and aspirate at Cycle 4 Day 1 (+ 15 day window) and then again at progression; 1 green top tube 
and 1 lavender top tube will be collected. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
j. Peripheral blood samples (2 lavender top tubes) will be collected at screening, Cycles 7, 13, 19, and 25, and at 
EOT. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
k. Required study visits include screening, Day 1 of Cycle -1, 1-13, and every three cycles thereafter through Cycle 
37/EOT. Non-study visits for daratumumab administration include Days 8, 15, and 22 of Cycle 1-2, Day 15 of 
Cycles 3-6, and Day 1 of Cycles 14, 15, 17, 18, 20, 21, 23, and 24. See Section 8.5 for more information.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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9.2.      Screening Phase 
  
 Informed consent 
 Demographic collection 
 Medical history 
 Concurrent medication reconciliation 
 Physical exam 
 Vital signs (including height and weight) 
 ECG 
 Pulmonary Function Testing with FEV1 measurement (only required 
for subjects with known history of Chronic Obstructive Pulmonary 
Disease or Reactive Airway Disease) 
 CBC with differential 
 Serum chemistry as outlined in Table I (CMP, LDH, phosphorus) 
 Serum pregnancy test (women of childbearing potential only) 
 Serum protein electrophoresis and immunofixation with free light 
chain analysis 
 Hepatitis and HIV screening  
o HBV serology testing does not need to be repeated if 
performed within three months prior to first dose. 
o If Hepatitis B surface or core ab or Hepatitis C ab are positive, 
reflex testing with PCR for either HBV DNA or HCV RNA 
should be performed. Subjects with serologic findings 
suggestive of vaccination (anti-HBs positivity as the only 
serologic marker) and known history of vaccination do not 
need HBV DNA PCR.  
 Blood typing 
 Bone marrow biopsy and aspirate collection (2 Research tubes 1 green 
top and 1 lavender top) 
 Peripheral blood research tube (2 lavender top from peripheral blood) 
 
9.3.       Treatment Phases  
 
Treatment will consist of the following phases: 
 
 Ibrutunib Lead-in (Cohort A only) 
 Induction Phase 
 Continuation Phase 
 Maintenance Phase 
 Ibrutinib Monotherapy Phase 
 
Ibrutinib Lead-In (Cohort A only) 
 


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The ibrutinib lead-in will apply to subjects in Cohort A only and will consist of one 
cycle of continuous daily ibrutinib monotherapy (Cycle -1) prior to beginning 
combination treatment as part of the induction phase. 
 
Induction Phase 
 
The induction phase will consist of two cycles of continuous ibrutinib daily dosing in 
combination with eight weekly doses of daratumumab. Daratumumab dosing can occur 
within a window of ±3 days. Induction will be defined as the first 8 weeks of 
combination treatment. 
 
Subjects in Cohort A will begin the induction phase after the one cycle ibrutinib lead-in. 
Subjects in Cohort B will begin overall study treatment with Cycle 1 of the induction 
phase. 
 
Continuation Phase 
 
The continuation phase will consist of four cycles of continuous ibrutinib daily dosing in 
combination with bimonthly dosing of daratumumab (Day 1 and 15 of each cycle [±3 
days]). Subjects from both cohorts will begin this phase after the induction phase. 
 
Maintenance Phase 
 
The maintenance phase will consist of 23 cycles of continuous ibrutinib daily dosing in 
combination with monthly dosing of daratumumab (Day 1 of cycle [±3 days]). Subjects 
from both cohorts will begin this phase after the continuation phase.  
 
Ibrutinib Monotherapy Phase 
 
The ibrutinib monotherapy phase will consist of 12 cycles of continuous ibrutinib daily 
dosing. Subjects from both cohorts will begin this phase after the maintenance phase.  
 
 
Study Visit Schedule 
 
Day 1 of Cycles -1 (Cohort A only), Cycles 1 – 13 and every 3 cycles thereafter (e.g. 16, 
19, 22, 25, etc.), and End of Treatment will be considered required study visits at which 
all procedures and labs listed below and in Table 1 will be performed. 
 
Subjects will also have doctor visits on each day of treatment with daratumumab that 
does not coincide with a required study visit (i.e. Days 8, 15, and 22 of Cycle 1-2, Day 15 
of Cycles 3-6, and Day 1 of Cycles 14, 15, 17, 18, 20, 21, 23, 24 – referred to as non-
study visits) at which the procedures and labs listed below and in Table 1 should be 


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performed prior to daratumumab administration in accordance with standard of care and 
per investigator discretion. 
 
 
 
 
 
9.3.1. Ibrutinib Lead-In (Cohort A only, Cycle -1) and Induction Phase (Cycles 1 
and 2) 
 
Cycle -1 D1 Cohort A Only 
 
 Medical history 
 Adverse event evaluation 
 Concurrent medications 
 Physical exam 
 Vital signs (including height and weight) 
 CBC with differential 
 Serum Chemistry (CMP, LDH, Phosphorus) 
 Immunoglobulin M measurement 
 Blood samples for research use 
 
Cycle 1 and 2 Day 1 
 
 Medical history 
 Concurrent medications 
 Physical exam 
 Vital signs (including height and weight) 
 CBC with differential 
 Serum chemistry (CMP, LDH, phosphorus) 
 Immunoglobulin M measurement 
 Blood type and screen (Cycle 1 only) 
 Adverse event evaluation 
 Daratumumab infusion 
 
Cycle 1 and 2 Days 8, 15, and 22 (non-study visits) 
 
 Physical exam 
 Vital signs (including height and weight) 
 CBC with differential 
 Serum chemistry (CMP, LDH, phosphorus) 
 Adverse event evaluation 
 Daratumumab infusion 
 
 
 
9.3.2. Continuation phase (Cycles 3-6)  
 


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The continuation phase will consist daratumumab infusions every other week starting from Cycle 
3 Day 1 through Cycle 6. During this period, study visits will occur on day 1 of each cycle. On 
non-study visits (i.e. Day 15 of each cycle), subjects will have daratumumab infusions, routine 
office visits, as well as routine lab work at the discretion of the investigator. On study visits, the 
listed labs and procedures below will occur.  
 
Cycle 3-6 Day 1 
 
 Medical history 
 Concurrent medications 
 Physical exam 
 Vital signs (including height and weight) 
 CBC with differential 
 Serum chemistry (CMP, LDH, phosphorus) 
 SIFE+ (Cycle 4 only) 
 Immunoglobulin M measurement 
 Research bone marrow biopsy/aspirate (1 green top and 1 lavendar top tube) (Cycle 
4 only [+15 day window]) 
 Daratumumab infusion.  
 HBV DNA PCR if at risk for reactivation (Cycle 4 only) 
 
Cycle 3-6 Day 15 (non-study visits) 
 
 Vital signs (including height and weight) 
 CBC with differential 
 Serum chemistry (CMP, LDH, phosphorus) 
 Immunoglobulin M measurement 
 Adverse event evaluation 
 Daratumumab administration 
 
9.3.3. Maintenance phase (Cycles 7-24) 
 
The maintenance phase will consist of daratumamb infusions every 28 days starting Cycle 7 Day 
1 study visits will occur every 28 days through Cycle 13 day 1. Subjects will be treated with 
daratumumab on all study visit days. From Cycle 13 day 1 up and through Cycle 24 day 1, 
daratumumab infusions will be given monthly but study visits will only occur every 3 cycles. On 
study visits the below listed labs and procedures will occur. 
 
Cycles 7 – 13, 16, 19, and 22 
 
 Medical history 
 Concurrent medications 
 Physical exam 


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 Vital signs (including height and weight) 
 CBC with differential 
 Serum chemistry (CMP, LDH, phosphorus) 
 SIFE+ (cycles specified in schedule of events) 
 Immunoglobulin M measurement (cycles specified in schedule of events) 
 Peripheral blood research tube (2 lavendar top tubes) (Cycle 7, 13, 19, and 25 only) 
 Adverse event evaluation 
 Daratumumab infusion 
 Radiographic evaluation (C7, C13, C19, day 1 only [+15 day window]) 
 HBV DNA PCR if at risk for reactivation (Cycle 7, 10, 13, 16, 19, and 22 only) 
 
 
Cycles 14, 15, 17, 18, 20, 21, 23, and 24 (non-study visits) 
 
 Medical history 
 Concurrent medications 
 Physical exam 
 Vital signs (including height and weight) 
 CBC with differential 
 Serum chemistry (CMP, LDH, phosphorus) 
 Immunoglobulin M measurement 
 Adverse event evaluation 
 Daratumumab infusion 
 
9.3.4. Ibrutinib Monotherapy phase 
 
The ibrutinib monotherapy phase will occur after patients have completed 24 cycles of 
combination therapy. After Cycle 24, study visits will still occur every 3 months but no 
daratumumab infusions will be given. On study visits, the below listed labs and procedures will 
occur. 
 
Cycles 25, 28, 31, and 34 
 
 Medical history 
 Concurrent medications 
 Physical exam 
 Vital signs (including height and weight) 
 CBC with differential 
 Serum chemistry (CMP, LDH, phosphorus) 
 SIFE+  
 Peripheral blood research tube (2 lavendar top tubes) (Cycle 25 only) 
 Adverse event evaluation 


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 Radiographic evaluation (Cycle 25 and 31 day 1 only [+ a 15 day window])  
 HBV DNA PCR if at risk for reactivation (Cycle 25, 28, and 31 only or every 12 
weeks for up to 6 months post-daratumumab therapy)  
 
9.3.5. End of Treatment or Progression 
 
Subjects that complete 3 years of therapy will then come off study. At C37D1, subjects will have 
EOT procedures collected. Additionally any subject that comes off for therapy early for toxicity, 
or progression will be required to return 28 days later for EOT procedures. 
 
EOT (to be done at Cycle 37 or at time of treatment discontinuation) 
 
 Medical history 
 Concurrent medications 
 Physical exam 
 Vital signs (including height and weight) 
 CBC with differential 
 Serum chemistry (CMP, LDH, phosphorus) 
 Immunoglobulin M 
 Research bone marrow biopsy/aspirate (at time of progression (1 green top and 1 
lavendar top) 
 Peripheral blood research tubes C37D1 (2 lavendar top tubes) 
 Adverse event evaluation 
 Radiographic evaluation (Cycle 31 day 1 only [+ a 15 day window])  
 
10. Treatment Administration 
 
Treatment will be administered on an outpatient basis. Appropriate dose modifications for 
daratumumab and ibrutinib are described in Section 6.   
 
Ibrutinib will be administered as 3, 140mg capsules daily for a total daily dose of 420mg. 
Subjects will be asked to take the capsules orally with or without food. Subjects will take the 
pills on a continuous daily basis with once cycle of treatment consisting of 28 days. Subjects will 
take their first dose of ibrutinib before or after their daratumumab infusion. On days in which 
they do not receive a daratumumab infusion, they will be asked to take their ibrutinib capsules at 
the same time each day. Subjects will continue daily dosing of ibrutinib until disease 
progression, toxicities, or study completion whichever comes first.  
 
Daratumumab will be administered per the current package insert. Subjects will receive 16mg/kg 
weekly for 8 total doses. They will then receive 16mg/kg of daratumumab every other week 
starting on Cycle 3-6. From Cycle 7-24, subjects will receive daratumumab 16mg/kg on an every 
4 week basis until disease progression, toxicities or study completion whichever comes first. 
Subjects will be premedicated with 100mg of methylprednisolone intravenously (IV), 650mg of 


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acetaminophen PO, and 25-50mg of Benadryl IV all taking 30 minutes prior to infusions with 
daratumumab. Methylprednisolone dosing may be reduced to 60mg IV with subsequent doses 
after the first infusion if no adverse events are recorded. Subjects will be asked to take 20mg of 
methylprednisolone PO for two days after each infusion and this can be eliminated after 
completion of the first cycle at the investigators discretion if no adverse events are recorded. 
 
10.1. 
General Concomitant Medication and Supportive Care Guidelines 
 
Supportive medications in accordance with standard practice (such as for emesis, diarrhea, etc.) 
are permitted and patient should receive full supportive care during study participation (including 
fluids and electrolyte replacement, and antibiotics when appropriate). Use of neutrophil growth 
factors (filgrastim and pegfilgrastim) or red blood cell growth factors (erythropoietin) is 
permitted per institutional policy. Transfusions may be given in accordance with institutional 
policy. After consultation with the Sponsor the following may be considered; localized hormonal 
or bone sparing treatment for non-B-cell malignancies, and localized radiotherapy for medical 
conditions other than the underlying B-cell malignancies. Short courses (≤14 days) of steroid 
treatment for non-cancer related medical reasons (eg, joint inflammation, asthma exacerbation, 
rash, antiemetic use and infusion reactions) at doses that do not exceed 100 mg per day of 
prednisone or equivalent are permitted. Treatment for autoimmune cytopenias are permitted for 
<14 days at doses that do not exceed 100 mg per day of prednisone or equivalent. 
 
Primary antiviral prophylaxis is permitted as per local standard of care.  Per protocol, HBV DNA 
testing by PCR is mandatory for subjects at risk for HBV reactivation. 
For subjects who are diagnosed with HBV reactivation while on treatment, study treatment should 
be interrupted until the infection is adequately controlled. If the benefits outweigh the risks, study 
treatment may be resumed with concomitant antiviral prophylaxis as per local standard of care. 
Consult a liver disease specialist as clinically indicated.  
10.2. 
Medications to be Used with Caution with Ibrutinib 
 
Ibrutinib is metabolized primarily by CYP3A4. The co-administration with strong CYP3A or 
moderate CYP3A inhibitors may increase ibrutinib concentrations which may increase the risk of 
drug-related toxicity. Dose modifications of ibrutinib are recommended when used 
concomitantly with posaconazole, voriconazole, and moderate CYP3A inhibitors. Avoid 
concomitant use of other strong CYP3A inhibitors. Avoid grapefruit and seveille oranges.  
 
Avoid concomitant use of strong CYP3A inducers (eg, carbamazepine, rifampin, phenytoin, and 
St. John’s Wort). Consider alternative agents with less CYP3A induction. In vitro studies 
indicated that ibrutinib is not a substrate of P-glycoprotein (P-gp). 
 
A list of common CYP3A inhibitors and inducers is provided in Appendix B. Please see table II 
for dose modification guidelines for ibrutinib if CYP3A inhibitors are required.  
 


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See below Table 2 for dose modification based on CYP3A inhibitor used. 
 
 
 
 
 
10.2.1. Antiplatelet Agents and Anticoagulants 
 
Warfarin or vitamin K antagonists should not be administered concomitantly with ibrutinib. 
Supplements such as fish oil and vitamin E preparations should be avoided. Use ibrutinib with 
caution in subjects requiring other anticoagulants or medications that inhibit platelet function. 
Subjects with congenital bleeding diathesis have not been studied. Subjects requiring the 
initiation of therapeutic anticoagulation therapy (eg, atrial fibrillation), consider the risks and 
benefits of continuing ibrutinib treatment. If therapeutic anticoagulation is clinically indicated, 
treatment with ibrutinib should be held and not be restarted until the subject is clinically stable 
and has no signs of bleeding. Subjects should be observed closely for signs and symptoms of 
bleeding. No dose reduction is required when study drug is restarted. 
 
10.2.2. Management of Minor Surgical Procedures 
 
For minor procedures such as (central line placement, needle biopsy, lumbar puncture, 
thoracentesis, or paracentesis) ibrutinib should be held for at least 3 days prior to the procedure 
and not restarted until 3 days after the procedure. Bone marrow biopsies may be performed while 
on ibrutinib.  
 
10.2.3. Management of Major Surgical Procedures 
 


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For any surgery or procedure that will require sutures or staples for closure, ibrutinib should be 
held for at least 7 days prior to the planned intervention and restarted at least 7 days after the 
procedure at the discretion of the investigator. For emergent surgical interventions, ibrutinib 
should be held immediately and until the site is healed or for at least 7 days whichever is longer.  
 
10.2.4. Prohibited Concomitant Medications on Study 
 
Any non-study protocol related chemotherapy, anti-cancer immunotherapy, experimental 
therapy, or radiotherapy are prohibited while the subject is receiving ibrutinib treatment. 
Corticosteroids for the treatment of the underlying malignancy are prohibited (Refer to Section 
9.1 for further guidance). 
 
11. Duration of Therapy and Criteria for Removal from Study 
 
In the absence of treatment delays due to adverse event(s) greater than 4 weeks from scheduled 
dose, combination treatment may continue for 2 years with 1 year of ibrutinib monotherapy or 
until one of the following criteria applies: 
 
o Disease progression, 
o Intercurrent illness that prevents further administration of treatment, 
o Unacceptable adverse event(s), 
o Patient decides to withdraw from the study, or 
o General or specific changes in the patient’s condition render the patient 
unacceptable for further treatment in the judgment of the investigator. 
 
11.1. 
Duration of Follow Up 
 
The anticipated duration of patients on study will be 3 years. Patients will be followed for 1 year 
after completion of combination treatment, or for 28 days after removal from study, or until 
death, whichever occurs first.  Patients removed from study for unacceptable adverse events will 
be followed until resolution or stabilization of the adverse event even if that period is longer than 
28 days. 
 
12. Dosage and Administration of Study Drugs.  
 
12.1. 
Study Drug Administration Overview 
 
Daratumumab and ibrutinib is to be administered as described in the Schedule of Events Table 1. 
Each cycle is 28 days. The first visit of a cycle should be 4 weeks after the start of the previous 
cycle. The start of each cycle may occur +/- 3 days of the scheduled day in order to 
accommodate the schedule of the site or the subject with Day 1 of each subsequent cycle 
adjusted accordingly to maintain the 28 day cycle duration. During weeks 1-24 daratumumab 
will be given weekly or bi weekly +/- 3 days in order to accommodate the schedule of the site or 
subject. During Screening and prior to daratumumab infusion on C1D1 blood type and screening 


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should be collected. 
 
 
12.1.1. Daratumumab Administration 
 
Daratumumab (16mg/kg) will be administered by IV infusion to subjects initially once weekly 
for 8 weeks, then every other week for 16 weeks, followed by infusion every 4 weeks thereafter 
until disease progression, unacceptable toxicity, or completion of 2 years of therapy.  
Each dose will be calculated based on the subject’s actual weight rounded to the nearest 
kilogram. Dosing will be based off the screening weight unless it changes +/- 10% at which point 
doses will be recalculated. All infusions will be performed as outpatient visits with vital sign 
monitoring to occur per institutional infusion guidelines.  
 
12.1.2. Daratumumab Preinfusion Medications 
 
Preinfusion medications are required for subjects on days they receive daratumumab infusions 
and will receive the following medications prior to each infusion: 
 
 Acetaminophen 650mg orally no more than 1 hour prior to daratumumab infusion 
 Diphenhydramine 25-50mg intravenous or orally 30 minutes prior to infusion.  
 Methylprednisolone 100mg intravenous 30 minutes prior to infusion. If patients tolerate 
the infusion without reactions, a lower dose of 60mg methylprednisolone may be 
substituted for subsequent infusions.  
 
12.1.3. Daratumumab Postinfusion Medications 
 
Subjects will be asked to take 20 mg of methylprednisolone or glucocorticoid equivalent dose for 
2 days post infusion. Consideration should be given to provide short acting beta adrenergic 
receptor agonists to provide supportive care should bronchospasm occur after returning home 
from the clinic. If there are no reactions after 4 doses then post-infusion medications may be 
waived at the investigator’s discretion.  
 
12.2. 
Management of Infusion-Related Reactions 
 
Trained study staff at the clinic should be prepared to intervene in case of any infusion reactions 
occurring, and resources necessary for resuscitation (e.g., agents such as epinephrine and 
aerosolized bronchodilator, also medical equipment such as oxygen tanks, and a defibrillator) 
must be available. Attention to staffing should be considered when multiple subjects will be 
dosed at the same time. 
 
If an infusion-related reaction develops, then the infusion should be paused. Subjects who 
experience adverse events during the infusion must be treated according to the investigator’s 
judgment and best clinical practice. The following guidelines may apply: 
 


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 Subjects should be treated with acetaminophen, antihistamine, or corticosteroids. 
Intravenous saline may be indicated. For bronchospasm, urticaria, or dyspnea, 
subjects may require antihistamines, oxygen, corticosteroids, or bronchodilators. For 
hypotension, subjects may require vasopressors. 
 In the event of a life-threatening infusion-related reaction (which may include 
pulmonary or cardiac events), or anaphylactic reaction, daratumumab should be 
discontinued and no additional daratumumab should be administered to the subject. 
Aggressive symptomatic treatment should be applied. 
 
If an infusion is paused, then a longer-than-anticipated infusion time may occur. Overnight stays 
at the hospital because of slow infusion times should not be reported as a serious adverse event. 
However, if the underlying cause of the delayed infusion time is an adverse event or serious 
adverse event, then that should be reported as such. 
 
12.2.1. Infusion-Related Events of Grade 1 or Grade2 
 
If the investigator assesses an adverse event to be related to the daratumumab infusion, then the 
infusion should be paused. When the subject’s condition is stable, the infusion may be restarted 
at the investigator’s discretion. Upon restart, the infusion rate should be half of that used before 
the interruption. Subsequently, the infusion rate may be increased at the investigator’s discretion. 
 
If the subject experiences a Grade 2 or higher event of laryngeal edema or a Grade 2 or higher 
event of bronchospasm that does not respond to systemic therapy and does not resolve within 6 
hours from the onset, then the subject must be withdrawn from treatment. 
 
12.2.2. Infusion-Related Reactions of Grade3 or Higher 
 
For infusion-related adverse events that are Grade 4, the infusion should be stopped and 
treatment with daratumumab will be discontinued for that subject. 
 
For infusion-related adverse events that are Grade 3, the daratumumab infusion must be stopped, 
and the subject must be observed carefully until the resolution of the adverse event or until the 
intensity of the event decreases to Grade 1, at which point the infusion may be restarted at the 
investigator’s discretion. Upon restart, the infusion rate should be half of that used before the 
interruption. Subsequently, the infusion rate may be increased at the investigator’s discretion. If 
the intensity of the adverse event returns to Grade 3 after restart of the infusion, then the 
procedure described in this section may be repeated at the investigator’s discretion.  
Should the intensity of the adverse event increase to Grade 3 for a third time, then treatment with 
daratumumab will be discontinued for that subject. 
 
12.3. 
Ibrutinib Administration 
 
Ibrutinib 420 mg (1m 420mg tablet) is administered orally once daily. The tablet is to be taken 
around the same time each day with 8 ounces (approximately 240 mL) of water. The tablet 


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should be swallowed intact and subjects should not attempt to open capsules or dissolve them in 
water. During treatment days with daratumumab combination dosing, ibrutinib should be taken 
0-2 hours prior to daratumumab with 8 ounces of water. 
 
If a dose is not taken at the scheduled time, it can be taken as soon as possible on the same day 
with a return to the normal schedule the following day. The subject should not take extra 
capsules to make up the missed dose. The first dose will be delivered in the clinic on Day 1, after 
which subsequent dosing is typically on an outpatient basis. Ibrutinib will be dispensed to 
subjects in bottles at each visit. Unused ibrutinib dispensed during previous visits must be 
returned to the site and drug accountability records updated at each visit. Returned capsules must 
not be dispensed to anyone. 
 
12.3.1. Ibrutinib Overdose 
 
Any dose of study drug administered in excess of that specified in this protocol is considered to 
be an overdose. Signs and symptoms of an overdose that meet any SAE criterion must be 
reported as a SAE in the appropriate time frame and documented as clinical sequelae to an 
overdose. 
 
There is no specific experience in the management of ibrutinib overdose in patients. No 
maximum tolerated dose (MTD) was reached in the Phase 1 study in which subjects received up 
to 12.5 mg/kg/day (1400 mg/day). Healthy subjects were exposed up to single dose of 1680 mg. 
One healthy subject experienced reversible Grade 4 hepatic enzyme increases (AST and ALT) 
after a dose of 1680 mg. Subjects who ingested more than the recommended dosage should be 
closely monitored and given appropriate supportive treatment. 
 
12.4. 
Dose Delays and Dose Modification 
 
Dose modification of daratumumab is not permitted, but dose delay remains the primary 
method for managing daratumumab-related toxicities. Ibrutinib and daratumumab therapy 
should be held until recovery upon the onset of any of the following toxicities:  
 
 Grade 4 hematologic toxicity 
 Grade 3 thrombocytopenia with bleeding 
 Febrile neutropenia of any grade 
 Grade 3 or higher nonhematologic toxicities with the following exceptions: 
o Grade 3 nausea that responds to anti-emetics within 7 days 
o Grade 3 vomiting that responds to anti-emetics within 7 days 
o Grade 3 diarrhea that responds to anti-diarrheal within 7 days 
o Grade 3 fatigue that was present at baseline or that lasts for <7 days. 
o Grade 3 asthenia that was present at baseline or that lasts for less than 7 days 
after. 
 
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Section 5.3. 
 
If the investigator feels the toxicities outlined above, are likely attributed to ibrutinib dosing, 
daratumumab dosing may continue without being held after discussion with the study monitor. 
Upon recovery of ≤ Grade 2, ibrutinib dosing should be the initial drug restarted. Daratumumab 
infusions should restart at least 7 days after ibrutinib dosing has resumed and there has been no 
recurrence of the toxicity.  
 
12.4.1. Daratumumab Dose Delay Management 
 
If dosing is delayed for either toxicity or other non-toxicity related issue then the following 
schedule should be followed during the specific phases of daratumumab treatment. 
  
During the induction phase (Cycles 1 and 2) if the dose is delayed >3 days then that week’s dose 
will be considered missed and treatment will commence the following week. If a missed dose 
occurs during induction, then that dose will not be made up and subjects will remain on schedule. 
 
 
During the consolidation phase (Cycles 3-6) if a dose is held greater than 1 week, then the next 
dose given should be the scheduled Day 15 dose.  
 
During the maintenance phase Cycle 7 and beyond if a dose is delayed greater than 2 weeks then 
it should be resumed with the subsequent cycle on day1.    
 
12.4.2. Ibrutinib Toxicity Management 
 
For toxicities outlined in Section 12.4 the following dose modifications are to be taken: 
 
 First Occurrence: Withhold ibrutinib until recovery to Grade 1 or less and restart at the 
original dose level 
 Second Occurrence: Withhold ibrutinib until recovery to Grade 1 or less, restart at 
280mg/day 
 Third Occurrence: Withhold ibrutinib until recovery to Grade 1 or less, restart at 
140mg/day 
 Fourth Occurrence: Discontinue ibrutinib.  
 
13. Pharmaceutical Information 
 
13.1. 
Investigational Agent-Daratumumab  
 
Daratumumab as a drug product is a colorless to yellow liquid concentrate. It is presented at a 
target concentration of 20 mg/mL in a 6R or 25R vial with a nominal fill volume of 5 mL or 20 
mL, respectively. It is intended for administration by the IV route after dilution in a sterile, 
pyrogen-free physiological saline solution (0.9% NaCl) provided by the investigation site. The 


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diluent will be a commercially available product approved by the competent authority of the 
relevant country. 
 
13.2. 
Availability of study drugs 
 
Daratumumab is an investigational agent supplied to investigators by Janssen. The study drug 
will be open-label with labeling fulfilling all requirements specified by governing regulations. 
Ibrutinib will be used per its FDA labeling and will be obtained through commercial mechanisms 
via the subject’s insurance.  
 
13.3. 
Daratumumab Accountability 
 
Daratumumab Inventory Records – The investigator, or a responsible party designated by the 
investigator, will maintain a careful record of the inventory and disposition of all agents received 
from Janssen on a Drug Accountability Record Form (DARF).  
   
14. Measurement of Effect 
 
During this study, participants will be evaluated every 4 weeks +/- 1 week for Cycles 1-12 and 
then every 12 weeks +/- 2 weeks for Cycles 13-26 during combination treatment to complete 2 
years of treatment. Subjects that complete combination treatment will be evaluated on single 
agent ibrutinib every 12 weeks +/- 2 weeks for an additional 1 year until study completion. 
Subjects will be assessed for efficacy according to the response criteria in Section 9.1 adopted by 
the Third International Workshop on WM.  
 
14.1. 
Response Criteria 
 
Subjects will be evaluable for a response if they have completed 2 Cycles of combination 
induction treatment (Weeks 1-8). See Appendix C for summary of response criteria.  
 
Complete Response (CR): A complete response (CR) is defined as having resolution of 
WM related symptoms, normalization of serum IgM levels with complete disappearance of 
IgM paraprotein by immunofixation, and resolution of any adenopathy or splenomegaly. A 
complete response requires reconfirmation demonstrating normal serum IgM levels, and 
absence of IgM paraprotein by immunofixation by a measurement repeated at least 2 weeks 
later. 
 
Very Good Partial Response (VGPR): ≥90% reduction in serum IgM levels, or 
normalization of serum IgM levels. 
 
Partial Response (PR): ≥ 50% reduction in serum IgM levels 
 
Minor Response (MR): 25-49% reduction in serum IgM levels 
 


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Progressive Disease (PD): >25% increase in serum IgM level occurs with an absolute 
increase of at least 500mg/dL from the lowest attained response value, or progression of 
clinically significant disease related symptoms. Reconfirmation of the initial IgM increase is 
required when the IgM is the sole criterion for progressive disease. For participants on active 
therapy who are on a drug hold for > 7 days an increase in serum IgM will not be considered 
progression if in the investigators opinion it is secondary to the drug hold. Subjects will be 
allowed reinitiation of drug. If after four consecutive weeks on active therapy there is no 
decrease in IgM, subjects will be considered to have progressive disease. If there is clinical 
benefit continuation on trial will be considered. Cases such as this should be discussed with 
the study sponsor. An increase of 1cm in any axis for adenopathy or 2 cm in the craniocaudal 
axis of the spleen will be considered progression. Development of central nervous system or 
transformation will be considered progressive events.  
 
Stable Disease (SD): <25% change in serum IgM levels in the absence of new or increasing 
adenopathy, splenomegaly or other signs of active WM.  
 
Overall Response: Includes MR, PR, VGPR, CR 
Major Response: Includes PR, VGPR, CR 
 
14.2. 
Time to Event Definitions 
  
 
Duration of Response (DoR): The duration of overall response is measured from the time 
measurement criteria are met for Minor response or better until the first date that recurrent or 
progressive disease is objectively documented (taking as reference for progressive disease the 
smallest IgM measurements recorded since the treatment started).  
 
 Progression-Free Survival (PFS): PFS is defined as the duration of time from start of 
treatment to time of progression or death. 
 
Overall Survival (OS): OS is defined as the duration of time from start of treatment to time of 
death or last follow-up.  
 
Time to Progression (TTP): TTP is defined as the time to tumor progression as defined in 
Section 9.1. If the subject has not progressed, then data will be censored at the last study visit at 
which a tumor assessment was performed.  
 
Evaluation of toxicity. All patients will be evaluable for toxicity from the time of their first 
treatment with Daratumumab. 
 
Evaluation of response. All patients included in the study will be assessed for response to 
treatment if they have completed Cycle 2. 
 
15. Data Reporting / Regulatory Considerations 
 


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15.1. 
Data Collection 
 
The data collection plan for this study is to utilize REDCap to capture all treatment, toxicity, 
efficacy, and adverse event data for all enrolled patients.  
 
15.2. 
REDCap 
 
REDCap (Research Electronic Data Capture) is a free data management software system that is 
fully supported by the Weill-Cornell Medical Center CTSC.  It is a tool for the creation of 
customized, secure data management systems that include Web-based data-entry forms, 
reporting tools, and a full array of security features including user and group-based privileges, 
authentication using institution LDAP system, with a full audit trail of data manipulation and 
export procedures.  REDCap is maintained on CTSC-owned servers that are backed up nightly 
and support encrypted (SSL-based) connections.  Nationally, the software is developed, 
enhanced and supported through a multi-institutional consortium led by the Vanderbilt 
University CTSA. 
 
 
15.3. 
Regulatory Considerations 
 
All protocol amendments and consent form modifications will be made by the Principal 
Investigator.  Janssen will have the opportunity to review and approve the changes prior to 
submission of these changes to the local IRB and distribution to participating sites. 
 
16. Statistical Considerations 
 
Because this is a pilot study, no formal sample size/power calculation is required.  However, 
with 12 patients each cohort, an exact binomial (Clopper-Pearson) 95% confidence interval for 
the toxicity proportion (i.e., primary endpoint) can be constructed to have a width of 
approximately 45.0% (1.6%, 46.5%) (i.e., separate confidence interval for each cohort).  This 
calculation assumes that the toxicity proportion for the incidence of non-hematologic Grade ≥ 3 
events will be no greater than 15% in either cohort.  Secondary endpoints include major response 
(PR/VGPR/CR), percentage of patients with deepening of response in Cohort B, duration of 
response, and time to progression. Given this is a pilot study with low subject enrollment and 
lack of power, analysis of outcomes will remain descriptive without comparison analyses 
between cohorts. The toxicity and major response proportions will be calculated for each cohort 
along with exact binomial (Clopper-Pearson) 95% confidence intervals.  Duration of response 
and time to progression will be descriptively reported for each cohort.  Assuming adequate 
follow-up time, Kaplan-Meier survival analysis will be used to assess progression-free survival 
(PFS) and overall survival (OS) in each cohort.  All p-values will be two-sided with statistical 
significance evaluated at the 0.05 alpha level.  Ninety-five percent confidence intervals for 1) the 
toxicity proportion, 2) the major response proportion, and 3) median PFS/OS-time and PFS/OS 
proportions, will be calculated to assess the precision of the obtained estimates.  All analyses will 


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be performed in SAS Version 9.4 (SAS Institute, Inc., Cary, NC) and Stata Version 15.0 
(StataCorp, College Station, TX). 
 
17. Reporting and Exclusions 
 
17.1. 
Adverse Events and Reporting Requirements  
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
investigator will be required to provide appropriate information concerning any findings that 
suggest significant hazards, contraindications, side effects, or precautions pertinent to the safe 
use of the drug or device under investigation.  Safety will be monitored by evaluation of adverse 
events reported by patients or observed by investigators or research staff, as well as by other 
investigations such as clinical laboratory tests, x-rays, electrocardiographs, etc.  
 
17.2. 
Adverse Event Definition 
 
An adverse event is any untoward medical occurrence in a clinical study subject administered a 
medicinal (investigational or non-investigational) product. An adverse event does not necessarily 
have a causal relationship with the treatment. An adverse event can therefore be any unfavorable 
and unintended sign (including an abnormal finding), symptom, or disease temporally associated 
with the use of a medicinal (investigational or non- investigational) product, whether or not 
related to that medicinal (investigational or non-investigational) product. (Definition per 
International Conference on Harmonisation [ICH]). This includes any occurrence that is new in 
onset or aggravated in severity or frequency from the baseline condition, or abnormal results of 
diagnostic procedures, including laboratory test abnormalities. 
 
17.3. Adverse Events of Special Interest for Daratumumab (DARZALEX®)  
 
Adverse events of special interest are events that Janssen Scientific Affairs, LLC is actively 
monitoring as a result of a previously identified signal (even if non-serious). These adverse 
events are: 
 
 Infusion reactions: ≥ grade 3  
 Infections: ≥ grade 4   
 Cytopenias: ≥ grade 4   
 HBV Reactivation 
 Visual Disturbance 
 Other malignancies  
 
Any Adverse Event of Special Interest that is to be reported to the COMPANY should be 
recorded on a Serious Adverse Event Report Form and be reported to the COMPANY within 24 
hours of knowledge of the event.  
 
 


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17.4. Adverse Events of Special Interest for Ibrutinib (Imbruvica®) 
Adverse events of special interest are events that Janssen Scientific Affairs, LLC is actively 
monitoring as a result of a previously identified signal (even if non-serious). These adverse 
events are: 
 
 Major Hemorrhage  
Major hemorrhage is defined as any hemorrhagic event that is Grade 3 or greater in severity or 
that results in 1 of the following: intraocular bleeding causing loss of vision, the need for a 
transfusion of 2 or more units of red cells or an equivalent amount of whole blood, 
hospitalization, or prolongation of hospitalization.  
 
 Intracranial Hemorrhage  
Any intracranial hemorrhage adverse event, including subdural hematoma/hemorrhage, 
epidural hematoma/hemorrhage and intracerebral hemorrhage, of any grade severity, will be 
captured as an event of special interest.  
 
 Other Malignancies   
In addition to all routine AE reporting, all new malignant tumors, including solid tumors, skin 
malignancies and hematologic malignancies, are to be reported for the duration of study 
treatment and during any protocol-specified follow-up periods including post-progression 
follow-up for overall survival.  
  
Any Adverse Event of Special Interest that is to be reported to the COMPANY should be 
recorded on a Serious Adverse Event Report Form and be reported to the COMPANY within 
24 hours of knowledge of the event.  
 
 
17.5. Individual Case Safety Report 
 
A valid ICSR must contain the four minimum criteria required to meet regulatory reporting 
requirements. 
 an identifiable subject (but not disclosing personal information)    
 an identifiable reporter (investigational site) 
 a Janssen medicinal product 
 an adverse event, outcome, or certain special situations 
 
The minimum information required is: 
 suspected Janssen medicinal product (doses, indication) 
 date of therapy (start and end date, if available) 
 batch or lot number, if available 
 subject details (subject ID and country) 
 gender 


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 age at AE onset 
 reporter ID 
 adverse event detail (AE verbatim in English), onset date, relatedness, causality, action 
taken, outcome, (if available) 
 
17.6. Product Quality Complaint 
 
A product quality compliant is defined as any suspicion of a product defect related to a potential 
quality issue during manufacturing, packaging, release testing, stability monitoring, dose 
preparation, storage or distribution of the product, or delivery system.  Not all PQCs involve a 
subject.  Lot and batch numbers are of high significance and need to be collected whenever 
available. 
 
Examples of PQC include but not limited to: 
• Functional Problem: e.g., altered delivery rate in a controlled release product 
• Physical Defect:  e.g. abnormal odor, broken or crushed tablets/capsules 
• Potential Dosing Device Malfunction: e.g., autoinjector button not working, needle 
detaching from syringe 
• Suspected Contamination 
• Suspected Counterfeit 
 
17.7.Serious Adverse Event (SAE) 
 
A serious adverse event based on ICH and EU Guidelines on Pharmacovigilance for Medicinal 
Products for Human Use is any untoward medical occurrence that at any dose: 
• Results in death 
• Is life-threatening 
(The subject was at risk of death at the time of the event. It does not refer to an event 
that hypothetically might have caused death if it were more severe.) 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability/incapacity 
• Is a congenital anomaly/birth defect 
• Is a suspected transmission of any infectious agent via a medicinal product 
• Is medically important* 
 
*Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
also appropriate in other situations, such as important medical events that may not be 
immediately life threatening or result in death or hospitalization but may jeopardize the subject 
or may require intervention to prevent one of the other outcomes listed in the definition above. 
These should usually be considered serious. 
 
NOTE: DEATH FOR ANY REASON SHOULD BE REPORTED AS A SERIOUS 
ADVERSE EVENT. 
 


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17.7.1. Hospitalization 
 
For reports of hospitalization, it is the sign, symptom or diagnosis which led to the 
hospitalization that is the serious event for which details must be provided. 
 
Any event requiring hospitalization or prolongation of hospitalization that occurs during the 
study must be reported as a serious adverse event, except hospitalizations for the following: 
 
 Hospitalizations not intended to treat an acute illness or adverse event (e.g., social 
reasons such as pending placement in long-term care facility) 
 Surgery or procedure planned before entry into the study. [Note: Hospitalizations that 
were planned before the start of data collection and where the underlying condition 
for which the hospitalization was planned has not worsened will not be considered 
serious adverse events. Any adverse event that results in a prolongation of the 
originally planned hospitalization is to be reported as a new serious adverse event.] 
 [For convenience the investigator may choose to hospitalize the subject for the 
duration of the treatment period.] 
 
17.7.2. Life-Threatening Conditions 
 
Disease progression should not be recorded as an adverse event or serious adverse event term; 
instead, signs and symptoms of clinical sequelae resulting from disease progression/lack of 
efficacy will be reported if they fulfill the serious adverse event definition. 
 
17.8.Unlisted (Unexpected) Adverse Event/Reference Safety Information 
 
An adverse event is considered unlisted if the nature or severity is not consistent with the applicable 
product reference safety information. For a medicinal product(s) with a marketing authorization, 
the expectedness of an adverse event will be determined by whether or not it is listed in the 
applicable product information.  
 
http://www.darzalex.com/shared/product/darzalex/darzalex-prescribing-information.pdf 
 
For DARZALEX™ (daratumumab),the expectedness of an adverse event will be determined by 
whether or not it is listed in the Investigator's Brochure 
 
18. Special Reporting Situations 
 
SAE’s include death, life threatening adverse experiences, hospitalization or prolongation 
of hospitalization, disability or incapacitation, overdose, congenital anomalies and any 
other serious events that may jeopardize the subject or require medical or surgical 
intervention to prevent one of the outcomes listed in this definition.  
 
Reporting of SAE to IRB 


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 All SAEs occurring on this study will be reported to the IRB according to the IRB policy, 
which can be accessed via the following link:  
https://research.weill.cornell.edu/sites/default/files/immediate_reporting_policy.pdf  
 
Reporting of SAE to FDA [For protocols where WCMC is the Sponsor-Investigator] 
 If an SAE occurs on this study, the event will be filed on a MedWatch form with the 
FDA. The investigator must notify the FDA of any SAE’s as soon as possible but no later 
than 7 calendar days after the initial receipt of the information 
 
Safety events of interest for a Janssen medicinal product that require expediting reporting and/or 
safety evaluation include, but are not limited to: 
 
 Drug exposure during pregnancy (maternal and paternal) 
 Overdose of a Janssen medicinal product  
 Exposure to a Janssen medicinal product from breastfeeding  
 Suspected abuse/misuse of a Janssen medicinal product 
 Inadvertent or accidental exposure to a Janssen medicinal product  
 Any failure of expected pharmacological action (i.e., lack of effect) of a Janssen 
medicinal product 
 Medication error involving a Janssen medicinal product (with or without patient 
exposure to the Janssen medicinal product, e.g., name confusion) 
 Suspected transmission of any infectious agent via administration of a medicinal 
product 
 Unexpected therapeutic or clinical benefit from use of a Janssen medicinal product 
 
These safety events may not meet the definition of an adverse event; however, from a 
Janssen Scientific Affairs, LLC perspective, they are treated in the same manner as 
adverse events. Special situations should be recorded on the Adverse Event page of the 
CRF. 
 
Any special situation that meets the criteria of a serious adverse event should be recorded on a 
Serious Adverse Event Report Form and be reported to Janssen Scientific Affairs, LLC within 
24 hours of becoming aware of the event. 
 
18.1.Pregnancy 
 
All initial reports of pregnancy must be reported to Janssen Scientific Affairs, LLC by the 
PRINCIPAL INVESTIGATOR within 24 hours of becoming aware of the event using the 
Serious Adverse Event Form. Abnormal pregnancy outcomes (e.g. spontaneous abortion, fetal 
death, stillbirth, congenital anomaly, ectopic pregnancy) are considered serious adverse events 
and must be reported using the Serious Adverse Event Form.  
 


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Any subject who becomes pregnant during the study must be promptly withdrawn from the study 
and discontinue further study treatment. 
 
Because the effect of the Janssen medicinal product on sperm is unknown, pregnancies in partners 
of male subjects exposed to a Janssen medicinal product will be reported by the PRINCIPAL 
INVESTIGATOR within 24 hours of their knowledge of the event using the Serious Adverse 
Event Form.  Depending on local legislation this may require prior consent of the partner. 
 
Follow-up information regarding the outcome of the pregnancy and any postnatal sequelae in the 
infant will be required. 
 
19. Maintenance of Safety Information 
 
All safety data should be maintained in a clinical database in a retrievable format. The 
PRINCIPAL INVESTIGATOR shall provide all adverse events, both serious and non-serious, in 
report format. However, in certain circumstances more frequent provision of safety data may be 
necessary, e.g. to fulfill a regulatory request, and as such the data shall be made available within 
a reasonable timeframe at Janssen Scientific Affairs, LLC request. 
 
20. Procedures for Reporting Safety Data and Product Quality Complaints for Janssen 
Medicinal Products to Janssen Scientific Affairs, LLC 
 
All adverse events and special situations, whether serious or non-serious, related or not related, 
following exposure to a Janssen medicinal product are to be documented by the investigator and 
recorded in the CRF and in the subject’s source records. Investigators must record in the CRF their 
opinion concerning the relationship of the adverse event to a Janssen medicinal product.  
All (serious and non-serious) adverse events reported for a Janssen medicinal product should be 
followed-up in accordance with clinical practice. 
 
20.1.SAEs, Adverse Events of Special Interest and Special Reporting Situations 
 
All serious adverse events that have not resolved by the end of the study, or that have not 
resolved upon discontinuation of the subject's participation in the study, must be followed until 
any of the following occurs: 
 
 The event resolves 
 The event stabilizes 
 The event returns to baseline, if a baseline value/status is available 
 The event can be attributed to agents other than the study drug or to factors unrelated 
to study conduct 
 It becomes unlikely that any additional information can be obtained (subject or health 
care practitioner refusal to provide additional information, lost to follow-up after 
demonstration of due diligence with follow-up efforts) 


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The PRINCIPAL INVESTIGATOR will transmit all SAEs, Adverse Events of Special Interest 
and special situations following exposure to a Janssen product under study in a form provided by 
Janssen Scientific Affairs, LLC in accordance with Section 15,Transmission Methods, in English 
within 24-hours of becoming aware of the event(s). 
 
In the event the study is blinded, the PRINCIPAL INVESTIGATOR will submit an unblinded 
SAE, Adverse Events of Special Interest or pregnancy exposure report to Janssen Scientific 
Affairs, LLC. 
 
All follow-up information for serious adverse events that are not resolved at the end of the study 
or by the time of patient withdrawal must be reported directly by the PRINCIPAL 
INVESTIGATOR, within 24 hours becoming aware, to Janssen Scientific Affairs, LLC using the 
Janssen Scientific Affairs, LLC Serious Adverse Event Report  
 
All available clinical information relevant to the evaluation of a related SAE, serious ADR or 
special situation is required. 
 
 
20.2.Non-Serious AEs 
 
All non-serious adverse events should be reported to Janssen Scientific Affairs, LLC according 
to the timeframe outlined in the Research Funding Agreement section entitled Reporting of Data. 
 
20.3.PQC Reporting 
 
A PQC may have an impact on the safety and efficacy of the product. Timely, accurate, and 
complete reporting and analysis of PQC information from studies are crucial for the protection of 
patients, investigators, and Janssen Scientific Affairs, LLC, and are mandated by regulatory 
agencies worldwide. Janssen Scientific Affairs, LLC has established procedures in conformity 
with regulatory requirements worldwide to ensure appropriate reporting of PQC information. Lot 
and/or Batch #s shall be collected for any reports failure of expected pharmacological action 
(i.e., lack of effect). The product should be quarantined immediately and if possible, take a 
picture. 
 
All initial PQCs involving a Janssen medicinal product under study must be reported to Janssen 
Scientific Affairs, LLC by the PRINCIPAL INVESTIGATOR within 24 hours after being made 
aware of the event. The Janssen contact will provide additional information/form to be 
completed. 
If the defect for a Janssen medicinal product under study is combined with either a serious 
adverse event or non-serious adverse event, the PRINCIPAL INVESTIGATOR must report the 
PQC to Janssen Scientific Affairs, LLC according to the serious adverse event reporting 
timelines.  A sample of the suspected product should be maintained for further investigation if 
requested by Janssen Scientific Affairs, LLC. 


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21. Transmission Methods 
 
The following methods are acceptable for transmission of safety information to Janssen Scientific 
Affairs, LLC: 
 Electronically via Janssen SECURE Email service (preferred) 
 For business continuity purposes, if SECURE Email is non-functional: 
o Facsimile (fax), receipt of which is evidenced in a successful fax transmission 
report 
 Telephone (if fax is non-functional). 
 
Please use the contact information and process information provided by Janssen Scientific Affairs, 
LLC.  
 
22. Data and Safety Monitoring Plan (DSMP) 
 
Monitoring activities will be commensurate with the nature, size and complexity of the trial in 
accordance with institutional policies and will be determined after IRB and Data Safety Monitoring 
Board (DSMB) review of the protocol immediately prior to study activation. For this study we will 
utilize a Weill Cornell Medicine DSMB. 
We will evaluate safety of combination therapy after 12 subjects have been enrolled onto the 
protocol and completed 8 weeks of combination induction therapy. The study team will review all 
subject data at this specified time point and provide a written report to the DSMB for review. 
Stopping rules will be employed in this study based on observed toxicities from monotherapy trials 
in subjects with multiple myeloma receiving daratumumab or WM subjects receiving monotherapy 
ibrutinib. For purposes of this safety analysis, each subject will be assessed individually and 
toxicities tabulated. Only toxicities occurring within the first 8 weeks of combination treatment 
will be considered for potential study termination.  
In monotherapy daratumumab or ibrutinib studies, Grade 3 or greater non hematologic toxicities 
were rare with the most common event being pneumonia noted in 6% of subjects respectively for 
daratumumab and ibrutinib (data from prescribing inserts). Grade 3 or greater hematologic 
toxicities when restricted to anemia, thrombocytopenia, or neutropenia were noted in up to 20% 
of subjects treated with daratumumab monotherapy and up to 19% in subjects treated with ibrutinib 
monotherapy.  
Based on these observed events we will stop the study if 5 of the first 12 subjects enrolled 
experience a Grade 3 or greater, toxicity (heme or non-heme) which leads to a study drug hold 
greater than 28 days or leads to either study drug discontinuation within the first two months of 
treatment. Any drug hold that occurs within the first 8 weeks but extends beyond the initial 8 week 
monitoring period will be followed for a full 28 days. For a toxicity to be included in this analysis, 
the toxicity must be considered due to the study drug per investigator assessment. Accrual will be 
held upon enrollment of the 12th evaluable subject until they have been observed through 
induction and the study team in consultation with the DSMB have made a determination regarding 
additional enrollment, this study hold is anticipated to last approximately 3 months. 


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 Type, severity, frequency, duration, and relationship to study drug of any AEs or 
abnormalities of laboratory tests, SAEs, or AEs leading to discontinuation will be recorded. 
 Monthly IgM serum levels and every 6 month CT scans will be recorded and used to assess 
efficacy. 
 Subjects may be discontinued at any time at the discretion of the Investigator. The 
following may be justifiable reasons for the Investigator to remove a subject from the 
study: 
o Non-compliance 
o Withdrawal of consent by the subject 
o Erroneous inclusion into the study 
o Development of defined exclusion criteria 
o Intolerable toxicity or adverse event 
o Pregnancy 
o Termination of the study by the sponsor  
 
 
 
 
 


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References 
 
1. 
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Appendix A: Treatment indications for patients entering study. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix B: Inhibitors and Inducers of CYP3A 
 
Inhibitors of CYP3A are defined as follows. A comprehensive list of inhibitors can be found at the 
following website: http://medicine.iupui.edu/clinpharm/ddis/main-table/. The general categorization into 
strong, moderate, and weak inhibitors according to the website is displayed below.  
 
Inhibitors of CYP3A 
Strong inhibitors: 
indinavir 
nelfinavir 
ritonavir 
clarithromycin 
itraconazole 
ketoconazole 
nefazodone 
saquinavir 
suboxone 
telithromycin 
cobicistat 
beceprevir 
telaprevir 
troleandomycin 
posaconazole 
 
Moderate Inhibitors: 
aprepitant 
amprenavir 
atazanavir 
ciprofloxacin 
crizotinib 
darunavir/ritonavir 
dronedarone 
erythromycin 
diltiazem 
fluconazole 
grapefruit juice 
Seville orange juice 
verapamil 
voriconazoleb  
imatinib 
Inducers of CYP3A 
carbamazepine 
efavirenz 
nevirapine 
barbituarates 
glucocorticoids 
modafinil 
oxcarbarzepine 
phenobarbital 
phenytoin 
pioglitazone 
rifabutin 
rifampin 
St. John’s Wort 
troglitazone 
 
Source: http://medicine.iupui.edu/clinpharm/ddis/main-table/ 
a. Based on PBPK simulations, up to 9.7-fold increase in AUC and 6.2-fold increase in Cmax could be observed. If ibrutinib needs to be 
administered with posaconazole, 140 mg ibrutinib will be dosed. 
b. Based on internal data, 140 mg ibrutinib dosed with voriconazole produces ibrutinib exposures similar to 560 mg ibrutinib dosed alone. 
Therefore, for this study, if ibrutinib needs to be administered with voriconazole, 140 mg ibrutinib will be dosed. 
 
 
 
 
 
 


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Appendix C: Consensus-based uniform response criteria for WM developed by the 
International 
Workshop on WM ,updated in the Sixth IWWM and published by Owen et al.