Clinical trial NCT03187262
Conditions: Waldenström Macroglobulinemia
Keywords: Waldenström Macroglobulinemia
Sponsor: Dana-Farber Cancer Institute
Start date: 2017-11-27; Completion date: 2021-12-31
Enrollment: 13 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This research study is studying Daratumumab as a possible treatment for Waldenström Macroglobulinemia.

Detailed description:
This research study is a Phase II clinical trial. Phase II clinical trials test the safety and effectiveness of an investigational drug to learn whether the drug works in treating a specific disease. "Investigational" means that the drug is being studied.

The FDA (the U.S. Food and Drug Administration) has not approved Daratumumab for this specific disease but it has been approved for other uses.

Daratumumab is a monoclonal human antibody. An antibody recognizes a specific protein and binds to it. Daratumumab binds to a protein called CD38 located on the surface of B cells like WM. Daratumumab has shown the ability to slow or stop the growth of cells that have CD38 on the cell surface when tested in laboratories.

In this research study, the investigators are evaluating the efficacy of Daratumumab as a single agent in participants with WM that has come back or has shown no response to previous treatment.

Arms: arm 1: * Daratumumab will be administered in three phases: Induction, consolidation and maintenance
* During induction, participants will receive daratumumab on days 1, 8, 15 and 22 of each 28-day
* During consolidation, daratumumab will be administered on days 1 and 15 of each 28-day cycle
* During maintenance, daratumumab will be administered on day 1 of each 28-day cycle
Interventions: intervention 1: Daratumumab
Intervention descriptions: intervention 1: Daratumumab is a monoclonal human antibody. Daratumumab has shown the ability to slow or stop the growth of cells that have CD38 on the cell surface when tested in laboratories

Protocol documents:
Prot_SAP_000.pdf: 
 
 
NCI Protocol #: 
N/A. 
 
DF/HCC Protocol #: 17-164  
 
TITLE:  A Phase 2 Study of Daratumumab in Patients with Relapsed or Refractory 
Waldenström Macroglobulinemia. 
 
 
Coordinating Center: 
 
 
Dana-Farber Cancer Institute 
 
 
 
 
 
 
 
 
 
450 Brookline Avenue 
 
 
 
 
 
 
 
 
 
Boston, MA 02215 USA 
 
Study Chair: 
Jorge J. Castillo, MD 
 
 
 
 
 
 
 
 
 
Dana-Farber Cancer Institute 
 
 
 
 
 
 
 
 
 
450 Brookline Avenue 
 
 
 
 
 
 
 
 
 
Boston, MA 02215 USA 
 
 
 
 
 
 
 
 
 
jorgej_castillo@dfci.harvard.edu  
 
Principal Investigator (PI): 
Jorge J. Castillo, MD 
 
 
 
 
 
 
 
 
 
Dana-Farber Cancer Institute 
 
 
 
 
 
 
 
 
 
450 Brookline Avenue 
 
 
 
 
 
 
 
 
 
Boston, MA 02215 USA 
 
 
 
 
 
 
 
 
 
jorgej_castillo@dfci.harvard.edu  
 
Other investigators: 
Steven P. Treon, MD. PhD 
 
 
 
 
 
 
 
 
 
Dana-Farber Cancer Institute 
 
 
 
 
 
 
 
 
 
450 Brookline Avenue 
 
 
 
 
 
 
 
 
 
Boston, MA 02215 USA 
 
steven_treon@dfci.harvard.edu  
 
 
Project Manager:  
 
 
 
Responsible Research Nurse: 
Kirsten Meid, MPH  
 
 
Toni Dubeau, NP 
Dana-Farber Cancer Institute 
 
 
Dana-Farber Cancer Institute 
450 Brookline Ave 
 
 
 
450 Brookline Ave 
Boston, MA 02215 USA 
 
 
Boston, MA 02215 USA 
Kirsten_Meid@dfci.harvard.edu  
 
toni_dubeau@dfci.harvard.edu  
 
Agent: Daratumumab (Darzalex®) 
 
IND #:134092 
IND Sponsor: Jorge J. Castillo, MD 
 
 
Protocol Type / Version # / Version Date: 
Version #9 2.1.19 
 


NCI Protocol #:N/A 
DF/HCC Protocol #: 17-164 
Protocol Version Date: 2.1.19 
 
SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Registration 
Daratumumab 
Each cycle is 4 weeks (28 days) 
Once every week for 8 weeks, then 
Once every 2 weeks for 16 weeks, then 
Once every 4 weeks for 48 weeks 
Response Evaluation 
Discontinue Protocol 
Therapy 
Event Monitoring for 2 
years 
Event Monitoring 
Progressive Disease 
(PD), Unacceptable 
Toxicity, No Response 
Stable Disease or Response 


NCI Protocol #:N/A 
DF/HCC Protocol #: 17-164 
Protocol Version Date: 2.1.19 
 
TABLE OF CONTENTS 
 
SCHEMA 
2 
1. 
OBJECTIVES 
1 
1.1 
Study Design 
1 
1.2 
Primary Objectives 
2 
2. 
BACKGROUND 
2 
2.1 
Study Disease 
2 
2.2 
Daratumumab 
3 
2.3 
Rationale 
4 
2.4 
Correlative Studies Background 
4 
3. 
PARTICIPANT SELECTION 
5 
3.1 
Eligibility Criteria 
5 
3.2 
Exclusion Criteria 
5 
3.3 
Inclusion of Women and Minorities 
6 
4. 
REGISTRATION PROCEDURES 
6 
4.1 
General Guidelines for DF/HCC Institutions 
6 
4.2 
Registration Process for DF/HCC Institutions 
7 
4.3 
General Guidelines for Other Investigative Sites 
7 
4.4 
Registration Process for Other Investigative Sites 
7 
5. 
TREATMENT PLAN 
7 
5.1 
Treatment Regimen 
8 
5.2 
Pre-Treatment Criteria 
8 
5.3 
Agent Administration 
9 
5.4 
General Concomitant Medication and Supportive Care Guidelines 
10 
5.5 
Criteria for Taking a Participant Off Protocol Therapy 
11 
5.6 
Duration of Follow Up 
12 
5.7 
Criteria for Taking a Participant Off Study 
12 
6. 
DOSING DELAYS/DOSE MODIFICATIONS 
12 
6.1 
Management of Hepatitis B Virus Reactivation 
14 
7. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS 
14 
7.1 
Expected Toxicities 
14 
7.2 
Adverse Event Characteristics 
15 
7.3 
Expedited Adverse Event Reporting 
15 
7.4 
Expedited Reporting to the Food and Drug Administration (FDA) 
17 
7.5 
Expedited Reporting to Janssen 
17 
7.6 
Expedited Reporting to Hospital Risk Management 
23 
7.7 
Routine Adverse Event Reporting 
23 
8. 
PHARMACEUTICAL INFORMATION 
23 
8.1 
Daratumumab 
23 
9. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
25 
9.1 
Biomarker Studies 
25 
10. 
STUDY CALENDAR 
27 


NCI Protocol #:N/A 
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Protocol Version Date: 2.1.19 
 
11. 
MEASUREMENT OF EFFECT 
29 
11.1 
Definitions 
29 
11.2 
Response Criteria 
29 
Overall Response Rate (ORR): Includes patients who achieved MR, PR, VGPR and CR.  The 
best overall response rate will be at any point on therapy. 
30 
11.3 
Time-to-event definition 
30 
11.4 
Relapsed/Refractory definitions 
30 
12. 
DATA REPORTING / REGULATORY REQUIREMENTS 
30 
12.1 
Data Reporting 
30 
12.2 
Data Safety Monitoring 
30 
12.3 
Multicenter Guidelines 
31 
12.4 
Collaborative Agreements Language 
31 
13. 
STATISTICAL CONSIDERATIONS 
31 
13.1 
Study Design/Endpoints 
31 
13.2 
Sample Size, Accrual Rate and Study Duration 
32 
13.3 
Stratification Factors 
32 
13.4 
Interim Monitoring Plan 
32 
13.5 
Analysis of Primary Endpoints 
32 
13.6 
Analysis of Secondary Endpoints 
33 
13.7 
Reporting and Exclusions 
33 
14. 
PUBLICATION PLAN 
33 
REFERENCES 
34 
Ngo HT, Leleu C, Lee J, Jia X, Melhem M, Runnels J, et al. SDF-1/CXCR4 and VLA-4 interaction 
regulates homing in Waldenstrom macroglobulinemia. Blood. 2008; 112(1):150-8. 
35 
APPENDIX A PERFORMANCE STATUS CRITERIA 
36 
APPENDIX B  Dana-Farber/Harvard Cancer Center Multi-Center oversight plan and Data and 
Safety Monitoring Plan version 2 8.2.2017 
37 
15. 
INTRODUCTION 
39 
15.1 
Purpose 
39 
15.2 
Multi-Center Data and Safety Monitoring Plan Definitions 
39 
16. 
GENERAL ROLES AND RESPONSIBILITIES 
40 
16.1 
DF/HCC Sponsor 
40 
16.2 
Coordinating Center 
41 
16.3 
Participating Institution 
41 
17. 
DF/HCC REQUIREMENTS FOR MULTI-CENTER PROTOCOLS 
42 
17.1 
Protocol Distribution 
42 
17.2 
Protocol Revisions and Closures 
42 
17.3 
Informed Consent Requirements 
43 
17.4 
IRB Documentation 
43 
17.5 
IRB Re-Approval 
44 
17.6 
Participant Confidentiality and Authorization Statement 
44 
17.7 
DF/HCC Multi-Center Protocol Registration Policy 
44 
17.8 
DF/HCC Protocol Case Number 
45 
17.9 
Safety Assessments and Toxicity Monitoring 
47 


NCI Protocol #:N/A 
DF/HCC Protocol #: 17-164 
Protocol Version Date: 2.1.19 
 
17.10 
Data Management 
48 
18. 
REQUISITIONING INVESTIGATIONAL DRUG 
48 
19. 
MONITORING: QUALITY CONTROL 
48 
19.1 
Ongoing Monitoring of Protocol Compliance 
48 
19.2 
Monitoring Reports 
49 
19.3 
Accrual Monitoring 
50 
20. 
AUDITING: QUALITY ASSURANCE 
50 
20.1 
DF/HCC Internal Audits 
50 
20.2 
Audit Notifications 
50 
20.3 
Audit Reports 
50 
20.4 
Participating Institution Performance 
50 
Appendix C: Investigational Product Management Plan 
52 


1 
 
1. OBJECTIVES 
1.1 
Study Design 
 
This is a Phase 2, multi-center study designed to evaluate the efficacy of single agent daratumumab 
in relapsed or refractory WM patients.  
 
A Screening visit will be conducted within 30 days of Day 1 of Cycle 1. If the Screening visit and 
screening laboratories are done within 14 days of Cycle 1, Day 1, then a separate visit and 
laboratories will not be required on Cycle 1, Day 1, though may be done at the investigator’s 
discretion. At the Screening visit, a medical history will be obtained, and a complete physical 
examination will be performed including vital signs and an ECOG performance status. A bone 
marrow aspirate and biopsy may be performed within 90 days prior to Cycle 1 Day 1, and CD38 
expression (by flow cytometry and/or immunohistochemistry), and MYD88 and CXCR4 mutation 
status will be determined. CT scanning of the chest, abdomen and pelvis with intravenous contrast, 
if possible, may be performed within 90 days prior to Cycle 1 Day 1. If a participant has known 
extramedullary disease outside of the chest, abdomen, or pelvis, then imaging of the lesion should 
be conducted by investigator-determined modality.  The same modality should be used throughout 
the study. Clinical laboratory tests including a complete blood count plus differential, 
comprehensive chemistry panel (electrolytes, BUN, creatinine, albumin, total protein, total 
bilirubin, AST, ALT, alkaline phosphatase), beta 2-microglobulin, serum and protein 
electrophoresis with quantification of immunoglobulins (IgM, IgG, IgA) and immunofixation 
studies, indirect antiglobulin testing, and serum pregnancy tests for women of child-bearing 
potential will also be performed at the Screening visit. 
 
Participants who meet the eligibility requirements will be enrolled on study and initiated on 
daratumumab. Daratumumab will be administered in three phases: Induction, consolidation and 
maintenance. The duration of each cycle is 28 days. During induction, participants will receive 
daratumumab on days 1, 8, 15 and 22 of each 28-day cycle for 2 cycles for a total of 8 infusions 
or 8 weeks of therapy. Consolidation will start 2 weeks +/- 3 days after completing induction. 
During consolidation, daratumumab will be administered on days 1 and 15 of each 28-day cycle 
for 4 cycles for a total of 8 infusions or 16 weeks of therapy. Maintenance will start 4 weeks +/- 7 
days after the 8th infusion of consolidation is completed. During maintenance, daratumumab will 
be administered on day 1 of each 28-day cycle for a total of 12 cycles or 48 weeks of therapy. 
Every effort should be made to keep subjects on the planned dosing schedule.  However, doses 
given within 3 days of the scheduled dose are permitted as long as the interval between doses is at 
least 5 days.  Daratumumab will be administered for a total of 28 infusions or until progression, 
unacceptable toxicity, or decision to withdraw from the trial. Dose reductions due to daratumumab-
related toxicity will not be permitted. The total duration of therapy is approximately 72 weeks (1.5 
years). Participants will remain on study as long as they do not have unacceptable toxicity or 
demonstrate progressive disease. 
 
Response criteria 
updated 
at 
the 
Sixth 
International 
Workshop 
on 
Waldenström 
macroglobulinemia (Owen 2013) will be used to assess response, stable disease, and progressive 
disease. 
 


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Protocol Version Date: 2.1.19 
 
2 
 
An interim safety analysis will be performed once at least 10 patients had received the first 4 
weekly doses of daratumumab.  
 
1.2 
Primary Objectives 
 
• To assess the best overall response rate (ORR) (>25% reduction in disease burden) to single 
agent daratumumab in relapsed or refractory WM patients at any point on therapy. 
 
1.2.1 Secondary Objectives 
 
• To assess the minor, partial, very good partial and complete response rate to single agent 
daratumumab in relapsed or refractory WM patients. 
• To determine Progression Free Survival (PFS) following daratumumab in relapsed or 
refractory WM patients 
• To evaluate the safety profile of daratumumab in patients with relapsed or refractory WM 
patients. 
 
1.2.2. Exploratory objectives 
 
• To observe differences (if any) in overall and major responses (PR or better) attainment, 
and time to response based on tumor CD38 expression, and MYD88 and CXCR4 genotype. 
 
2. BACKGROUND 
 
2.1 
Study Disease 
 
Waldenström macroglobulinemia is a malignant B-cell lymphoma associated with the 
accumulation of clonal lymphoplasmacytic cells and monoclonal IgM secretion. Whole genome 
sequencing has revealed activating somatic mutations in MYD88 (L265P) and the C-terminal 
domain of CXCR4 in Waldenström macroglobulinemia (Treon et al, NEJM 2012; Hunter et al, 
Blood 2014). In tumor cells, MYD88L265P triggers NFkB activation via two divergent pathways 
involving Bruton tyrosine kinase (BTK) and IRAK1/IRAK4 (Yang et al, Blood 2013). Ibrutinib is 
an orally administered, small molecule inhibitor of BTK, which triggers apoptosis of MYD88L265P 
expressing Waldenström macroglobulinemia cells. In a multicenter prospective study, 63 
symptomatic Waldenström’s macroglobulinemia patients with a median of 2 (range 1-9) prior 
therapies, 40% of whom were refractory to their prior therapy received ibrutinib (420 mg PO once 
daily) until progression or unacceptable toxicity (Treon et al, NEJM 2015). Post-therapy, median 
serum IgM levels declined from 3,520 to 880 mg/dL; hemoglobin rose from 10.5 to 13.8 g/dL, and 
bone marrow involvement declined from 60% to 25% (p<0.01 for all comparisons). The median 
response time was 4 weeks. Overall and major response rates were 90.5% and 73.0%, and were 
highest in patients with MYD88L265PCXCR4Wild-Type (WT) (100% and 91.7%), followed by 
MYD88L265PCXCR4WHIM (85.7% and 61.9%), and MYD88WTCXCR4WT (60% and 0%) (Treon et 
al, NEJM 2015b). No complete responses were observed. Ten patients achieved a VGPR (15.8%), 
8 of whom had CXCR4WT disease. Patients with MYD88L265PCXCR4WHIM showed delayed major 
response kinetics in comparison to patients with the MYD88L265PCXCR4WT genotype (Treon et al, 


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NEJM 2015). 
 
Given the impact of CXCR4WHIM mutations on ibrutinib responses and response kinetics, we 
sought to address the functional significance of WHIM-like mutations in CXCR4 that are present 
in up to 40 percent of WM patients, and represent the first reporting of CXCR4 somatic mutations 
in cancer. We showed that CXCR4WHIM mutations conferred decreased receptor down-regulation, 
as well as enhanced and sustained AKT and ERK activation following treatment with SDF-1a, the 
ligand for CXCR4 (Cao et al, Leukemia 2014; Cao et al, BJH 2015). Use of the CXCR4 antagonist 
AMD3100 blocked SDF-1a triggered AKT and ERK activation in CXCR4WHIM expressing WM 
cells. The central finding of these studies was that the CXCR4 WHIM-like mutations conferred 
resistance to ibrutinib triggered apoptosis in WM cells, a finding that was associated with persistent 
AKT and ERK activation. The finding that enhanced AKT and ERK activity following SDF-1a is 
present in CXCR4WHIM expressing cells, and that inhibition of these targets potentiated ibrutinib 
killing provides support for a potential explanation for the clinical results obtained in WM patients 
treated with ibrutinib. Consistent with these in vitro findings, robust pAKT staining was observed 
in tumor samples from CXCR4WHIM patients, which contrasted against marginal pAKT staining in 
tumor samples from CXCR4WT patients (Cao et al, Leukemia 2014). Importantly, pAKT staining 
remained robust despite continuous ibrutinib therapy for 6 months in CXCR4WHIM patients, and 
continued to be marginal in CXCR4WT patients. Conversely, low level pERK staining was 
observed at baseline, and following ibrutinib therapy in bone marrow samples, without any 
discernible differences between CXCR4WT and CXCR4WHIM patients. These findings depict 
constitutive AKT activity, which functions as a powerful survival factor in WM, as being relevant 
to in vivo CXCR4WHIM signaling, and likely in view of the aggregate findings of this study as a 
likely contributor to clinical resistance to ibrutinib. The additional finding that SDF-1a protected 
against apoptosis triggered by other WM relevant therapeutics including bendamustine, 
fludarabine, bortezomib, and idelalisib in WM cells engineered to express the CXCR4WHIM 
mutation is of great interest, and suggests the relevance of these findings against a broader array 
of agents used to treat WM (Cao et al, BJH 2015).  
 
2.2 
Daratumumab 
 
Daratumumab is an IgG1ĸ human monoclonal antibody that targets CD38. Potential mechanisms 
of action have been investigated in both in vitro and in vivo studies. The results denote that 
complement-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity 
(ADCC) are major mechanisms of action for daratumumab. Half-maximal killing of myeloma 
cells in vitro by CDC and ADCC occurred at antibody levels of approximately 0.1 μg/mL and 0.03 
μg/mL, respectively. Trials in the xenograft lymphoma model in severe combined 
immunodeficiency mice have shown that daratumumab potently inhibits the in vivo growth of 
CD38-expressing tumor cells at concentrations from 0.5 mg/kg.  
 
In November 2015, the FDA granted accelerated approval for daratumumab to treat patients with 
multiple myeloma who have received at least 3 prior treatments. Daratumumab is not approved 
for the treatment of Waldenström Macroglobulinemia.  Daratumumab is the first monoclonal 
antibody approved for treating multiple myeloma. The safety and efficacy of daratumumab were 
demonstrated in 2 open-label studies. In a phase I/II multicenter study, 104 patients with multiple 
myeloma were exposed to daratumumab (Lokhorst et al NEJM 2015). In the group that received 


NCI Protocol #:N/A 
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Protocol Version Date: 2.1.19 
 
4 
 
16 mg/kg IV doses, the ORR was 36%, including 2 patients with CR and 2 with VGPR. The 
median PFS was 5.6 months and 65% of the patients who responded did not have progression at 
12 months. In a multicenter randomized phase II study, 106 patients received 16 mg/kg doses 
(Lonial et al Lancet 2016). The ORR was 29% with 3% stringent CR and 9% with VGPR. The 
median time to first response was 1 month, the median duration of response was 7.4 months and 
the median PFS was 3.7 months. 
 
2.3 
Rationale 
 
CD38 surface expression is present on many cell types in different tissues including subsets of B 
and T-lymphocytes. Marked expression of CD38 has been demonstrated on plasma cells. 
Interestingly, no CD38 expression has been detected on pluripotent (early) CD34+ stem cells, 
while more mature (intermediate) CD34+ cells do express CD38. In WM, a substantial component 
of the malignant clone (40-70%) expresses CD38 (21-23). Results from in vitro trials of 
daratumumab show ADCC and CDC activity against fresh tumor cells (myeloma) and inhibition 
of the CD38 enzyme activity. CD38 catalyzes production of second messengers that affect calcium 
mobilization. Furthermore, daratumumab prevents in vivo tumor growth in a prophylactic (murine) 
xenograft model. Recent data supports that daratumumab therapy was associated with expansion 
of CD4+ T-helper as well as CD8+ cytotoxic cells, and increase in clonality of the T-cell receptor 
repertoire, which could enhance cytotoxic T-cell responses. Such finding is supported by the 
observation than responders to daratumumab have increased T-cell responses to viral and 
alloantigens suggesting an upregulation of antitumor immune response. Such changes in T-cell 
expansion were more evident in responders than in non-responders to daratumumab. 
 
2.4 
Correlative Studies Background 
 
MYD88 L265P is a recently identified somatic mutation present in >90-95% of WM patients. 
MYD88 L265P supports growth and survival of WM cells by activation of Bruton tyrosine kinase 
(BTK), as well as IRAK1/4 (Yang et al, Blood 2013). Based on these findings, a clinical trial using 
the BTK inhibitor ibrutinib was investigated in 63 patients with relapsed or refractory WM (Treon 
et al, NEJM 2015). The study showed ibrutinib to be safe and effective, and supported the approval 
of ibrutinib by the US FDA, EMA, and Health Canada. Both MYD88 and CXCR4 tumor mutation 
status impacted responses to ibrutinib. Absence of MYD88 mutations, and presence of CXCR4 
mutations were associated with lower response rates to ibrutinib. Moreover, responses were 
delayed by 6-12 months in subjects harboring CXCR4 mutations. In most WM patients, CXCR4 
mutations are subclonal with an estimated median cancer cell fraction of 40-50%, though 
transcriptional signature remains relatively homogeneous (Hunter et al, Blood 2016; Xu et al, BJH 
2016). Transduction of WM cells with CXCR4 WHIM receptors, results in enhanced activation of 
the growth factors pAKT and pERK (Cao et al, Leukemia 2014; Cao et al, BJH 2015). 
 
Bone marrow aspirate (approximately 30 cc) will be collected at baseline, at initiation of 
maintenance, and within 4 weeks following completion of maintenance. Samples will be evaluated 
for the presence of MYD88 and CXCR4 mutations, as well as CD38 expression by flow cytometry 
and/or immunohistochemistry. 
 
 


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5 
 
3. PARTICIPANT SELECTION 
3.1 
Eligibility Criteria  
 
Participants must meet the following criteria on screening examination to be eligible to participate 
in the study: 
 
3.1.1 Clinicopathological diagnosis of Waldenström Macroglobulinemia (Owen et al. 2003), and 
meeting criteria for treatment using consensus panel criteria from the Second International 
Workshop on Waldenström macroglobulinemia (Kyle et al. 2003) 
3.1.2 Bone marrow at screening positive for CD38 expression by flow cytometry and/or 
immunohistochemistry 
3.1.3 At least one previous treatment for WM with either documented disease progression or 
no response (stable disease) to the most recent treatment regimen 
3.1.4 Measurable disease, defined as presence of serum immunoglobulin M (IgM) with a 
minimum IgM level of >2 times the upper limit of normal of each institution is required 
3.1.5 Participants with symptomatic hyperviscosity or serum IgM >5,000 mg/dL to undergo 
plasmapheresis prior to treatment initiation 
3.1.6 Age ≥18 years 
3.1.7 ECOG performance status ≤2 (see Appendix A) 
3.1.8 Participants must have preserved organ and marrow function as defined below: 
− 
Absolute neutrophil count 
≥ 1,000/mcL 
− 
Platelets 
≥ 50,000/mcL 
− 
Hemoglobin 
≥ 8 g/dL 
− 
Total bilirubin 
≤ 1.5 mg/dL or < 2 mg/dL if attributable to hepatic  
                                               infiltration by neoplastic disease 
− 
AST/ALT  
 
 
 
≤ 2.5 × institutional upper limit of normal 
− 
EGFR 
≥ 30 ml/min 
3.1.9 Not on any active therapy for other malignancies with the exception of topical therapies 
for basal cell or squamous cell cancers of the skin.  Participants progressing on ibrutinib 
therapy (or other BTK inhibitor) may continue on therapy through screening, stopping at 
least 1 day prior to Cycle 1 Day 1. 
3.1.10 Females of childbearing potential (FCBP) must agree to use two reliable forms of 
contraception simultaneously or have or will have complete abstinence from heterosexual 
intercourse during the following time periods related to this study: 1) while participating 
in the study; and 2) for at least 90 days after discontinuation from the study.  FCBP must 
be referred to a qualified provider of contraceptive methods if needed.  FCBP must have a 
negative serum pregnancy test at screening. 
3.1.11 Men must agree to use a latex condom during sexual contact with a FCBP even if they 
have had a successful vasectomy.  
3.1.12 Able to adhere to the study visit schedule and other protocol requirements. 
3.1.13 Ability to understand and the willingness to sign a written informed consent document. 
 
3.2 
Exclusion Criteria 
 
Participants who exhibit any of the following conditions at screening will not be eligible for 
admission into the study: 


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3.2.1 Any serious medical condition, laboratory abnormality, uncontrolled intercurrent illness, 
or psychiatric illness/social condition that would prevent study participation.  
3.2.2 Concurrent use of any other anti-cancer agents or treatments or any other investigational 
agents. 
3.2.3 Any condition, including the presence of laboratory abnormalities, which places the 
participant at unacceptable risk if he/she were to participate in the study or confounds the 
ability to interpret data from the study. 
3.2.4 Known CNS lymphoma. 
3.2.5 New York Heart Association classification III or IV heart failure. 
3.2.6 Known history of Human Immunodeficiency Virus (HIV).  
3.2.7 Active infection with Hepatitis B Virus (HBV) including participants with positive 
HBsAg testing at screening.  Participants with evidence of resolved infection (i.e. 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 are excluded.  EXCEPTION: Participants 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.  
3.2.8 Active infection with Hepatitis C Virus (HCV) (except in the setting of a sustained 
virologic response [SVR], defined as aviremia at least 12 weeks after completion of 
antiviral therapy). 
3.2.9 Lactating or pregnant women. 
3.2.10 Grade >2 toxicity (other than alopecia) continuing from prior anti-cancer therapy. 
3.2.11 History of non-compliance to medical regimens. 
 
3.3 
Inclusion of Women and Minorities 
 
Both men and women of all races and ethnic groups are eligible for this trial. 
 
4. REGISTRATION PROCEDURES 
 
4.1 
General Guidelines for DF/HCC Institutions 
 
Institutions will register eligible participants in the Clinical Trials Management System (CTMS) 
OnCore. Registrations must occur prior to the initiation of protocol therapy. Any participant not 
registered to the protocol before protocol therapy begins will be considered ineligible and 
registration will be denied. 
 
An investigator will confirm eligibility criteria and a member of the study team will complete the 
protocol-specific eligibility checklist. 
 
Following registration, participants may begin protocol therapy. Issues that would cause treatment 
delays should be discussed with the Overall Principal Investigator (PI). If a participant does not 
receive protocol therapy following registration, the participant’s registration on the study must be 
canceled. Registration cancellations must be made in OnCore as soon as possible.  


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4.2 
Registration Process for DF/HCC Institutions 
 
DF/HCC Standard Operating Procedure for Human Subject Research Titled Subject Protocol 
Registration (SOP #: REGIST-101) must be followed.   
 
4.3 
General Guidelines for Other Investigative Sites 
 
Eligible participants will be entered on study centrally at the Dana-Farber Cancer Institute by the 
Study Coordinator. All sites should call the Study Coordinator 617-632-5598 or 617-582-8667 to 
verify dose level availabilities.   
Following registration, participants should begin protocol therapy within 5 days. Issues that would 
cause treatment delays should be discussed with the Overall PI.  If a participant does not receive 
protocol therapy following registration, the participant’s registration on the study must be 
canceled.  The Study Coordinator should be notified of cancellations as soon as possible. 
 
4.4 
Registration Process for Other Investigative Sites 
 
To register a participant, the following documents should be completed by the research nurse 
and/or data manager, and faxed (617-632-6752) or e-mailed (kirsten_meid@dfci.harvard.edu) to 
the Study Coordinator: 
• Copy of serum protein electrophoresis, CBC, CMP, CT of the chest, abdomen and 
pelvis, and bone marrow biopsy report 
• Screening visit note 
• Signed participant consent form 
• HIPAA authorization form 
• Eligibility Checklist 
 
The Eligibility Checklist should be filled out by a clinical study staff member and the 
“Screening Staff” section must be signed by them.  Study staff at the Coordinating Center will 
review the eligibility documentation and sign as the “Enrollment Monitor.” 
 
The research nurse or data manager at the participating site will then call [617-632-5598 or e-mail 
[kirsten_meid@dfci.harvard.edu] the Project Manager to verify eligibility.  To complete the 
registration process, the Coordinator will follow DF/HCC Standard Operating Procedure for 
Human Subject Research Titled Subject Protocol Registration (SOP #: REGIST-101B) and 
register the participant on the protocol.  The coordinator will fax or e-mail the participant study 
number, and if applicable the dose treatment level, to the participating site.  The coordinator will 
also call the research nurse or data manager at the participating site and verbally confirm 
registration 
 
5. TREATMENT PLAN 
 
Treatment will be administered on an outpatient basis. No investigational or commercial agents or 
therapies other than those described below may be administered with the intent to treat the 


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8 
 
participant’s malignancy.   
 
5.1 
Treatment Regimen 
 
Daratumumab will be administered in three phases: Induction, consolidation and maintenance. The 
duration of each cycle is 28 days. During induction, participants will receive daratumumab on days 
1, 8, 15 and 22 of each 28-day cycle for 2 cycles for a total of 8 infusions or 8 weeks of therapy. 
Consolidation will start 2 weeks +/- 3 days after completing induction. During consolidation, 
daratumumab will be administered on days 1 and 15 of each 28-day cycle for 4 cycles for a total 
of 8 infusions or 16 weeks of therapy. Maintenance will start 4 weeks +/- 7 days after the 8th 
infusion of consolidation is completed. During maintenance, daratumumab will be administered 
on day 1 of each 28-day cycle for a total of 12 cycles or 48 weeks of therapy. Every effort should 
be made to keep subjects on the planned dosing schedule.  However, doses given within 3 days of 
the scheduled dose are permitted as long as the interval between doses is at least 5 days.  
Daratumumab will be administered for a total of 28 infusions or until progression, unacceptable 
toxicity, or decision to withdraw from the trial. Dose reductions due to daratumumab-related 
toxicity will not be permitted. The total duration of therapy is approximately 78 weeks (1.5 years). 
 
Regimen Description 
Agent 
Premedications; 
Precautions Approximately 
60 minutes before 
daratumumab infusion 
Dose 
Route 
Schedule 
Cycle 
Length 
Daratumumab 
Pre-medications will be 
given as per section 5.4.1 
16 mg/kg 
IV 
Induction: 2 cycles of 
weekly infusions 
Consolidation: 4 cycles 
of every other week 
infusions 
Maintenance: 12 cycles 
of monthly infusions 
28 days  
(4 weeks) 
 
 
Reported adverse events and potential risks are described in Section 7.  
 
5.2 
Pre-Treatment Criteria 
 
Cycle 1, Day 1 results do not need to meet eligibility parameters. Day 1 chemistry and hematology 
laboratories must be reviewed prior to treatment. 
 
Participants must meet the following criteria on treatment days of all cycles: 
• No grade 3 or higher non-hematologic toxicities with the following exceptions: 
o Grade 3 nausea or Grade 3 vomiting that responds to antiemetic treatment within 7 
days, 
o Grade 3 diarrhea that responds to antidiarrheal treatment within 7 days 
o Grade 3 fatigue or asthenia that was present at baseline or that lasts for <7 days 
after the last administration of daratumumab 
• Neutrophil count ≥ 500/μL (growth factor permitted, including on day of treatment) 


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9 
 
• No Febrile neutropenia of any grade 
• Platelet count ≥ 50,000/μL in the presence of bleeding (platelet transfusion permitted, 
including on day of treatment) 
• Platelet count ≥ 25,000 μL without bleeding (platelet transfusion permitted, including on 
day of treatment) 
 
Daratumumab treatment should be resumed when the toxicity has resolved to <Grade 2.  If the 
daratumumab administration does not commence within the pre-specified window of the 
scheduled administration date, then the dose will be considered a missed dose. Administration 
may resume at the next planned dosing date. A missed dose will not be made up. 
 
5.3 
Agent Administration 
 
Daratumumab 16 mg/kg will be administered per the Table 5.3.1. Participants should be observed 
for 30 minutes after the completion of the infusion. 
 
Table 5.3.1. Daratumumab infusion instructions 
 
 
Dilution volume 
Initial rate (first 
hour) 
Rate increment 
Maximum rate 
First infusion 
1000 mL 
50mL/hour 
50 mL/hour every 
hour 
200 mL/hour 
Second infusiona 
500 mL 
50 mL/hour 
50 mL/hour every 
hour 
200 mL/hour 
Subsequent 
infusionsb 
 
500 mL 
100 mL/hour 
50 mL/hour every 
hour 
200 mL/hour 
a    Escalate only if there were no Grade 1 (mild) or greater infusion reactions during the first 3    
     hour of the first infusion. 
b      Escalate only if there were no Grade 1 (mild) or greater infusion reactions during a final infusion      
     rate of > 100 mL/hr in the first two infusions. 
 
Vital signs (blood pressure, temperature, heart rate, respiratory rate) will be obtained before 
infusion, every 60 minutes (± 10 minutes) during the infusion period, and at 30 minutes (± 5 
minutes) after the completion of infusion.   
 
5.3.1 Infusion Related Reactions 
 
For infusion reactions of any grade/severity, immediately interrupt the daratumumab infusion 
and manage symptoms. Management of infusion reactions may further require reduction in the 
rate of infusion, or treatment discontinuation of daratumumab as outlined below:  
 
• Grade 1-2 (mild to moderate): Once reaction symptoms resolve, resume the infusion at no 
more than half the rate at which the reaction occurred. If the patient does not experience 
any further reaction symptoms, infusion rate escalation may resume at increments and 
intervals as appropriate (Table 5.3.1). 


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• Grade 3 (severe): If the intensity of the reaction decreases to Grade 2 or lower, consider 
restarting the infusion at no more than half the rate at which the reaction occurred. If the 
patient does not experience additional symptoms, resume infusion rate escalation at 
increments and intervals as outlined in Table 5.3.1. Repeat the procedure above in the 
event of recurrence of Grade 3 symptoms. Permanently discontinue daratumumab upon 
the third occurrence of a Grade 3 or greater infusion reaction.  
 
• Grade 4 (life threatening): Permanently discontinue daratumumab treatment 
 
Product description and storage information is described in Section 8. 
5.4 
General Concomitant Medication and Supportive Care Guidelines 
 
Participants will be instructed not to take any additional medications (including over-the-counter 
products) during the course of the study without prior consultation with the investigator. At each 
visit, the investigator will ask the participant about any new medications he/she is or has taken 
after the start of the study drug. 
 
5.4.1 Prophylactically Prescribed Medication 
 
All prophylactic premedication administration is mandatory. An antiviral should be prescribed for 
herpes zoster prophylaxis, with the participant initiating treatment within one week prior to starting 
Daratumumab and continuing for 3 months after treatment ends.   
 
Premedications1: 
1st & 2nd Daratumumab 
Infusion 
3rd & Subsequent Infusions* 
60 minutes before 
daratumumab infusion 
1. Acetaminophen 975mg 
PO 
2. Diphenhydramine 25-
50mg IV or PO 
3. Methylprednisolone 
100mg IV 
4. Famotidine 20 mg IV 
5. Montelukast 10mg PO  
6. Fexofenadine 60mg PO 
1. Acetaminophen 975mg 
PO 
2. Diphenhydramine 25-
50mg IV or PO 
3. Methylprednisolone 
60mg IV 
2 hours after start of the 
infusion (Daratumumab 
infusion to be paused at this 
point) 
1. Methylprednisolone 
40mg IV 
2. Famotidine 20mg IV 
3. Diphenhydramine 25 mg 
IV 
n/a 
Post infusion 
1. Methylprednisolone 
20mg PO 24 & 48 hours 
after infusioncompletion 
2. Albuterol Nebulizer 
solution 2.5mg Q6hours 
PRN wheezing** 
1. Methylprednisolone 
20mg PO 24 & 48 hours 
after infusion 
completion 
2. Albuterol Nebulizer 
solution 2.5mg Q6hours 
PRN wheezing ** 


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11 
 
*If patient has not experienced any infusion reaction.  Otherwise, continue with the 1st and 2nd 
infusion premedication schedule until 2 consecutive infusions given without infusion reaction 
** The Albuterol Nebulizer is only for patients with a higher risk of respiratory complications.  It 
can be administered for the first 4 infusions and after that, if there is no reaction, it can be 
discontinued.   
1Sites outside DF/HCC may follow their internal standard practice for daratumumab 
premedications. 
 
Methylprednisolone may be dose reduced per investigator discretion for participants who cannot 
tolerate the higher dose.  Post infusion methylprednisolone may be discontinued per investigator 
discretion. 
 
5.4.2 Permitted Treatments 
 
Subjects may receive DVT prophylaxis (if needed) with LMWH, warfarin, or similar. All 
anticoagulants, and/or aspirin should be held in case the platelet count is <50,000 mm3. 
The following medications and supportive therapies are examples of support therapies that may 
be used during the study: 
• Colony stimulating factors, erythropoietin, and transfusion of platelets and red cells; 
• It is important to prevent constipation (eg, adequate hydration, high-fiber diet, and stool 
softeners if needed); 
• Plasmapheresis to prevent and/or treat IgM flare and symptomatic hyperviscosity 
 
5.4.3 Avoidance of Medications 
• Subjects taking oral or parenteral corticosteroids should be tapered off this medication for 
5 half-lives prior to the first dose of daratumumab and must remain discontinued from all 
oral and parenteral corticosteroids while participating in the study (unless used for 
treatment of infusion reactions, rash, antiemetic prophylaxis or as part of the protocol 
chemotherapy regimen or subjects on low-dose corticosteroids (≤20 mg prednisone or 
equivalent) for chronic conditions. Investigators should discuss individual cases with the 
medical monitor. 
 
5.5 
Criteria for Taking a Participant Off Protocol Therapy 
 
Duration of therapy will depend on individual response, evidence of disease progression and 
tolerance. In the absence of treatment delays due to adverse event(s), treatment may continue for 
18 cycles or until one of the following criteria applies: 
 
• 
Disease progression. 
• 
Intercurrent illness that prevents further administration of treatment. 
• 
Unacceptable adverse event(s). 
• 
Participant demonstrates an inability or unwillingness to comply with the oral 
medication regimen and/or documentation requirements. 
• 
Participant decides to withdraw from the protocol therapy. 


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12 
 
• 
General or specific changes in the participant's condition render the participant 
unacceptable for further treatment in the judgment of the treating investigator. 
 
Participants will be removed from the protocol therapy when any of these criteria apply.  The 
reason for removal from protocol therapy, and the date the participant was removed, must be 
documented in the case report form (CRF). Alternative care options will be discussed with the 
participant. 
 
In the event of unusual or life-threatening complications, treating investigators must immediately 
notify the PI, Jorge J. Castillo at 617-632-3352.  
 
 
5.6 
Duration of Follow Up 
 
Participants will be followed for up to 24 months after discontinuation from protocol therapy or 
start of new therapy or until death, whichever occurs first.  Participants removed from protocol 
therapy for unacceptable adverse event(s) will be followed until resolution or stabilization of the 
adverse event. 
 
5.7 
Criteria for Taking a Participant Off Study 
 
Participants will be removed from study when any of the following criteria apply: 
• Lost to follow-up 
• Withdrawal of consent for data submission 
• Death 
 
The reason for taking a participant off study, and the date the participant was removed, must be 
documented in the case report form (CRF). 
 
For Decentralized Subject Registrations, the research team updates the relevant Off Treatment/Off 
Study information in OnCore.  
 
6. DOSING DELAYS/DOSE MODIFICATIONS 
 
Dose delays will be made as indicated in the following table(s). No dose modification will be 
allowed.  The descriptions and grading scales found in the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for dose delays and. A copy of 
the CTCAE version 4.0 can be downloaded from the CTEP website 
 http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
 
If possible, symptoms should be managed symptomatically. In the case of toxicity, appropriate 
medical treatment should be used (including anti-emetics, anti-diarrheals, etc.). All adverse events 
experienced by participants will be collected from the time of the first dose of study treatment, 
through the study and until the final study visit. Participants continuing to experience toxicity at 
the off study visit may be contacted for additional assessments until the toxicity has resolved or is 
deemed irreversible. 


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13 
 
 
For patients who are unable to tolerate the protocol-specified dosing schedule, dose adjustments 
are permitted. If administration of daratumumab must be interrupted because of unacceptable 
toxicity, drug dosing will be interrupted or missed according to rules described in below.   
 
Dosing will be held for any of the following drug-related conditions: 
• Grade 3 or higher non-hematologic toxicities with the following exceptions: 
o Grade 3 nausea or Grade 3 vomiting that responds to antiemetic treatment within 7 
days, 
o Grade 3 diarrhea that responds to antidiarrheal treatment within 7 days 
o Grade 3 fatigue or asthenia that was present at baseline or that lasts for <7 days 
after the last administration of daratumumab 
• Neutrophil count < 500/μL (growth factor permitted) 
• Febrile neutropenia of any grade 
• Platelet count < 50,000/μL in the presence of bleeding 
• Platelet count < 25,000 μL without bleeding 
 
Participants can be retreated according to the following guidelines once non-hematological toxicity 
has resolved to < Grade 2, ANC ≥500/ μL, and/or platelets are ≥25,000/ μL without bleeding.  If 
the toxicity has not resolved within 28 days, patients should discontinue treatment, unless allowed 
to continue by PI discretion. 
 
Daratumumab treatment should be resumed when the toxicity has resolved to < Grade 2. If the 
daratumumab administration does not commence within the pre-specified window (+/- 3 days 
and at least 5 days between doses) of the scheduled administration date, then the dose will be 
considered a missed dose.  Administration may resume at the next planned dosing date. A missed 
dose will not be made up.  If participants require a dose delay for plasmapheresis then the dose 
can be given up to 1 week later.  This would not be considered a missed dose.  If more than 2 
consecutive planned doses of daratumumab are missed due to AEs, treatment continuation 
should be discussed with the overall PI before resumption of therapy. 
 
Potential for IgM flare 
 
Abrupt increases in serum IgM levels following administration of anti-CD20 monoclonal 
antibodies and intravenous immunoglobulin are well recognized in WM patients (Treon et al, Ann 
Oncol 2004; Ghobrial et al, Cancer 2004; Yang et al, ASH 2010; Furman et al, ASH 2011). Such 
abrupt increases can prompt symptomatic hyperviscosity in patients with high serum IgM levels, 
i.e. >5,000 mg/dL and can contribute to worsening of IgM related morbidity such as 
cryoglobulinemia, cold agglutinemia, and demyelinating neuropathy. Plasmapheresis is therefore 
used to treat symptomatic IgM flares, as well as prophylax in patients with high serum IgM levels. 
Following plasmapheresis, serum IgM levels will return to steady state in 5 weeks. As such, WM 
patients who undergo plasmapheresis will be non-evaluable for response purposes within 4 weeks 
of last plasmapheresis. It is recommended that patients with symptomatic hyperviscosity or a pre-
treatment serum IgM level >5,000 mg/dL undergo plasmapheresis before treatment with 
daratumumab. Treatment with daratumumab may be delayed for up to one week if plasmapheresis 


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14 
 
is warranted. Close serial monitoring of serum IgM levels (at least weekly) is recommended for 
all participants during cycles 1 and 2. After cycle 2, monitoring would be per protocol on Days 1 
& 15 of Cycles 3-6, and Day 1 of Cycles 7-18 unless directed otherwise by treating physician. 
 
6.1 
Management of Hepatitis B Virus Reactivation 
 
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 see Section 10. 
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.  
 
7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The following 
list of reported and/or potential AEs (Section 7.1) and the characteristics of an observed AE 
(Section 7.2) will determine whether the event requires expedited reporting in addition to routine 
reporting. 
7.1 
Expected Toxicities 
 
7.1.1 Adverse Events List 
 
7.1.1.1 
Adverse Event List(s) for Daratumumab 
 
Among the subjects treated with a therapeutic dose of daratumumab 16 mg/kg administered 
intravenously as monotherapy: 
 
• 6 subjects (4%) discontinued daratumumab treatment due to a treatment emergent 
adverse event (TEAE), none of which were considered by the investigator to be related to 
daratumumab. 
• 3 subjects (2%) died due to TEAEs; no deaths due to daratumumab-related TEAEs were 
reported. 
• The most frequently reported TEAEs were fatigue (40%); nausea and anemia (28% 
each); back pain (26%); neutropenia (23%); pyrexia (22% each), upper respiratory tract 
infection (22%) and thrombocytopenia (21%). 
• SAEs were reported in 33% of subjects, the most frequently reported SAEs were 
 pneumonia (6%) and pyrexia, hypercalcemia, and general physical health deterioration 
(3% each). 
• Grade 3 or 4 AEs were reported in 56% of subjects; most commonly these were anemia 
(17%), thrombocytopenia (14%), neutropenia (12%), lymphopenia (6%), leukopenia, 
pneumonia, and hypertension (5% each). 
• Infusion-related reactions (IRRs) were reported in 48% of subjects. Of the subjects who 


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15 
 
experienced an IRR, 95% experienced an IRR at the first infusion; 11% had an IRR at 
more than one infusion. Bronchospasm was reported in 3% of subjects. Grade 3 IRRs 
were reported in 3% of subjects, no Grade 4 or 5 IRRs were reported. Grade 3 IRRs 
included bronchospasm (reported in 2 subjects [1%]); the remaining Grade 3 IRRs of 
dyspnea, hypoxia, and hypertension were reported in 1 subject (0.6%) each. 
• AEs of infections were reported in 59% of subjects. The most frequently reported were 
upper respiratory tract infection (22%), nasopharyngitis (15%), pneumonia (9%), sinusitis 
(7%), and urinary tract infection (6%). Grade 3 or higher TEAEs of infections or 
infestations were reported in 10% of subjects and 1% of subjects, respectively. 
 
7.2 
Adverse Event Characteristics 
 
• CTCAE term (AE description) and grade:  The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.0 will be utilized for AE reporting.  All appropriate treatment areas should have access 
to a copy of the CTCAE version 4.0.  A copy of the CTCAE version 4.0 can be downloaded 
from the NCI web site http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_8.5x11.pdf  
 
• For expedited reporting purposes only:   
- 
AEs for the agent(s) that are listed above should be reported only if the adverse event 
varies in nature, intensity or frequency from the expected toxicity information which is 
provided. 
- 
Other AEs for the protocol that do not require expedited reporting are outlined in the 
next section (Expedited Adverse Event Reporting) under the sub-heading of Protocol-
Specific Expedited Adverse Event Reporting Exclusions. 
 
• Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
7.3 
Expedited Adverse Event Reporting  
 
7.3.1 Investigators must report to the Overall PI any serious adverse event (SAE) that occurs 
after the initial dose of study treatment, during treatment, or within 30 days of the last dose 
of treatment on the local institutional SAE form.  
 
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 


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16 
 
• 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) 
 
7.3.2 For multi-institution studies where a DF/HCC investigator is serving as the Overall 
Principal Investigator, each participating institution must abide by the reporting 
requirements set by the DF/HCC. This applies to any medical event equivalent to an 
unexpected grade 2 or 3 with a possible, probable or definite attribution, all grade 4 
toxicities, and grade 5 (death) regardless of study phase or attribution. 
 
7.3.3 DF/HCC Expedited Reporting Guidelines 
 
Investigative sites within DF/HCC will report AEs directly to the DFCI Office for Human 
Research Studies (OHRS) per the DFCI IRB reporting policy.  
 
Other investigative sites will report AEs to their respective IRB according to the local 
IRB’s policies and procedures in reporting adverse events. A copy of the submitted 
institutional AE form should be forwarded to the Overall PI within the timeframes detailed 
in the table below.   
 
 
 
 
Attribution 
DF/HCC Reportable AEs 
Gr. 2 & 3 AE 
Expected 
Gr. 2 & 3 AE 
Unexpected 
Gr. 4 AE 
Expected 
Gr. 4 AE 
Unexpected 
Gr. 5 AE 
Expected or 
Unexpected 
Unrelated 
Unlikely 
Not required 
Not required 
5 calendar days# 
5 calendar days 
24 hours* 
Possible 
Probable 
Definite 
 
Not required 
 
5 calendar days 
 
5 calendar days# 
 
5 calendar days 
 
24 hours* 
# If listed in protocol as expected and not requiring expedited reporting, event does not need to be reported. 
 
* For participants enrolled and actively participating in the study or for AEs occurring within 30 days of the last 
intervention, the AE should be reported within 1 business day of learning of the event. 
 
 
The Overall PI will submit AE reports from outside institutions to the DFCI OHRS 
according to DFCI IRB policies and procedures in reporting adverse events.  
 
7.3.4 Protocol-Specific Expedited Adverse Event Reporting Exclusions 
 
For this protocol only, the AEs/grades listed below do not require expedited reporting to 
the Overall PI or the DFCI IRB.  However, they still must be reported through the routine 
reporting mechanism (i.e. case report form). 


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17 
 
 
CTCAE SOC 
Adverse Event 
Grade 
Hospitalization/ 
Prolongation of 
Hospitalization 
Attribution 
Comments 
Investigations 
Platelet count 
decreased 
4 
No 
Related 
If hospitalization required, 
must be reported to DFCI 
IRB and PI 
Investigations 
Neutrophil 
count 
decreased 
4 
No 
Related 
If hospitalization required, 
must be reported to DFCI 
IRB and PI 
 
7.4 
Expedited Reporting to the Food and Drug Administration (FDA) 
 
The Overall PI, as study sponsor, will be responsible for all communications with the FDA. The 
Overall PI will report to the FDA, regardless of the site of occurrence, any serious adverse event 
that meets the FDA’s criteria for expedited reporting following the reporting requirements and 
timelines set by the FDA. 
 
7.5 
Expedited Reporting to Janssen 
 
7.5.1 Overview 
 
As the sponsor of the Study, PRINCIPAL INVESTIGATOR shall be solely responsible 
for complying, within the required timelines, any safety reporting obligation to competent 
Health Authorities, IRB/ECs and any participating (co or sub) investigators, as defined in 
applicable laws and regulations.  For the purposes of this section, safety data includes 
adverse events, product quality complaints (PQCs), and special situations including 
pregnancies. 
 
The PRINCIPAL INVESTIGATOR will provide safety information to Janssen Scientific 
Affairs, LLC on adverse events, special situations including pregnancies and product 
quality complaints as defined within this section. 
 
7.5.2 Management of Safety Data 
This Study has been designated as an interventional study.  As such, all adverse events 
for Janssen Medicinal Products regardless of causality and special situations excluding 
those from subjects not exposed to a Janssen Medicinal Product and product quality 
complaints with or without an adverse event as described in this Exhibit will be reported 
from the time a subject has signed and dated an Informed Consent Form (ICF) until 
completion of the subject’s last study-related procedure (which may include contact for 
follow-up safety).  Serious adverse events will be reported for 30 days after the last dose 
of study drug. 
 
For the purposes of this study, the Janssen medicinal product is: DARZALEX™ 
(daratumumab). 
 


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18 
 
7.5.3 Definitions 
 
7.5.3.1 
Adverse Event (AE) 
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. 
 
7.5.3.2 
Adverse Events of Special Interest  
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 
• Tumor lysis syndrome 
• Other malignancies  
• Intravascular hemolysis – all grades 
 
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. 
 
7.5.3.3 
Individual Case Safety Report (ICSR) 
A valid ICSR must contain the four minimum criteria required to meet regulatory 
reporting requirements. 
• an identifiable subject (but not disclosing personal information such as the 
subject’s name, initials or address) 
• 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) 


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19 
 
• gender 
• age at AE onset 
• reporter ID 
• adverse event detail (AE verbatim in English), onset date, relatedness, 
causality, action taken, outcome, (if available) 
• Janssen protocol ID 
 
7.5.3.4 
Product Quality Complaint (PQC) 
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 
 
7.5.3.4.1  Procedures for Reporting Safety Data and Product Quality Complaints (PQCs) 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. 
 
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 or 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 


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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. 
 
7.5.3.5 
Serious Adverse Event (SAE), Adverse Events of Special Interest and Special Reporting 
Situations (see section 7.5.3.2) 
 
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 English within 24-
hours of becoming aware of the event(s). 
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, Adverse 
Event of Special Interest, serious ADR or special situation is required. 
 
• The PRINCIPAL INVESTIGATOR is responsible for ensuring that these cases are 
complete and if not are promptly followed-up. A safety report is not considered 
complete until all clinical details needed to interpret the case are received. 
Reporting of follow-up information should follow the same timeline as initial 
reports. 
 
• Copies of any and all relevant correspondences with regulatory authorities and 
ethics committees regarding any and all serious adverse events, irrespective of 
association with the Janssen Product under study, are to be provided to Janssen 
Scientific Affairs, LLC using a transmission method in Section 10 within 24 hours 
of such report or correspondence being sent to applicable health authorities. 
 
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 


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• 
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. 
 
7.5.3.5.1    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.]  
 
7.5.3.5.2    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. 
 
7.5.3.5.3    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.  
 
Any subject who becomes pregnant during the study must be promptly withdrawn 


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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. 
 
7.5.3.6 
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. 
 
7.5.3.7  Special Reporting Situations 
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. 
 


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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. 
 
7.5.3.8 
 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. 
 
 
7.5.3.9 
Reporting Procedures for Reporting Safety Data and Product Quality Complaints (PQCs)  
 
SAE Email Address:  IIS-BIO-VIRO-GCO@its.jnj.com  
SAE Facsimile Number:  1-866-651-0219 
If only limited information is initially available, follow-up reports are required. (Note: 
Follow-up SAE reports should include the same investigator term(s) initially reported.)  
If an ongoing SAE changes in its intensity or relationship to study drug or if new 
information becomes available, a follow-up SAE report should be sent within 24 hours 
to the Janssen (or designee) using the same procedure used for transmitting the initial 
SAE report.  
All SAEs should be followed to resolution or stabilization. 
7.6 
Expedited Reporting to Hospital Risk Management 
 
Participating investigators will report to their local Risk Management office any participant safety 
reports or sentinel events that require reporting according to institutional policy.  
 
7.7 
Routine Adverse Event Reporting 
 
All Adverse Events must be reported in routine study data submissions to the Overall PI on the 
toxicity case report forms.  AEs reported through expedited processes (e.g., reported to the 
IRB, FDA, etc.) must also be reported in routine study data submissions. 
 
8. PHARMACEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated with the investigational agent 
administered in this study can be found in Section 7.1. 
 
8.1 
Daratumumab 
 
8.1.1 Description 
 
Daratumumab, a CD38 antagonist, is being developed for the treatment of multiple myeloma and 
other malignancies. The active ingredient, daratumumab, is a human immunoglobulin G1 kappa 


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(IgG1κ) monoclonal antibody (mAb) that binds CD38 expressing cells with high affinity in a 
variety of hematological malignancies, including myeloma, lymphomas, and leukemias, as well 
as other cell types and tissues with various expression levels. 
 
8.1.2 Form 
 
The active ingredient, daratumumab, of the IMP is a human mAb that specifically recognizes 
CD38 protein expressed on the surface of plasma cells, but also other cell types and tissues with 
various levels of CD38 expression. It is produced in a mammalian CHO suspension culture and 
purified by affinity and ion exchange chromatography (IEC), as well as by specific viral 
clearance procedures. 
 
Daratumumab consists of the known structure of an IgG1κ mAb, which includes 2 peptide heavy 
chains and 2 peptide light chains. The 2 heavy chains are connected to each other by 2 interchain 
disulfide bonds, and 1 light chain is attached to each heavy chain by a single interchain disulfide 
bond. The light chain has 2 intrachain disulfide bonds and the heavy chain has 4 intrachain 
disulfide bonds. The IgG1κ antibody has an isoelectric point at approximately 8.4 – 9.0 as 
determined by imaging capillary isoelectric focusing. 
 
The molecular weight (MW) of the antibody is approximately 148 kDa as determined by 
MALDI-TOF-MS. Using SDS-PAGE under reducing condition the MW of the light chain was 
found to be 26 kDa and the MW of the heavy chain to be 53 kDa. 
 
The mAb is N-linked glycosylated at Asn302. The antibody glycosylation profile predominantly 
contains bi-antennary core fucosylated glycans with varying amounts of terminal galactose. 
 
Daratumumab drug product is formulated as a concentrate of 20. mg/mL ± 2. mg/mL in an 
isotonic buffer consisting of sodium acetate, sodium chloride, mannitol and polysorbate 20 at pH 
5.5. 
 
8.1.3 Storage, Stability and Handling 
 
The daratumumab vials should be stored in the original carton in a refrigerator at 2ºC to 8ºC and 
must not be utilized after the expiry date printed on the label. The product must be protected 
from light and must not be frozen. Since daratumumab does not contain preservatives, any 
unused portion remaining in the vial must be discarded. Daratumumab will be diluted in a sterile, 
pyrogen-free physiological saline solution (0.9% NaCl) prior to IV administration. 
 
8.1.4 Compatibility, Preparation and Administration 
 
Daratumumab 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 20 mL, 
respectively. It is administered by the intravenous (IV) route after dilution in a sterile, pyrogen-
free physiological saline solution (0.9% NaCl) provided by the investigation site.   
 
Infusion bags/containers must be made of polyvinylchloride (PVC), polypropylene (PP), 


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polyethylene (PE), or polylefin blend (PP+PE).   
 
Following dilution, the infusion bag/container may be stored for up to 24 hours in a refrigerator 
at 2 ºC to 8 ºC (36 ºF to 46 ºF), protected from light.  Infusion should be completed within 15 
hours.  Do not store any unused portion of the infusion solution for reuse.  Any unused product 
or waste material should be disposed of in accordance with local requirements.   
 
Administer the diluted solution by intravenous infusion using an infusion set fitted with a flow 
regulator and with an in-line, sterile, non-pyrogenic, low protein-binding polyethersulfone (PES) 
filter (pore size 0.22 or 0.2 micrometer).  Polyurethane (PI), polybutadiene (PBD), PVC, PP, or 
PE administration sets must be used.   
 
8.1.5 Availability and Ordering 
 
Daratumumab will be provided free of charge by Janssen Scientific Affairs, LLC as 400mg/20ml 
vials.  Biologics, Inc. will provide drug distribution services for the study.  In the event that 
400mg/20mL vials are not available, Janssen Scientific Affairs, LLC will provide an equivalent 
formulation of daratumumab in 100mg vials as a substitute. 
 
Biologics, Inc. contact details for drug ordering: 
Fax: 919-256-0794 
Email: CRSOrders@biologicsinc.com 
 
Throughout the course of the study, a Biologics, Inc. clinical hotline support, staffed with clinical 
pharmacists, is made available 24/7/365 in the event an investigator or site coordinator has a 
question.  Hotline phone: 1-800-693-4906 
 
8.1.6 Accountability 
 
The investigator, or a responsible party designated by the investigator, should maintain a careful 
record of the inventory and disposition of the agent using the NCI Drug Accountability Record 
Form (DARF) or another comparable drug accountability form.  (See the NCI Investigator’s 
Handbook for Procedures for Drug Accountability and Storage.) 
 
8.1.7 Destruction and Return 
 
The Drug Accountability Log will contain the date and amount of study drugs received and 
dispensed. All used and partially used study drug will be destroyed by the site, in accordance with 
the site’s standard operating procedures (SOPs).  All expired drug and any unused drug remaining 
once all patients are off study treatment will be destroyed on site in accordance with the site’s 
standard operating procedures (SOPs). 
 
9. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
9.1 
Biomarker Studies 
 


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9.1.1 Laboratory Correlative Studies 
 
Bone marrow aspirate (approximately 30 cc in 2 heparinized syringes & 1 purple top or 3 purple 
tops for outside sites) will be collected at baseline, prior to administration of cycle 7, and within 4 
weeks following completion of therapy. At each time point, the samples will be genotyped for 
MYD88 and CXCR4 by the Bing Center for WM laboratory.  The samples will be used until 
depletion.  All samples from sites other than DFCI will be shipped ambiently priority overnight 
Monday-Thursday by a qualified carrier to: 
 
Christopher Patterson 
Administrative Director 
Dana-Farber Cancer Institute, Harvard Medical School Bing Center for Waldenstrom’s 
Macroglobulinemia 
450 Brookline Avenue, Mayer 548 
Boston, MA 02215 
Ph: 617-632-6285 
Fx: 617-632-4862 
cpatterson@partners.org 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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10. STUDY CALENDAR 
 
 
 
 
Screening* 
 
≤ 30 days 
from study 
entry 
Treatment Phase 
Off Treatment 
Assessment 
 
Within 4 weeks of 
completion or 
removal from study ± 
2 weeks 
Follow-Up Phase 
 
Post Treatment; Every 
12 ± 2 weeks for 24 
months or until next 
therapy 
Induction 
Cycles 
1 and 2 (+/- 3 days) 
 
Consolidation 
(Beginning 2 
weeks +/- 3 
days after C2 
completion) 
Cycles 
3 to 6 
Maintenance 
(Beginning 4 
weeks +/- 7 
days after C6 
D15) 
Cycles 
7 to 18 
Day 
1 
Day 
8 (+/- 3 
days) 
Day 
15 
(+/- 3 
days) 
Day 
22 
(+/- 3 
days) 
Day 
1 (+/- 
3 
days) 
Day 
15 
(+/- 3 
days) 
Day 
1 (+/- 3 days) 
Physical exam1, weight, 
height 
X 
X 
 
 
 
X 
 
X 
X 
X 
Medical History 
X 
 
 
 
 
 
 
 
 
 
ECOG performance 
status (see Appendix A) 
X 
X 
 
 
 
X 
 
X 
X 
X 
CT of the chest & 
abdomen / pelvis2 
X 
 
 
 
 
 
 
X2 
X2 
X (if applicable) 
Bone marrow biopsy 
and aspiration3 
X 
 
 
 
 
 
 
X3 
X3 
X  (if applicable) 
Serum immuno-
electropheresis & 
Response assessment 
X 
 X 
 
 
 
X 
 
X 
X 
X 
Serum IgM 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum IgA, IgG 
X 
X 
 
 
 
X 
 
X 
X 
X 
Complete Blood Count 
plus differential1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulation profile: PT, 
PTT, PT-INR 
X 
 
 
 
 
 
 
 
 
 
Chemistry including: 
Electrolytes, Renal 
(BUN, Creatinine) and 
Hepatic function testing 
[ALT, AST, Alk phos, 
total Bilirubin], 
albumin, total protein 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs (Temp, HR, 
RR, BP)** 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Beta-2 microglobulin, 
Von Willebrand 
screening 
X 
 
 
 
 
 
 
 
 
 
Pregnancy Test4 
X 
 
 
 
 
 
 
 
 
 
HBsAg, HBsAb, 
HBcAB 
X 
X6 
 
 
 
X6 
 
X6 
 
 
HCV Ab 
X 
 
 
 
 
 
 
 
 
 
Indirect antiglobulin 
testing 
X 
 
 
 
 
 
 
 
 
 
Daratumumab 
administration 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Adverse event 
monitoring5 
 
X 
 
 
 
X 
 
X 
X 
X 
 
* Physical exam, laboratory tests, vital signs, and weight do not need to be repeated if Cycle 1, 
Day 1 is within 14 days of Screening. Cycle 1, Day 1 labs, if drawn, do not need to re-confirm 
eligibility prior to administering first dose.  
**Vital signs (Blood pressure, heart rate, respiratory rate, temperature) should be taken prior to 
infusion, and every 60 minutes during the infusion period (+ 10 minutes), and 30 minutes (+ 5 


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minutes) after the completion of the infusion. 
 
1More frequent visits may be required at the discretion of the treating physician.  
 
2If CT scans of the chest, abdomen and pelvis have been collected and done within 90 days 
of Cycle 1 Day 1 they will not be required at the screening visit. If the participant has 
known extramedullary disease outside the chest, abdomen, or pelvis, imaging should 
be performed with investigator-preferred modality.  Scans will be repeated just before 
Cycle 7 and at End of Treatment for participants with extramedullary disease at 
baseline defined as adenopathy >1.5 cm in any axis, and splenomegaly >15 cm in the 
craniocaudal axis. If participant has disease only outside chest, abdomen, and pelvis, only 
the affected area will need to be re-imaged with the same modality as at screening.  Scans 
will also be repeated to confirm a complete response, if the participant has no detectable 
monoclonal protein and had extramedullary disease at baseline and at the discretion of the 
investigator. 
 
3 If bone marrow aspirate and biopsy had been collected within 90 days of Cycle 1 Day 1 
they will not be required at the screening visit. Bone marrow biopsy and aspiration 
will be performed just before cycle 7 and at the end of treatment. Bone marrow aspiration 
and biopsy may also be done at the investigator’s discretion, and at any time to confirm a 
complete response, if the participant has no detectable monoclonal protein.  
 
4For women of childbearing potential only: Serum pregnancy test is required at screening. 
 
5Please refer to Section 6 for Dose Delays. 
 
6Participants who have serologic evidence of HBV exposure at screening but are HBsAg 
negative and do not have active HBV infection are allowed to enroll on study.  
Participants with resolved infection (ie, 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.  Participants who have unclear interpretation (HBsAg negative and anti-
HBc positive and anti-HBs negative) must also be screened using real-time PCR and 
those who are PCR positive will be excluded.  Retesting of HBV DNA only should be 
done every three months while on therapy for any participants with evidence of prior 
HBV exposure at screening. 
 
 


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11.  MEASUREMENT OF EFFECT 
 
11.1 
Definitions 
 
Evaluable for toxicity: All participants who receive at least one dose of study treatment will 
be evaluable for toxicity from the time of their first treatment. 
 
Evaluable for objective response: Only those participants who have measurable disease 
present at baseline, have received at least one cycle of therapy, and have had their disease 
re-evaluated will be considered evaluable for response. Response will be assessed on Day 1 of 
each cycle starting with Cycle 2 unless the participant has undergone plasmapheresis within the 
previous 4 weeks.  Participants discontinuing BTK inhibitors might not be evaluable for 
response due to IgM rebound until Cycle 4 Day 1 (Gustine JN, et al. Ibrutinib discontinuation 
in Waldenstrom macroglobulinemia. Am J Hematol 2018; 93:511-517).  These participants will 
have their response classified according to the definitions stated below. (Note: Participants 
who exhibit objective disease progression or die prior to the end of cycle 1 will also be 
considered evaluable.) 
 
11.2 
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): is defined as ≥90% reduction in serum IgM levels, or 
normalization of serum IgM levels. 
 
Partial Response (PR): Partial response (PR) is defined as achieving a ≥50% reduction in serum 
IgM levels. 
 
Minor Response (MR): A minor response (MR) is defined 25-49% reduction in serum IgM levels. 
 
Progressive Disease (PD): Progressive disease (PD) is defined as occurring when a greater than 
25% increase in serum IgM level occurs with an absolute increase of at least 500 mg/dL from the 
lowest attained response value, or progression of clinically significant disease related symptom(s). 
Reconfirmation of the initial IgM increase is required when IgM is the sole criterion for 
progressive disease confirmation.  Death from any cause or initiation of a new anti-neoplastic 
therapy will also be considered a progression event. An increase of 1 cm in any axis for 
adenopathy, or 2 cm in the craniocaudal axis of the spleen will be considered evidence of 
progression of extramedullary disease. Development of Bing Neel syndrome, or other 
extramedullary disease manifestations, as well as disease transformation will be considered as 
progressive events. 
 
Stable Disease (SD): Stable disease is defined as having < 25% change in serum IgM levels, in 


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the absence of new or increasing adenopathy or splenomegaly and/or other progressive signs or 
symptoms of WM. 
 
Overall Response Rate (ORR): Includes patients who achieved MR, PR, VGPR and CR.  The 
best overall response rate will be at any point on therapy. 
 
11.3 
Time-to-event definition 
 
• Progression-Free Survival (PFS) is defined as the duration of time from start of treatment to 
time of objective disease progression (including initiation of new therapy or death).  
 
11.4 
Relapsed/Refractory definitions 
 
Refractory disease:  Disease that is non-responsive (failure to achieve minimal response or 
development of progressive disease (According to the Sixth International Workshop on WM) 
while on therapy), or progresses within 60 days of last therapy.   
 
Relapsed disease:  Previously treated disease that progresses (According to the Sixth 
International Workshop on WM) while on therapy) and requires initiation of new therapy that 
does not meet criteria for refractory. 
 
12. DATA REPORTING / REGULATORY REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 
(Adverse Events: List and Reporting Requirements). 
 
12.1 Data Reporting 
 
12.1.1 Method 
 
The Office of Data Quality (ODQ) will collect, manage, and perform quality checks on 
the data for this study. 
 
12.1.2 Responsibility for Data Submission 
 
Investigative sites within DF/HCC or DF/PCC are responsible for submitting data and/or 
data forms to the Office of Data Quality in accordance with DF/HCC SOPs. 
 
12.2 Data Safety Monitoring 
 
The DF/HCC Data and Safety Monitoring Committee (DSMC) will review and monitor toxicity 
and accrual data from this study. The committee is composed of clinical specialists with experience 
in oncology and who have no direct relationship with the study. Information that raises any 
questions about participant safety will be addressed with the Overall PI and study team. 
 
The DSMC will review each protocol up to four times a year or more often if required to review 


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toxicity and accrual data. Information to be provided to the committee may include: up-to-date 
participant accrual; current dose level information; DLT information; all grade 2 or higher 
unexpected adverse events that have been reported; summary of all deaths occurring with 30 days 
of intervention for Phase I or II protocols; for gene therapy protocols, summary of all deaths while 
being treated and during active follow-up; any response information; audit results, and a summary 
provided by the study team. Other information (e.g. scans, laboratory values) will be provided 
upon request.  
12.3 Multicenter Guidelines 
 
This protocol will adhere to the policies and requirements of the DF/HCC Multi-Center Data and 
Safety Monitoring Plan.   
 
• The Overall PI/Coordinating Center is responsible for distributing all IND Action Letters 
or Safety Reports to all participating institutions for submission to their individual IRBs 
for action as required. 
 
• Mechanisms will be in place to ensure quality assurance, protocol compliance, and adverse 
event reporting at each site. 
 
• Except in very unusual circumstances, each participating institution will order the study 
agent(s) directly from supplier.  A participating site may order the agent(s) only after the 
initial IRB approval for the site has been forwarded to the Coordinating Center. 
 
12.4 Collaborative Agreements Language 
 
Not applicable 
 
13. STATISTICAL CONSIDERATIONS 
 
This is a phase II single-arm, open-label prospective study aimed at evaluating the efficacy of 
daratumumab, an anti-CD38 monoclonal antibody, in patients with relapsed and/or refractory 
WM. With a double-sided alpha of 0.04 and power of 0.92, a sample size of 30 patients would 
suffice to show a statistical difference between the alternative hypothesis of obtaining an ORR of 
70% versus the null hypothesis of obtaining an ORR of 40%. If 18 patients or more obtain a 
response, then daratumumab will continue further evaluation. If 17 patients or less obtain a 
response, then daratumumab should not continue further evaluation. The critical value of 18 means 
to include 70% as the upper level of the 95% CI, while the critical value of 6 patients means to 
exclude 40% as the upper level of 95% CI based on a exact binomial estimate ( STATA SE 13.1). 
In addition, assuming that an adverse event associated with study drug has a true incidence of 10%, 
with an estimated sample size of 30 patients, the likelihood of observing at least 1 adverse event 
would be at least 95% 
 
13.1 Study Design/Endpoints 
 
This is a phase II single-arm, open-label prospective study aimed at evaluating the efficacy and 


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safety of daratumumab in patients with relapsed and/or refractory WM. With a double-sided type 
I error of 4% and power of 92%, a sample size of 30 patients would suffice to show a statistical 
difference between the alternative hypothesis of obtaining an ORR (see section 1.2) of 70% versus 
the null hypothesis of obtaining an ORR of 40%. If 18 patients or more obtain a response, then 
daratumumab will continue further evaluation. If 17 patients or less obtain a response, then 
daratumumab should not continue further evaluation. The primary endpoint is ORR. Secondary 
endpoints include MR, PR, VGPR, CR and PFS. 
 
13.2 Sample Size, Accrual Rate and Study Duration 
 
A total of 30 patients will be accrued. Accrual time will be approximately 1 year, at a rate of 2-3 
patients per month. The individual study duration will be approximately 1.5 years. Patients will 
then be followed up for 2 years after completion or discontinuation of therapy or until death, 
whichever occurs first. The total study duration will be approximately 4.5 years (1 year of 
accrual, 1.5 years of therapy and 2 years of follow-up). The individual study duration will be 
approximately 3.5 years (1.5 years of therapy and 2 years of follow-up). 
 
Accrual Targets 
Ethnic Category 
Sex/Gender 
Females 
 
Males 
 
Total 
Hispanic or Latino 
1 
+ 
4 
= 
5 
Not Hispanic or Latino 
5 
+ 
20 
= 
25 
Ethnic Category: Total of all subjects 
6 
(A1) + 
24 
(B1) = 
30 
(C1) 
Racial Category 
 
American Indian or Alaskan Native 
 
+ 
 
= 
 
Asian 
 
+ 
1 
= 
1 
Black or African American 
1 
+ 
1 
= 
2 
Native Hawaiian or other Pacific 
Islander 
 
+ 
 
= 
 
White 
5 
+ 
22 
= 
27 
Racial Category: Total of all subjects 
6 
(A2) + 
24 
(B2) = 
30 
(C2) 
 
(A1 = A2) 
 
(B1 = B2) 
 
(C1 = C2) 
 
13.3 Stratification Factors 
 
No stratification factors will be applied to any analysis. 
 
13.4 Interim Monitoring Plan 
 
Please refer to section 13.1 and 13.2. 
 
13.5 Analysis of Primary Endpoints 
 


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Primary analysis will be performed in the Full Analysis Set (FAS) for the primary assessment of 
efficacy.  The FAS will include those participants who have received at least one dose of 
therapy.  The primary analysis will include calculating the proportion of patients having at least a 
25% reduction in serum IgM (minor response or better) at any point on therapy.  Confidence 
intervals (95%) around these point estimates will be presented.   
. 
13.6 Analysis of Secondary Endpoints 
 
Secondary analyses will be performed in the FAS.  Time to progression (TTP) will be estimated 
using Kaplan Meier methodology with median time plus 25th and  75th percentile along with 95% 
confidence intervals, as appropriate.   
 
Minor, partial, very good partial, and complete response rates will be estimated in the FAS 
population by calculating the proportion of patients having those responses and calculating the 
95% confidence intervals around these point estimates. 
 
All participants who receive at least one dose of daratumumab during the study will be included 
in the safety analysis. 
 
13.7 Reporting and Exclusions 
 
13.7.1 Evaluation of Toxicity 
 
All participants who receive at least one dose of any test material during the study will be included 
in the safety analysis. 
 
13.7.2 Evaluation of the Primary Efficacy Endpoint 
 
All participants included in the study must be assessed for response to treatment, even if there are 
major protocol treatment deviations or if they are ineligible. Each participant should be assigned a 
response category based on the response criteria in Section 9.1.2.  According to section 11.1.2, 
patients who underwent plasmapheresis less than 4 weeks prior to response assessment will be 
deemed non-evaluable, according to Section 11.1.2. 
 
All participants who met the eligibility criteria and were enrolled in the trial will be included in 
the main analysis of the response rate. All conclusions will be based on all eligible participants. 
 
14. PUBLICATION PLAN 
 
Interim study results will be presented at a major scientific meeting (American Society of 
Hematology and/or the International Workshop on Malignant Lymphoma) once all patients 
complete 6 months of therapy. A full report that will include primary and secondary endpoints will 
be published in a peer-reviewed journal that meets the requirements of the International Committee 
of Medical Journal Editors within 24 months of reaching the end of the study. 
 
 


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34 
 
REFERENCES 
 
Cao Y, Hunter ZR, Liu X, Xu L, Yang G, Chen J, Patterson CJ, Tsakmaklis N, Kanan S, Rodig 
S, Castillo JJ, Treon SP. The WHIM-like CXCR4(S338X) somatic mutation activates AKT and 
ERK, and promotes resistance to ibrutinib and other agents used in the treatment of 
Waldenstrom's Macroglobulinemia. Leukemia. 2015;29(1):169-76. 
 
Cao Y, Hunter ZR, Liu X, Xu L, Yang G, Chen J, Tsakmaklis N, Kanan S, Castillo JJ, Treon SP. 
CXCR4 WHIM-like frameshift and nonsense mutations promote ibrutinib resistance but do not 
supplant MYD88(L265P) -directed survival signalling in Waldenström macroglobulinaemia 
cells. Br J Haematol. 2015 Mar;168(5):701-7. 
 
Furman RR, Eradat H, DiRienzo CG, Hayman SR, Hofmeister CC, Avignon NA, Leonard JP, 
Coleman M, Advani R, Switzky JC, Liao Q, Shah DN, Lisby S, Lin TS. A Phase II Trial of 
Ofatumumab in Subjects with Waldenstrom's Macroglobulinemia. Blood. 2011;118(21):3701. 
 
Ghobrial IM, Fonseca R, Greipp PR, Blood E, Rue M, Vesole DH, Gertz MA. Initial 
immunoglobulin M 'flare' after rituximab therapy in patients diagnosed with Waldenstrom 
macroglobulinemia: an Eastern Cooperative Oncology Group Study. Cancer. 2004;101(11):2593-
8. 
 
Hunter ZR, Xu L, Yang G, Tsakmaklis N, Vos JM, Liu X, Chen J, Manning RJ, Chen JG, 
Brodsky P, Patterson CJ, Gustine J, Dubeau T, Castillo JJ, Anderson KC, Munshi NM, Treon 
SP. Transcriptome sequencing reveals a profile that corresponds to genomic variants in 
Waldenström macroglobulinemia. Blood. 2016;128(6):827-38. 
 
Hunter ZR, Xu L, Yang G, Zhou Y, Liu X, Cao Y, et al. The genomic landscape of Waldenstöm’s 
Macroglobulinemia is characterized by highly recurring MYD88 and WHIM-like CXCR4 
mutations, and small somatic deletions associated with B-cell lymphomagenesis. Blood 2014; 
123(11): 1637-46. 
 
Kyle RA, Treon SP, Alexanian R, et al. Prognostic markers and criteria to initiate therapy in 
Waldenström’s macroglobulinemia: Consensus Panel Recommendations from the Second 
International Workshop on Waldenström’s macroglobulinemia. Semin Oncol. 2003; 30:116–120. 
 
Lokhorst HM, Plesner T, Laubach JP, Nahi H, Gimsing P, Hansson M, Minnema MC, Lassen U, 
Krejcik J, Palumbo A, van de Donk NW, Ahmadi T, Khan I, Uhlar CM, Wang J, Sasser AK, 
Losic N, Lisby S, Basse L, Brun N, Richardson PG. Targeting CD38 with Daratumumab 
Monotherapy in Multiple Myeloma. N Engl J Med. 2015;373(13):1207-19. 
 
Lonial S, Weiss BM, Usmani SZ, Singhal S, Chari A, Bahlis NJ, Belch A, Krishnan A, Vescio 
RA, Mateos MV, Mazumder A, Orlowski RZ, Sutherland HJ, Bladé J, Scott EC, Oriol A, 
Berdeja J, Gharibo M, Stevens DA, LeBlanc R, Sebag M, Callander N, Jakubowiak A, White D, 
de la Rubia J, Richardson PG, Lisby S, Feng H, Uhlar CM, Khan I, Ahmadi T, Voorhees PM. 
Daratumumab monotherapy in patients with treatment-refractory multiple myeloma (SIRIUS): 
an open-label, randomised, phase 2 trial. Lancet. 2016;387(10027):1551-60. 


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Protocol Version Date: 2.1.19 
 
35 
 
 
Ngo HT, Leleu C, Lee J, Jia X, Melhem M, Runnels J, et al. SDF-1/CXCR4 and VLA-4 interaction 
regulates homing in Waldenstrom macroglobulinemia. Blood. 2008; 112(1):150-8. 
 
Owen RG, Kyle RA, Stone MJ, et al. Response assessment in Waldenstrom Macroglobulinaemia: 
Update from the VIth International Workshop. Br J Haematol. 2013; 160(2): 171-6. 
Roccaro A, Sacco A, Jimenez C, Maiso P, Moschetta M, Mishima Y, et al. A novel activating 
mutation of CXCR4 plays a crucial role in Waldenstrom Macroglobulinemia biology. Blood 2014; 
123(26): 4120-31.  
Treon SP. How I treat Waldenström macroglobulinemia. Blood 2009; 114: 2375–2385. 
Treon SP, Xu L, Yang G, Zhou Y, Liu X, Cao Y, et al: MYD88 L265P somatic mutation in 
Waldenstrom's macroglobulinemia. N Engl J Med 2012; 367(15):826-332. 
 
Treon SP, Tripsas CK, Meid K, Warren D, Varma G, Green R, et al. Ibrutinib in previously treated 
Waldenstrom’s Macroglobulinemia. N Engl J Med 2015; 372:1430-40. 
 
Treon SP, Xu L, Hunter ZR. MYD88 mutations and response to ibrutinib in Waldenstrom’s 
Macroglobulinemia. N Engl J Med 2015; 373:584-6. 
 
Xu L, Hunter ZR, Tsakmaklis N, Cao Y, Yang G, Chen J, et al. Clonal architecture of CXCR4 
WHIM-like mutations in Waldenström Macroglobulinaemia. Br J Haematol. 2016;172(5):735-44.  
 
Yang G, Zhou Y, Liu X, Xu L, Cao Y, Manning RJ, et al. A mutation in MYD88 (L265P) supports 
the survival of lymphoplasmacytic cells by activation of Bruton tyrosine kinase in Waldenstrom 
macroglobulinemia. Blood 2013; 122:1222-32. 
 
Yang G, Xu L, Hunter Z, Liu X, Cao Y, Jiang J, Tseng H, et al. The rituximab and IVIG Related 
IgM flare in Waldenstrom's Macroglobulinemia is associated with monocytic activation of 
FcGRIIIA signaling, and triggering of IL-6 release by the PI3K/AKT and MAPK Pathways. Blood 
2010; 116:2870. 
 


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36 
 
APPENDIX A 
PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able to 
carry on all pre-disease performance 
without restriction. 
100 
Normal, no complaints, no evidence of 
disease. 
90 
Able to carry on normal activity; minor 
signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  Restricted in 
physically strenuous activity, but 
ambulatory and able to carry out work of 
a light or sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some signs or 
symptoms of disease. 
70 
Cares for self, unable to carry on normal 
activity or to do active work. 
2 
In bed <50% of the time.  Ambulatory 
and capable of all self-care, but unable to 
carry out any work activities.  Up and 
about more than 50% of waking hours. 
60 
Requires occasional assistance, but is able 
to care for most of his/her needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable of only 
limited self-care, confined to bed or chair 
more than 50% of waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization indicated.  
Death not imminent. 
4 
100% bedridden.  Completely disabled.  
Cannot carry on any self-care.  Totally 
confined to bed or chair. 
20 
Very sick, hospitalization indicated. Death 
not imminent. 
10 
Moribund, fatal processes progressing 
rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX B  DANA-FARBER/HARVARD CANCER CENTER MULTI-CENTER OVERSIGHT PLAN 
AND DATA AND SAFETY MONITORING PLAN VERSION 2 8.2.2017 
 
DFCI IRB Protocol #:17-164 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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TABLE OF CONTENTS 
15. 
INTRODUCTION ..................................................................................................................................... 39 
15.1 
Purpose ........................................................................................................................................................................... 39 
15.2 
Multi-Center Data and Safety Monitoring Plan Definitions .................................................................. 39 
16. 
GENERAL ROLES AND RESPONSIBILITIES ................................................................................... 40 
16.1 
DF/HCC Sponsor ......................................................................................................................................................... 40 
16.2 
Coordinating Center ................................................................................................................................................. 41 
16.3 
Participating Institution ........................................................................................................................................ 41 
17. 
DF/HCC REQUIREMENTS FOR MULTI-CENTER PROTOCOLS ................................................ 42 
17.1 
Protocol Distribution ............................................................................................................................................... 42 
17.2 
Protocol Revisions and Closures ......................................................................................................................... 42 
17.3 
Informed Consent Requirements ........................................................................................................................ 43 
17.4 
IRB Documentation .................................................................................................................................................. 43 
17.5 
IRB Re-Approval ......................................................................................................................................................... 44 
17.6 
Participant Confidentiality and Authorization Statement .................................................................... 44 
17.7 
DF/HCC Multi-Center Protocol Registration Policy .................................................................................. 44 
17.8 
DF/HCC Protocol Case Number .......................................................................................................................... 45 
17.9 
Safety Assessments and Toxicity Monitoring ................................................................................................ 47 
17.10 
Data Management ............................................................................................................................................... 48 
18. 
REQUISITIONING INVESTIGATIONAL DRUG ............................................................................... 48 
19. 
MONITORING: QUALITY CONTROL ................................................................................................ 48 
19.1 
Ongoing Monitoring of Protocol Compliance ............................................................................................... 48 
19.2 
Monitoring Reports ................................................................................................................................................... 49 
19.3 
Accrual Monitoring ................................................................................................................................................... 50 
20. 
AUDITING: QUALITY ASSURANCE ................................................................................................... 50 
20.1 
DF/HCC Internal Audits .......................................................................................................................................... 50 
20.2 
Audit Notifications .................................................................................................................................................... 50 
20.3 
Audit Reports ............................................................................................................................................................... 50 
20.4 
Participating Institution Performance ............................................................................................................ 50 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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15. INTRODUCTION 
 
The Dana-Farber/Harvard Cancer Center Multi-Center Data and Safety Monitoring Plan 
(DF/HCC DSMP) outlines the procedures for conducting a DF/HCC Multi-Center research 
protocol. The DF/HCC DSMP serves as a reference for any sites external to DF/HCC that 
are participating in a DF/HCC clinical trial. 
 
15.1 
Purpose 
 
To establish standards that will ensure that a Dana-Farber/Harvard Cancer Center Multi-
Center protocol will comply with Federal Regulations, Health Insurance Portability and 
Accountability Act (HIPAA) requirements and applicable DF/HCC Standard Operating 
Procedures.        
 
15.2 
Multi-Center Data and Safety Monitoring Plan Definitions 
 
DF/HCC Multi-Center Protocol:  A research protocol in which one  or more outside 
institutions are collaborating with Dana-Farber/Harvard Cancer Center where  a DF/HCC 
investigator is the sponsor. DF/HCC includes Dana-Farber/Partners Cancer Care (DF/PCC) 
Network Clinical Trial Affiliates.  
 
Lead Institution:  One of the Dana-Farber/Harvard Cancer Center consortium members 
(Dana-Farber Cancer Institute (DFCI), Massachusetts General Hospital (MGH), Beth Israel 
Deaconess Medical Center (BIDMC), Boston Children’s Hospital (BCH), Brigham and 
Women’s Hospital (BWH) responsible for the coordination, development, submission, and 
approval of a protocol as well as its subsequent amendments per the DFCI IRB and 
applicable regulatory guidelines (CTEP, Food and Drug Administration (FDA), Office of 
Biotechnology Activities (OBA) etc.).  The Lead Institution is typically the home of the 
DF/HCC Sponsor. The Lead Institution also typically serves as the Coordinating Center for 
the DF/HCC Multi-Center Protocol.   
 
DF/HCC Sponsor:  The person sponsoring the submitted Multi-Center protocol who takes 
responsibility for initiation, management and conduct of the protocol at all research 
locations. In applicable protocols, the DF/HCC Sponsor will serve as the single liaison with 
any regulatory agencies (i.e. FDA). The DF/HCC Sponsor has ultimate authority over the 
protocol and is responsible for the conduct of the study at DF/HCC and all Participating 
Institutions. In most cases the DF/HCC Sponsor is the same person as the DF/HCC Overall 
Principal Investigator; however, both roles can be filled by two different people.  
 
Participating Institution:  An institution that is outside the DF/HCC and DF/PCC 
consortium that is collaborating with DF/HCC on a protocol where the sponsor is a DF/HCC 
Investigator.  The Participating Institution acknowledges the DF/HCC Sponsor as having 
the ultimate authority and responsibility for the overall conduct of the study.    
Coordinating Center: The entity (i.e. Lead Institution, Medical Monitor, Contract 
Research Organization (CRO), etc) that provides administrative support to the DF/HCC 
Sponsor in order that he/she may fulfill the responsibilities outlined in the protocol 


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document and DSMP, and as specified in applicable regulatory guidelines (i.e. CTEP Multi-
Center Guidelines). In general, the Lead Institution is the Coordinating Center for the 
DF/HCC Multi-Center Protocol.  
 
DF/HCC Office of Data Quality (ODQ): A group within DF/HCC responsible ensuring 
high-quality standards are used for data collection and the ongoing management of clinical 
trials, auditing, and data and safety monitoring. ODQ also coordinates quality assurance 
efforts related to multi-center clinical research. 
 
DF/HCC Clinical Trials Research Informatics Office (CTRIO): A group within 
DF/HCC responsible for providing a comprehensive data management platform for 
managing clinical trial data. 
 
16. GENERAL ROLES AND RESPONSIBILITIES 
For DF/HCC Multi-Center Protocols, the DF/HCC Sponsor, the Coordinating Center, and 
the Participating Institutions are expected to adhere to the following general responsibilities:  
 
16.1 
DF/HCC Sponsor 
 
The DF/HCC Sponsor, Jorge J. Castillo will accept responsibility for all aspects of 
conducting a DF/HCC Multi-Center protocol which includes but is not limited to:  
• Oversee the coordination, development, submission, and approval of the protocol as 
well as subsequent amendments.  
• Ensure that the investigators, study team members, and Participating Institutions are 
qualified and appropriately resourced to conduct the protocol.  A current CV will be 
collected at study initiation. 
• Include the Multi-Center Data and Safety Monitoring Plan as an appendix to the 
protocol. 
• Ensure all Participating Institutions are using the correct version of the protocol, as 
well as current Investigator Brochure or product information. 
• Ensure that each participating investigator and study team member receives 
adequate protocol training (and/or a Site Initiation Visit prior to enrolling 
participants) and throughout trial’s conduct as needed.  All site Principal 
Investigators will sign protocol signature pages at study initiation and each protocol 
version change. 
• Ensure the protocol will be provided to each participating site in a language 
understandable to all applicable site personnel when English is not the primary 
language.  
• Monitor progress and overall conduct of the study at all Participating Institutions.  
• Ensure all DFCI Institutional Review Board (IRB), DF/HCC and other applicable 
(i.e. FDA) reporting requirements are met.  
• Review data and maintain timely submission of data for study analysis.  
• Act as the single liaison with FDA (investigator-held IND trials), as applicable.  Any 
delegated Sponsor/Investigator responsibilities (i.e. to CROs, drug distribution 


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41 
 
vendor, etc) will be documented and the appropriate regulatory authority will be 
informed. 
• Ensure compliance with all requirements as set forth in the Code of Federal 
Regulations, applicable DF/HCC requirements, HIPAA requirements, and the 
approved protocol. 
• Commit to the provision that the protocol will not be rewritten or modified by 
anyone other than the DF/HCC Sponsor. 
• Identify and qualify Participating Institutions and obtain accrual commitments prior 
to extending the protocol to that site. 
• Monitor accrual and address Participating Institutions that are not meeting their 
accrual requirements.  
 
16.2 
Coordinating Center  
 
The general responsibilities of the Coordinating Center may include but are not limited to: 
• Assist in protocol development.  
• Maintain FDA correspondence, as applicable. 
• Review registration materials for eligibility and register participants from 
Participating Institutions in the DF/HCC clinical trial management system 
(CTMS). 
• Distribute protocol and informed consent document updates to Participating 
Institutions as needed. 
• Oversee the data collection process from Participating Institutions. 
• Maintain documentation of Serious Adverse Event (SAE) reports and 
deviations/violation submitted by Participating Institutions and provide to the 
DF/HCC Sponsor for timely review and submission to the DFCI IRB, as 
necessary.  
• Distribute serious adverse events reported to the DF/HCC Sponsor that fall under 
the DFCI IRB Adverse Event Reporting Policy to all Participating Institutions. 
• Provide Participating Institutions with information regarding DF/HCC requirements 
that they will be expected to comply with. 
 
• Carry out plan to monitor Participating Institutions either by on-site or remote 
monitoring.  Source data will be maintained and Case Report Forms (CRFs) will be 
verified with source data, as applicable.  
• Maintain Regulatory documents of all Participating Institutions which includes but 
is not limited to the following: local IRB approvals/notifications from all 
Participating Institutions, confirmation of Federalwide Assurances (FWAs) for all 
sites,  all SAE submissions, Screening Logs for all sites, IRB approved consents 
for all sites 
• Conduct regular communications with all Participating Institutions (conference 
calls, emails, etc) and maintain documentation all relevant communications. 
 
16.3 
Participating Institution 
 


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Each Participating Institution is expected to comply with all applicable federal regulations 
and DF/HCC requirements, the protocol and HIPAA requirements.  
 
The general responsibilities for each Participating Institution may include but are not limited 
to: 
• Document the delegation of research specific activities to study personnel. 
• Commit to the accrual of participants to the protocol. 
• Submit protocol and/or amendments to their local IRB. 
• Maintain regulatory files as per sponsor requirements. 
• Provide the Coordinating Center with regulatory documents or source documents as 
requested. 
• Participate in protocol training prior to enrolling participants and throughout the trial 
as required (i.e. teleconferences). 
• Update Coordinating Center with research staff changes on a timely basis. 
• Register participants through the Coordinating Center prior to beginning research 
related activities.  
• Submit Serious Adverse Event (SAE) reports to local IRB per institutional 
requirements and to the Coordinating Center, in accordance with DF/HCC 
requirements.  
• Submit protocol deviations and violations to local IRB per institutional requirements 
and to the DF/HCC Sponsor in accordance with DF/HCC requirements. 
• Order, store and dispense investigational agents and/or other protocol mandated 
drugs per federal guidelines and protocol requirements as listed in the IP 
Management Plan 
• Have office space, office equipment, and internet access that meet HIPAA standards. 
• Participate in any quality assurance activities and meet with monitors or auditors at 
the conclusion of a visit to review findings. 
• Promptly provide follow-up and/or corrective action plans for any monitoring 
queries or audit findings. 
 
17. DF/HCC REQUIREMENTS FOR MULTI-CENTER PROTOCOLS 
  
The following section will clarify DF/HCC Requirements and further detail the expectations 
for participating in a DF/HCC Multi-Center protocol.  
 
17.1 
Protocol Distribution 
 
The Coordinating Center will distribute the final DFCI IRB approved protocol and any 
subsequent amended protocols to all Participating Institutions.    
 
17.2 
Protocol Revisions and Closures 
 
The Participating Institutions will receive notification of protocol revisions and closures 
from the Coordinating Center.  It is the individual Participating Institution’s responsibility 
to notify its IRB of these revisions. 


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• Non life-threatening revisions: Participating Institutions will receive written 
notification of protocol revisions regarding non life-threatening events from the 
Coordinating Center. Non-life-threatening protocol revisions must be IRB approved 
and implemented within 90 days from receipt of the notification. 
 
• Revisions for life-threatening causes: Participating Institutions will receive 
immediate notification from the Coordinating Center concerning protocol revisions 
required to protect lives with follow-up by fax, mail, e-mail, etc.  Life-threatening 
protocol revisions will be implemented immediately followed by IRB request for 
approval. 
 
• Protocol closures and temporary holds: Participating Institutions will receive 
notification of protocol closures and temporary holds from the Coordinating Center. 
Closures and holds will be effective immediately.  In addition, the Coordinating 
Center, will update the Participating Institutions on an ongoing basis about protocol 
accrual data so that they will be aware of imminent protocol closures. 
 
17.3 
Informed Consent Requirements 
 
The DF/HCC approved informed consent document will serve as a template for the 
informed consent for Participating Institutions. The Participating Institution consent form 
must follow the consent template as closely as possible and should adhere to specifications 
outlined in the DF/HCC Guidance Document on Model Consent Language for PI-Initiated 
Multi-Center Protocols.  This document will be provided separately to each Participating 
Institution upon request. 
 
Participating Institutions are to send their version of the informed consent document and 
HIPAA authorization, if a separate document, to the Coordinating Center for review and 
approval prior to submission to their local IRB. The approved consent form must also be 
submitted to the Coordinating Center after approval by the local IRB for all consent 
versions. 
 
The Principal Investigator (PI) at each Participating Institution will identify the physician 
members of the study team who will be obtaining consent and signing the consent form for 
therapeutic protocols. Participating institutions must follow the DF/HCC requirement that 
only attending physicians obtain informed consent and re-consent for all interventional 
drug, biologic, or device research.  Informed consent will be explained to each study 
participant and signed and dated by the participant prior to participation.  The consent will 
be retained by the investigator. 
 
17.4 
IRB Documentation 
 
The following must be on file with the Coordinating Center: 
• Initial approval letter of the Participating Institution's IRB.  


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• Copy of the Informed Consent Form(s) approved by the Participating Institution’s 
IRB.  
• Participating Institution’s IRB approval for all amendments. 
• Annual approval letters by the Participating Institution's IRB. 
 
 
17.5 
IRB Re-Approval 
 
Verification of IRB re-approval from the Participating Institutions is required in order to 
continue research activities.  There is no grace period for continuing approvals. 
 
The Coordinating Center will not register participants if a re-approval letter is not received 
from the Participating Institution on or before the anniversary of the previous approval date.   
 
 
17.6 
Participant Confidentiality and Authorization Statement 
 
In 1996, congress passed the first federal law covering the privacy of health information 
known as the Health Insurance Portability and Accountability Act (HIPPA). Any 
information, related to the physical or mental health of an individual is called Protected 
Health Information (PHI). HIPAA outlines how and under what circumstances PHI can be 
used or disclosed.  
 
In order for covered entities to use or disclose protected health information during the course 
of a study, the study participant must sign an authorization statement.  This authorization 
statement may or may not be separate from the informed consent document.  The 
Coordinating Center, with the approval from the DFCI IRB, will provide a consent template, 
with information regarding authorization for the disclosure of protected health information.  
 
The DF/HCC Sponsor will use all efforts to limit its use of protected health information in 
its trials. However, because of the nature of these trials, certain protected health information 
must be collected. DF/HCC has chosen to use authorizations, signed by the participant in 
the trial, rather than limited data sets with data use agreements. 
 
17.6.1  DF/HCC Multi-Center Protocol Confidentiality 
 
All documents, investigative reports, or information relating to the participant are strictly 
confidential. Whenever reasonably feasible, any participant specific reports (i.e. Pathology 
Reports, MRI Reports, Operative Reports, etc.) submitted to the Coordinating Center should 
be de-identified. It is recommended that the assigned protocol case number (as described 
below) be used for all participant specific documents. Participant initials may be included 
or retained for cross verification of identification.  
 
17.7 
DF/HCC Multi-Center Protocol Registration Policy 
 


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17.7.1  Participant Registration and Randomization  
To register a participant, the following documents should be completed by the 
Participating 
Institution 
and 
faxed 
(617-632-6752) 
or 
e-mailed 
(kirsten_meid@dfci.harvard.edu) to the Coordinating Center  
• Copy of serum protein electropheresis, CBC with diff, Chemistries, CT C/A/P, 
bone marrow biopsy 
• Screening visit note 
• Signed informed consent document 
• HIPAA authorization form (if separate from the informed consent document) 
• Eligibility Checklist 
 
The Coordinating Center will review the submitted documents in order to verify 
eligibility and consent. To complete the registration process, the Coordinating Center 
will: 
• Register the participant on the study with the DF/HCC Clinical Trial Management 
System (CTMS). 
• Upon receiving confirmation of registration, the Coordinating Center will inform 
the Participating Institution and provide the study specific participant case number, 
and, if applicable, assigned treatment and/or dose level.  
 
Treatment may not begin without confirmation from the Coordinating Center 
that the participant has been registered.  
 
Randomization can only occur during normal business hours, Monday through Friday from 
8:00 AM to 5:00 PM Eastern Standard Time. 
 
17.7.2  Initiation of Therapy 
 
Participants must be registered with the DF/HCC CTMS before the initiation of treatment 
or other protocol-specific interventions. Treatment and other protocol-specific interventions 
may not be initiated until the Participating Institution receives confirmation of the 
participant’s registration from the Coordinating Center. The DF/HCC Sponsor and DFCI 
IRB must be notified of any violations to this policy. 
 
17.7.3  Eligibility Exceptions 
 
No exceptions to the eligibility requirements for a protocol without DFCI IRB approval will 
be permitted. All Participating Institutions are required to fully comply with this 
requirement. The process for requesting an eligibility exception is defined below. 
 
17.8 
DF/HCC Protocol Case Number 
 
At the time of registration, the following identifiers are required for all subjects: initials, 
date of birth, gender, race and ethnicity. Once eligibility has been established and the 
participant successfully registered, the participant is assigned a unique protocol case 


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number.  Participating Institutions should submit all de-identified subsequent 
communication and documents to the Coordinating Center, using this case number to 
identify the subject.   
 
17.8.1 Protocol Deviations, Exceptions and Violations 
 
Federal Regulations require an IRB to review proposed changes in a research activity to 
ensure that researchers do not initiate changes in approved research without IRB review 
and approval, except when necessary to eliminate apparent immediate hazards to the 
participant. DF/HCC requires all departures from the defined procedures set forth in the 
IRB approved protocol to be reported to the DF/HCC Sponsor, who in turn is responsible 
for reporting to the DFCI IRB. 
 
 
For reporting purposes, DF/HCC uses the terms “violation”, “deviation” and “exception” 
to describe departures from a protocol. All Participating Institutions must adhere to these 
requirements for reporting to the DF/HCC Sponsor and will follow their institutional policy 
for reporting to their local IRB. 
 
17.8.2  Definitions 
 
Protocol Deviation: Any departure from the defined procedures set forth in the IRB-
approved protocol which is prospectively approved prior to its implementation. 
 
Protocol Exception:  Any protocol deviation that relates to the eligibility criteria, e.g. 
enrollment of a participant who does not meet all inclusion/exclusion criteria. 
 
 
 
Protocol Violation: Any protocol departure that was not prospectively approved by the IRB 
prior to its initiation or implementation.  
 
 
17.8.3  Reporting Procedures 
 
DF/HCC Sponsor: is responsible for ensuring that clear documentation is available in the 
medical record and/or regulatory documents to describe all protocol exceptions, deviations 
and violations. The DF/HCC Sponsor will also be responsible for ensuring that all protocol 
violations/deviations are promptly reported per DFCI IRB guidelines.  
 
Participating Institutions: Protocol deviations require prospective approval from the DFCI 
IRB. The Participating Institution must submit the deviation request to the Coordinating 
Center who will then submit the deviation request to the DFCI IRB. Upon DFCI IRB 
approval the deviation is submitted to the Participating Institution IRB, per institutional 
policy. A copy of the Participating Institution’s IRB report and determination will be 
forwarded to the Coordinating Center within 10 business days after the original submission.  
The deviation may not be implemented without all required approvals. 
 


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All protocol violations must be sent to the Coordinating Center in a timely manner. The 
Coordinating Center will provide training for the requirements for the reporting of 
violations.  
 
Coordinating Center:  Upon receipt of the violation/deviation report from the Participating 
Institution, the Coordinating Center will submit the report to the DF/HCC Sponsor for 
review. Subsequently, the Participating Institution’s IRB violation/deviation report will be 
submitted to the DFCI IRB for review per DFCI IRB reporting guidelines. DF/HCC will 
forward all violation reports to CTEP via an internal DF/HCC process, as applicable. 
 
17.9 
Safety Assessments and Toxicity Monitoring 
 
The study teams at all participating institutions are responsible for protecting the safety, 
rights and well-being of study participants. Recording and reporting of adverse events that 
occur during the course of a study help ensure the continuing safety of study participants.  
 
All participants receiving investigational agents and/or other protocol mandated therapy 
will be evaluated for safety. The safety parameters include all laboratory tests and 
hematological abnormalities, physical examination findings, and spontaneous reports of 
adverse events reported by participants.  All toxicities encountered during the study will 
be evaluated according to the NCI criteria specified in the protocol. Life-threatening 
toxicities must be reported immediately to the DF/HCC Sponsor via the Coordinating 
Center.  
 
Additional safety assessments and toxicity monitoring will be outlined in the protocol. 
 
17.9.1 Guidelines for Reporting Serious Adverse Events  
 
Guidelines for reporting Adverse Events (AEs) and Serious Adverse Events (SAEs) are 
detailed in protocol section 7. 
 
 
 
 
 
 
Participating Institutions must report the SAEs to the DF/HCC Sponsor and the 
Coordinating Center following the DFCI IRB Adverse Event Reporting Policy.  
 
The Coordinating Center will maintain documentation of all Participating Institution 
Adverse Event reports and be responsible for communicating to all participating 
investigators, any observations reportable under the DFCI IRB Reporting Requirements.  
Participating Institutions will review and submit to their IRB according to their institutional 
policies and procedures 
 
 
17.9.2 Guidelines for Processing IND Safety Reports  
 
The DF/HCC Sponsor will review all IND Safety Reports and ensure that all IND Safety 
Reports are distributed to the Participating Institutions. Participating Institutions will 
review/submit to their IRB according to their institutional policies and procedures. 


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17.10 Data Management 
  
DF/HCC CTRIO develops case report forms (CRF/eCRFs), for use with the protocol.  These 
forms are designed to collect data for each study. DF/HCC CTRIO provides a web based 
training for all eCRF users. 
   
17.10.1 Data Forms Review 
 
Data submissions are monitored for timeliness and completeness of submission. If study 
forms are received with missing or questionable data, the submitting institution will receive 
a written or electronic query from the DF/HCC Office of Data Quality, Coordinating Center, 
or designee.  
 
Responses to all queries should be completed and submitted within 14 calendar days.   
 
Responses may be returned on the written query or on an amended paper case report form, 
or in the case of electronic queries, within the electronic data capture (eDC) system. In the 
case of a written query for data submitted on a paper case report form, the query must be 
attached to the specific data being re-submitted in response.   
 
If study forms are not submitted on schedule, the Participating Institution will periodically 
receive a Missing Form Report from the Coordinating Center noting the missing forms.  
 
18. REQUISITIONING INVESTIGATIONAL DRUG 
 
 
The ordering of investigational agent is specified in the protocol section 8.  
 
Participating Institutions should order their own agent regardless of the supplier. (i.e., NCI 
or a pharmaceutical company.)  Daratumumab will be supplied by Janssen Scientific Affairs, 
LLC and a drug distribution vendor will be utilized for shipment to each institution.   
 
If the agent is investigational, ensure that the pharmacy will be able to receive and store the 
agent according to state and federal requirements. The local IRB should be kept informed of 
who will supply the agent (i.e., NCI or a pharmaceutical company) so that any regulatory 
responsibilities can be met in a timely fashion.  
 
19. MONITORING: QUALITY CONTROL 
 
The quality control process for a clinical trial requires verification of protocol compliance 
and data accuracy. The Coordinating Center, with the aid of the DF/HCC Office of Data 
Quality, provides quality control oversight for the protocol. 
 
19.1 
Ongoing Monitoring of Protocol Compliance 
 


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The Participating Institutions may be required to submit participant source documents to the 
Coordinating Center for monitoring. Participating Institution may also be subject to on-site 
monitoring conducted by the Coordinating Center.  
 
The Coordinating Center will implement ongoing monitoring activities to ensure that 
Participating Institutions are complying with regulatory and protocol requirements, data 
quality, and participant safety. Monitoring practices may include but are not limited to 
source data verification, and review and analysis of eligibility requirements, informed 
consent procedures, adverse events and all associated documentation, review of study drug 
administration/treatment, regulatory files, protocol departures reporting, pharmacy records, 
response assessments, and data management.  
 
Additionally, regular and ongoing communication with Participating Institutions will be 
accomplished by holding all site teleconferences at quarterly until enrollment is completed 
and the last participant in has been on study for at least 6 months.  After this there will be 
teleconferences every 6 months until all participants are off treatment.  Additional 
teleconferences will take place as needed for significant events (i.e. change in accrual, 
event involving participant, etc.)  The Lead Institution will keep in close touch with the 
Participating Institutions via email and phone. Source documents from Participating 
Institutions, will be collected at specific data points that support the primary and or 
secondary endpoints. 
 
Remote Monitoring 
 
Participating Institutions will be required to forward de-identified copies of participants’ 
medical record and source documents to the Coordinating Center to aid in source data 
verification.  Each participant’s initial consent and eligibility will be reviewed within 30 
days of enrollment.  Study visits and corresponding CRFs will be reviewed every 6 months 
for protocol compliance, AEs, SAEs, study drug administration, dose modifications, and 
follow-up of action items.  Pharmacy records will be remotely reviewed every 6 months. 
 
On-Site Monitoring 
 
Participating Institutions will have annual on-site visits to for a Pharmacy site review, 
Regulatory binder review, and to meet with the site PI (if available).   
 
Closeout Monitoring 
 
Closeout monitoring will be done remotely at the end of the study. 
 
19.2 
Monitoring Reports 
 
The DF/HCC Sponsor will review all monitoring reports to ensure protocol compliance.  
Monitoring logs will also be maintained to document monitoring activities.  The DF/HCC 
Sponsor may increase the monitoring activities at Participating Institutions that are unable 


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to comply with the protocol, DF/HCC Sponsor requirements or federal and local 
regulations.  
 
19.3 
Accrual Monitoring 
 
Prior to extending a protocol to an external site, the DF/HCC Sponsor will establish 
accrual requirements for each participating institution. Accrual will be monitored for each 
participating institution by the DF/HCC Sponsor or designee. Sites that are not meeting 
their accrual expectations may be subject to termination. Due to the small patient 
population, the accrual minimum requirement is at least 1 patient every two years. 
 
 
20. AUDITING: QUALITY ASSURANCE 
 
Auditing is a method of Quality Assurance and involves the systematic and independent 
examination of all trial related activities and documents.  Audits determine if evaluated 
activities were appropriately conducted and whether data was generated, recorded and 
analyzed, and accurately reported per the protocol, applicable Standard Operating 
Procedures (SOPs), and the Code of Federal Regulations (CFR). 
 
20.1 
DF/HCC Internal Audits 
  
 All Participating Institutions are subject to audit by the DF/HCC Office of Data Quality 
(ODQ). Typically, approximately 3-4 participants would be audited at the site over a 2 day 
period. If violations which impact participant safety or the integrity of the study are found, 
more participant records may be audited.  
 
20.2 
Audit Notifications 
 
It is the Participating Institution’s responsibility to notify the Coordinating Center of all 
scheduled audit dates (internal or NCI) and re-audit dates (if applicable), which involve this 
protocol. All institutions will forward a copy of final audit and/or re-audit reports and 
corrective action plans (if applicable) to the Coordinating Center, within 12 weeks after the 
audit date.  
 
20.3 
Audit Reports  
 
The DF/HCC Sponsor will review all final audit reports and corrective action plans, if 
applicable. The Coordinating Center, must forward any reports to the DF/HCC ODQ per 
DF/HCC policy for review by the DF/HCC Audit Committee. For unacceptable audits, the 
DF/HCC Audit Committee would forward the final audit report and corrective action plan 
to the DFCI IRB as applicable. 
 
20.4 
Participating Institution Performance 
 


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The DF/HCC Sponsor and the DFCI IRB, is charged with considering the totality of an 
institution’s performance in considering institutional participation in the protocol. 
 
Participating Institutions that fail to meet the performance goals of accrual, submission of 
timely and accurate data, adherence to protocol requirements, and compliance with state 
and federal regulations, may be recommended for a six-month probation period. Such 
institutions must respond with a corrective action plan and must demonstrate during the 
probation period that deficiencies have been corrected, as evidenced by the improved 
performance measures. Participating Institutions that fail to demonstrate significant 
improvement will be considered by the DF/HCC Sponsor for revocation of participation. A 
DF/HCC Sponsor and/or the DFCI IRB may terminate a site’s participation if it is 
determined that a site is not fulfilling its responsibilities as described above. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX C: INVESTIGATIONAL PRODUCT MANAGEMENT PLAN 
 
A Phase 2 Study of Daratumumab in Patients with Relapsed or Refractory Waldenström 
Macroglobulinemia. 
 
Overall Principal Investigator: Jorge J. Castillo, MD 
Coordinating Center: Dana-Farber Cancer Institute 
 
Version 4  
Version Date January 11, 2018 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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1. IP Forecasts 
1.1 IP projections for the duration of the IIS 
 
Patients will be treated with daratumumab at a dose level of 16mg/kg on the following schedule: 
 
Cycle 
Dosing Schedule 
Cycle 1-2 
Days 1, 8, 15, 22 
Cycle 3-6 
Days 1, 15 
Cycle 7-
18 
Day 1 
 
Dosing will be an IV infusion following the guidance for commercial daratumumab 
administration outlined in the United States Package Insert as well as according to site policy. 
Each cycle will be 28 days.  
 
With an expected patient accrual of 30 who can each receive a maximum of 28 doses of 
daratumumab, the projections are below for 400mg vials: 
• Assuming 4 vials per dose per patient, and patient weight of 100kg:400mg vials 
• 4 vials of 400mg daratumumab X 28 doses X 30 patients= 3,360 vials 
 
With an expected patient accrual of 30 who can each receive a maximum of 28 doses of 
daratumumab, the projections are below for 100mg vials: 
• Assuming 16 vials per dose per patient, and patient weight of 100kg:100mg vials 
• 16 vials of 100mg daratumumab X 28 doses X 30 patients= 13,440 vials 
 
Drug 
Vials/ 
dose 
(400mg 
vials) 
Total 
Doses 
# 
Patients 
Vials/ 
Patient 
Total 
Vials 
10% 
Overage 
20% 
Overage 
Daratumumab 
4 
28 
30 
112 
3360 
3696 
4032 
 
Drug 
Vials/ 
dose 
(100mg 
vials) 
Total 
Doses 
# 
Patients 
Vials/ 
Patient 
Total 
Vials 
10% 
Overage 
20% 
Overage 
Daratumumab 
16 
28 
30 
448 
1344
0 
14784 
16128 
 
1.2 Overall plan per Quarter for IP requirements (inclusive of each participating site, over-
all subject enrollment rate, current inventory and expiring IP at each site) 
 
The team anticipates accrual at 2 patients/month to complete accrual of 30 patients in 15 months.  
Each patient will be dispensed study drug at the timepoints described in section 1.1 of this IP 


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Management Plan. Each subsite will be allowed to maintain IP dispensation and accountability 
records per their individual site SOPs. Dana-Farber Cancer Institute, as the coordinating center 
will review each sites SOPs to ensure they comply with GCP and ICH guidelines. Each subsite 
will maintain drug destruction records per their sites individual SOPs. Dana-Farber Cancer 
Institute, as the coordinating center, will collect all pharmacy records at the completion of the 
study.  
 
1.3 Process to re-evaluate IP requirements (inclusive of all participating sites) 
 
DFCI will submit monthly enrollment updates to Janssen Scientific Affairs, LLC.  The study 
team will inform the pharmacy when a new patient is enrolled.  Biologics, Inc., the drug 
distribution center, will provide monthly dispensing and accountability reports to Janssen 
Scientific Affairs, LLC and Dana-Farber Cancer Institute. 
 
2 Inventory Control 
2.1 Record of receipt and disposition of IP 
 
Biologics, Inc.,the drug distribution center, will receive and check all incoming shipments with 
proper documentation, enter into a 21CFR Part 11 compliant system, and place in proper and 
monitored storage. Upon destruction, or return of study drug, all documents are completed, 
accountability logs are signed off on and closed, and drug is disposed of or returned properly. 
 
Biologics, Inc. will ship the study drug to each participating site.  All study drug will be shipped 
in original manufacturer’s packaging with a protocol-specific label adhered to the outer 
packaging.  Study Drug is shipped in a Biologics branded package with appropriate materials to 
maintain temperature stability.  All drug orders are shipped via FedEx for Priority Overnight 
delivery for shipments to US sites. 
 
Each shipment includes a label on the Ziploc bags with the following information: 
o The Study Number 
o IND caution statement and/or local regulatory statements 
o Drug identification  
o Lot Number  
o Expiration date 
o Dosing instructions (i.e., “Administer as Directed per Protocol”) 
o Storage instructions (i.e., “Store at controlled refrigerated temperature, 2-8°C”) 
o Emergency contact instructions 
 
For all shipments from Biologics: 
o A complete accountability record including date of dispense, site name, quantity 
dispensed, and balance forward will be recorded.  Study accountability records are 
documented in electronic 21 CFR format and are kept in a secured area for duration 
of the study. 


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55 
 
o Provide a Pharmacist review; a licensed pharmacist checks off package for 
accuracy of contents, authorizing order via 21 CFR compliant trial accountability 
log. 
o Enclose a packing slip that includes the quantity of drug provided with a section to 
be completed once received by the site coordinator. This section includes 
confirmation of drug receipt, verification of package contents, and instruction to 
fax the completed packing slip to Biologics.  
o Process and ship authorized and completed orders “same day” of receipt if received 
before 2:00 p.m. ET Monday through Thursday. Authorized and completed orders 
received after 2:00 pm ET Monday through Thursday will be processed and 
shipped the next business morning.  
o Packages are tracked until confirmed delivered and delivery exceptions are 
managed with the highest level of urgency to ensure therapy start date adherence. 
Packing slips with the shipment tracking number included will be faxed to the 
designated site coordinator for all shipments. 
 
DFCI will receive and check all incoming shipments with proper documentation.  DFCI keeps 
the shipping receipt and records the disposition of the drug.  DFCI will receive and check all 
incoming shipments with proper documentation, and place in proper and monitored storage. 
Upon destruction all documents are completed, accountability logs are signed off on and closed, 
and drug is disposed. 
 
Each participating sub-site will maintain records of drug accountability and destruction 
according to their local SOPs, which will be reviewed by the coordinating center for compliance 
with GCP and ICH guidelines. 
 
2.2 Periodic review and documentation of current supply of all IP 
 
Biologics will effectively manage inventory to reduce waste due to expiration issues through 
strict adherence to FIFO inventory procedures, just in time inventory management, and end of 
day and monthly audits. 
 
 Each day Biologics will perform an end of day audit for all trial specific drugs that were 
dispensed on that particular day.  The end of day audit reconciles the physical shelf inventory to 
accountability records.  During the monthly inventory report Biologics personnel will compare 
shelf inventory against the balance as stated on the drug accountability report.  Perpetual 
inventory audits are documented via 21 CFR Part 11 compliant accountability records 
throughout the duration of the study and with oversight by the Director of Clinical Trial Services. 
 
The DFCI pharmacy routinely reviews the amount of IP on site and re-orders as needed based on 
current enrollment. 
 
2.3 Plan for resupply of IP based upon overall IIS use and/or expiration of IP 
 
Biologics, Inc. will request resupply as needed based on inventory level and expiry dates from 


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Janssen Scientific Affairs.   The coordinating center will liaise with the drug distribution center 
as needed based on drug supply levels via telephone or email to review currently supply and 
expiry dates. Each individual sub-site will measure drug supply levels and forecast needed drug 
supply based on local practice.  
 
2.4 System to quarantine and control expired or recalled IP 
 
All study product that requires quarantine will immediately be recorded in the accountability 
record, moved from general storage, placed into a secure quarantined area separate from other 
study drug. Janssen Scientific Affairs, LLC will be notified and the supply will be handled as 
required. 
 
3 Storage 
3.1 IP storage conditions 
All participating sites are required to maintain adequate accountability and storage of 
investigational agents as specified in the study protocol and the study data safety monitoring 
plan.  Each individual sub-site may store IP per their local SOP for storage procedures for 
investigational drug supply. 
 
Biologics, Inc. will store the study drug in secure temperature and humidity controlled storage 
for the duration of the study.  Drug and the accountability log is reviewed and signed off by the 
qualified personnel as outlined in Biologics operating procedures.  This quality check is 
documented via Clinical Trial Material Accountability/Quality Assurance Log (Receipt) and the 
document is then stored in the trial files for the duration of the study.  All study drugs will be 
stored at controlled temperatures until shipment with access limited to essential personnel only.   
 
Daratumumab will be stored at controlled refrigerated temperatures of 2-8°C.  Biologics will 
assume receipt of one study drug supply on at least a quarterly basis.  Temperature and humidity 
monitoring that is 21 CRF Part 11 compliant is provided 24/7/365 throughout the duration of the 
study. During non-operational hours, electronic surveillance alerts Biologics after-hour’s 
response personnel to out of range fluctuations in temperature and humidity. Biologics will 
provide temperature monitoring reports upon request.  Temperature excursions will be 
communicated to the manufacturer & Coordinating Center to provide an assessment of affected 
drug supplies. 
 
Biologics will maintain separate inventories for protocol-specific drug supplies.  
Inventory Maintenance includes: 
• Separate physical locations with shelf labeling 
• Study, Drug, Strength, Expiration shelf labeling 
• Inventory management within Biologics information system 
• Inventory reports on agreed fields submitted on agreed schedule 
 
DFCI will store the study drug in secure temperature and humidity controlled storage for the 
duration of the study.  All study drugs will be stored at controlled temperatures with access 
limited to essential personnel only.   


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3.2 Plan for maintaining documentation of proper storage conditions according to the 
package insert/IP guidelines 
 
Biologics, Inc. will include proper storage and drug usage information on packing slips and 
auxiliary documents in all shipments sent to the study sites.  
 
Proper storage and drug usage information is contained in section 8 of the protocol.   All 
participating sites are required to maintain adequate accountability and storage of investigational 
agents as specified in the study protocol and the study data safety monitoring plan. 
 
Each individual sub-site may follow their local SOP for maintaining documentation of drug 
supply. Each sites SOP will be reviewed by the coordinating center to ensure it complies with 
GCP and ICH guidelines. 
 
3.3 IP storage separate from non-clinical material, in secure location and limited access  
 
Prior to distribution, the IP will remain separate from other study drugs and will be stored in a 
secure facility at the drug distribution center, Biologics, Inc., as described in the drug distribution 
center’s SOPs. 
 
All drug is received in dry dock and then sent to the DFCI Pharmacy.  Once the packages are 
opened the packing slip is examined.  Proper documentation of the Janssen specific protocol 
number is required on the packing slips.  The pharmacy technicians identify the received drug as 
investigational and the drug is transferred to the investigational pharmacy for receipt and 
acknowledgement.  Investigational drug is stored according to the DFCI protocol number in 
research refrigerators, separated from non-research material. 
 
Each individual sub-site will be allowed to utilize their local SOP for investigational product 
once the SOP is reviewed by the coordinating center for compliance with GCP and ICH 
guidelines. 
 
3.4 Temperature excursions  
 
Biologics, Inc. should follow their standard of practice as well as the guidance from the protocol 
document regarding temperature excursions. 
 
DFCI pharmacy refrigerators record temperatures continuously and are attached to an alarm for 
any excursion.  If an excursion happens after hours a pharmacist is on call to answer the alarm.  
Investigational product is then quarantined according to the requirements per protocol. 
 
Each individual sub-site should follow their local standard of practice as well as the guidance 
from the protocol document regarding temperature excursions. The coordinating center will 
review each SOP to ensure that it complies with GCP and ICH guidelines.  
Store in a refrigerator at 2ºC to 8ºC (36ºF to 46ºF). Do not freeze or shake. Protect from light. 
This product contains no preservative. If the storage temperature falls outside of the range noted 


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58 
 
above per institutional SOP, this is considered a temperature excursion. When a temperature 
excursion occurs, each individual sub-site must quarantine the product and inform the 
coordinating center as soon as possible. The coordinating center is responsible for liaising with 
Janssen Scientific Affairs, LLC for guidance on continued use of the product and will inform 
sites whether the product is suitable for continued use. 
 
4 IP Accountability 
4.1 IP use in accordance with this IIS  
 
Biologics, Inc. will include pertinent information on all packing slips and include auxiliary 
documents to inform sites of instructions for use. In all communications with the sites prior to 
shipment, the drug distribution center can review this information with the receiver.  
 
Each supply of investigational product will come equipped with a packing slip from Janssen 
Scientific Affairs, LLC. This packing slip will have the Janssen Scientific Affairs, LLC study 
number. Each participating site will be informed during the Site Initiation Visit that 
investigational product should only be used for the IIS. 
 
4.2 Process for maintaining IP transaction logs  
 
All participating sites are required to maintain adequate accountability and storage of 
investigational agents. As outlined in the study protocol and study data safety monitoring plan.  
 
5 IP Destruction 
5.1 Confirmation of each site’s SOP to destroy IP at site  
 
Because of their participation in studies using DFCI-supplied investigational drug, all DFCI 
institutions have the capability of either destroying Study Product at their site or have an SOP for 
return of the Study Product to the distributor for destruction.  
 
5.2 Confirmation that documentation of each site’s SOP for IP destruction will be retained  
 
A copy of the sub-site drug destruction SOP will be filed in the Trial Master File. 
 
5.3 Confirmation that each site will retain documentation of IP destruction  
 
Drug destruction and/or pharmacy records will be kept current and reviewed during routine 
monitoring visits and prior to study closeout at all participating sites, as outlined in the study 
protocol and study data safety monitoring plan.  
 
6 IP Distribution 
6.1 Shipping information contacts at S-I site or at drug distribution supplier for sites 
participating in the IIS 
 


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59 
 
Biologics, Inc. and the coordinating center will provide drug ordering instructions to all 
participating sites.  
 
Biologics, Inc. contact details for drug ordering: 
Fax: 919-256-0794 
Email: CRSOrders@biologicsinc.com 
 
Throughout the course of the study, a clinical hotline support, staffed with clinical pharmacists, 
is made available 24/7/365 in the event an investigator or site coordinator has a question.  
Hotline phone: 1-800-693-4906 
 
During the approval and activation process, the coordinating center will inform Janssen 
Scientific Affairs, LLC and the drug distribution center of any new site prior to activation of said 
site and prior to any IP shipment to said site.  
 
6.2 Confirmation that all necessary documents are in place prior to shipment to any 
participating site 
 
Biologics, Inc. and DFCI will execute a contract prior to study launch. DFCI will execute any 
agreements required with the sub-sites prior to the activation of said site. DFCI has existing 
process in place for confirmation of local IRB review prior to patient registration.  Each site will 
be unable to request shipment until IRB approval centrally at the coordinating center is received 
and all regulatory documents (e.g. CVs, MLs, DOA, etc.) have been filed in the Trial Master 
File.   
 
6.3 Distribution/coordination plan for shipping IP to participating sites  
 
In general, a minimum of a three-month forecasted supply of study drug will be shipped to each 
participating site to ensure that drug shipments do not occur more frequently than once a quarter 
to each site. Exceptions to this rule of thumb should be reviewed with DFCI. 
 
6.4 Confirmation that S-I or IP distribution supplier will record and maintain shipping 
documentation of IP to participating sites 
 
Biologics, Inc. will record a complete accountability record including date of dispense, site 
name, quantity dispensed, and balance forward will be recorded. Study accountability records are 
documented in electronic 21CFR format and are kept in a secured area for the duration of the 
study.  
 
Each individual sub-site will maintain a record of shipment according to their local SOPs for 
maintaining documentation of IP shipment. This SOP will be reviewed by the coordinating 
center for compliance with GCP and ICH guidelines.  
 
7 Packaging and Labeling 
7.1 IP should be clearly identified to be used only for the specified IIS 


NCI Protocol #:N/A 
DF/HCC Protocol #: 17-164 
Protocol Version Date: 2.1.19 
 
60 
 
 
Biologics, Inc. will include a disclaimer that IP is to be used only for the specified IIS on the 
packing slip, or on auxiliary documentation that is placed on the study product prior to dispense 
to the study site.  
 
Janssen Scientific Affairs, LLC will include the Janssen protocol number clearly on the packing 
slip or auxiliary documentation in the shipment of study drug to Biologics, Inc. 
 
The coordinating center will ensure a yearly monitoring review of pharmacy drug accountability 
records. The drug accountability record and the drug destruction log will be collected at the end 
of the study per DFCI SOPs.  
 
7.2 Any additional participating sites’ labeling requirements per institution’s policy/SOP 
and/or local and/or country regulations 
 
Biologics, Inc. will create, submit, and agree upon the shipping label with DFCI prior to study 
launch and any requirements at specific study sites will need to be discussed during this process.  
Shipping and handling from the drug distribution vendor to each site will follow the drug 
distribution vendor’s standards of practice. The practices will meet all GCP and ICH guidelines 
as appropriate.