Clinical trial NCT03225716
Conditions: Waldenstrom's Macroglobulinemia
Keywords: Waldenstrom's Macroglobulinemia
Sponsor: Dana-Farber Cancer Institute
Start date: 2017-10-20; Completion date: 2022-12-31
Enrollment: 13 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This research study is studying Ulocuplumab combined with ibrutinib as a possible treatment for symptomatic Waldenstrom's Macroglobulinemia (WM).

Detailed description:
This was planned to be a Phase I/II clinical trial. A Phase I clinical trial tests the safety of an investigational drug and also tries to define the appropriate dose of the investigational drug to use for further studies. "Investigational" means that the drug is being studied. The study was halted early and did not open the Phase II portion.

The FDA (the U.S. Food and Drug Administration) has not approved Ulocuplumab as a treatment for any disease. Ulocuplumab is a type of protein called an antibody that attacks CXCR4, a protein that is found on B-cells like WM.

The FDA (the U.S. Food and Drug Administration) has Ibrutinib as a treatment option for this disease.

Ibrutinib has been under investigation in research studies in participants with recurrent B-cell lymphoma, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), and prolymphocytic leukemia, and WM. In a study of ibrutinib in relapsed/refractory WM patients, response rates were high and the treatment was well tolerated. In that study participants who had a CXCR4 mutation had a lower response rate to ibrutinib than those without a mutation.

In this research study, the investigators are evaluating the safety of ulocuplumab in combination with ibrutinib participants with symptomatic WM who have a CXCR4 mutation. The investigators are also evaluating how well the ulocuplumab works in combination with ibrutinib

Arms: arm 1: * Ibrutinib administered orally once daily for 48 cycles
* Ulocuplumab administered intravenously at 400mg for Cycle 1 on Days 1, 8, 15, and 22. Ulocuplumab administered IV at 800mg for Cycles 2-6 on Days 1 and 15. arm 2: * Ibrutinib administered orally once daily for 48 cycles
* Ulocuplumab administered intravenously at 800mg for Cycle 1 on Days 1, 8, 15, and 22. Ulocuplumab administered IV at 1200mg for Cycles 2-6 on Days 1 and 15. arm 3: * Ibrutinib administered orally once daily for 48 cycles
* Ulocuplumab administered intravenously at 800mg for Cycle 1 on Days 1, 8, 15, and 22. Ulocuplumab administered IV at 1600mg for Cycles 2-6 on Days 1 and 15.
Interventions: intervention 1: Ulocuplumab intervention 2: Ibrutinib
Intervention descriptions: intervention 1: Ulocuplumab is a type of protein called an antibody that attacks CXCR4 intervention 2: Ibrutinib small-molecule inhibitor of Bruton's tyrosine kinase (BTK) with potential antineoplastic activity

Protocol documents:
Prot_SAP_000.pdf: 
 
 
NCI Protocol #: 
N/A. 
 
DF/HCC Protocol #: 17-235  
 
TITLE:  A Phase 1/2 Study of Ulocuplumab And Ibrutinib in symptomatic patients with 
mutated CXCR4 Waldenstrom’s Macroglobulinemia. 
 
 
Coordinating Center: 
 
 
Dana-Farber Cancer Institute 
 
 
 
 
 
 
 
 
 
450 Brookline Avenue 
 
 
 
 
 
 
 
 
 
Boston, MA 02215 USA 
 
Principal Investigator (PI): 
Steven P. Treon, MD, PhD 
 
 
 
 
 
 
 
 
 
Dana-Farber Cancer Institute 
 
 
 
 
 
 
 
 
 
450 Brookline Avenue 
 
 
 
 
 
 
 
 
 
Boston, MA 02215 USA 
 
 
 
 
 
 
 
 
 
Steven_treon@dfci.harvard.edu 
 
Co-Investigator (Co-I): 
Jorge J. Castillo, MD 
 
 
 
 
 
 
 
 
 
Dana-Farber Cancer Institute 
 
 
 
 
 
 
 
 
 
450 Brookline Avenue 
 
 
 
 
 
 
 
 
 
Boston, MA 02215 USA 
 
 
 
 
 
 
 
 
 
jorgej_castillo@dfci.harvard.edu 
 
 
 
 
Project Manager:  
Kirsten Meid 
Dana-Farber Cancer Institute 
450 Brookline Ave 
Boston, MA 02215 USA 
Kirsten_Meid@dfci.harvard.edu 
 
Agents: BMS-936564 Ulocuplumab & Ibrutinib 
 
 
IND #: 134563 
IND Sponsor:  Steven P. Treon, MD 
 
 
Protocol Type / Version # / Version Date: 
Original/Version #4 11.21.22 
 
 
 


NCI Protocol #: N/A 
DF/HCC Protocol #:17-235 
Protocol Version Date: 11.21.22 
2 
SCHEMA 
 
Phase I Dose Escalation Trial Part 
 
 
Phase II Single Arm Trial Part 
 
 
 
 
 
*After the first 6 participants are enrolled on Phase II, accrual will be
held until DSMC safety review has been conducted (see section 5.6 & 13.4).
Registration 
Ibrutinib daily starting C1D1 maximum 47 
4 week cycles 
Ulocuplumab at Phase 1 MTD maximum 6 
4 week cycles 
Response Evaluation 
Discontinue Protocol 
Therapy 
Event Monitoring 
Event Monitoring 
Progressive Disease 
(PD), Unacceptable 
Toxicity, No Response 
Stable Disease or Response 
Start at dose level 
1 
Treat cohort (3 
participants) 
Number of 
DLTs 
No further 
escalation 
>2 
=1
Recruit 3 more 
participants 
Further 
DLTs? 
Stop 
Yes 
No 
Escalate 
0 
Registration* 


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Protocol Version Date: 11.21.22 
 
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TABLE OF CONTENTS 
1. 
OBJECTIVES ......................................................................................................................1 
1.1 
Study Design ............................................................................................................1 
1.2 
Primary Objectives...................................................................................................2 
1.3 
Secondary Objectives...............................................................................................2 
2. 
BACKGROUND .................................................................................................................3 
2.1 
Study Disease ...........................................................................................................3 
2.2 
IND Agent Ulocuplumab .........................................................................................6 
2.3 
Other Agent Ibrutinib ...............................................................................................7 
2.4 
Rationale ................................................................................................................11 
2.5 
Correlative Studies Background ............................................................................11 
3. 
PARTICIPANT SELECTION ...........................................................................................12 
3.1 
Eligibility Criteria ..................................................................................................12 
3.2 
Exclusion Criteria ..................................................................................................13 
3.3 
Inclusion of Women and Minorities ......................................................................14 
4. 
REGISTRATION PROCEDURES ...................................................................................14 
4.1 
General Guidelines for DF/HCC Institutions ........................................................14 
4.2 
Registration Process for DF/HCC Institutions .......................................................14 
4.3 
General Guidelines for Other Investigative Sites ..................................................14 
4.4 
Registration Process for Other Investigative Sites.................................................14 
5. 
TREATMENT PLAN ........................................................................................................14 
5.1 
Treatment Regimen ................................................................................................15 
5.2 
Pre-Treatment Criteria ...........................................................................................16 
5.3 
Treatment Administration ......................................................................................16 
5.4 
Definition of Dose-Limiting Toxicity (DLT) for Ulocuplumab (Phase I 
only) .......................................................................................................................18 
5.5 
Definition of Maximum Tolerated Dose (MTD) for Ulocuplumab (from 
Phase I)...................................................................................................................19 
5.6 
Ulocuplumab Dose for Phase II Part of Study .......................................................19 
5.7 
General Concomitant Medication and Supportive Care Guidelines ......................19 
5.8 
Criteria for Taking a Participant Off Protocol Therapy .........................................21 
5.9 
Duration of Follow Up ...........................................................................................22 
5.10 
Criteria for Taking a Participant Off Study ...........................................................22 
6. 
DOSING DELAYS/DOSE MODIFICATIONS ...............................................................22 
7. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................26 
7.1 
Expected Toxicities ................................................................................................26 
7.2 
Adverse Event Characteristics ...............................................................................30 
7.3 
Expedited Adverse Event Reporting ......................................................................31 
7.4 
Expedited Reporting to the Food and Drug Administration (FDA) ......................31 
7.5 
Expedited Reporting to BMS Worldwide Safety...................................................32 


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7.6 
Routine AE reporting to BMS ...............................................................................33 
7.7 
Expedited Reporting to Hospital Risk Management .............................................33 
7.8 
Routine Adverse Event Reporting .........................................................................33 
8. 
PHARMACEUTICAL INFORMATION ..........................................................................34 
8.1 
Ulocuplumab ..........................................................................................................34 
8.2 
Ibrutinib..................................................................................................................37 
9. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................38 
9.1 
Biomarker Studies ..................................................................................................38 
10. 
STUDY CALENDAR .......................................................................................................39 
11. 
MEASUREMENT OF EFFECT........................................................................................41 
12. 
DATA REPORTING / REGULATORY REQUIREMENTS ...........................................42 
12.1 
Data Reporting .......................................................................................................42 
12.2 
Data Safety Monitoring..........................................................................................42 
12.3 
Multicenter Guidelines...........................................................................................42 
12.4 
Collaborative Agreements Language .....................................................................43 
13. 
STATISTICAL CONSIDERATIONS...............................................................................43 
13.1 
Study Design/Endpoints.........................................................................................43 
13.2 
Sample Size, Accrual Rate and Study Duration ....................................................44 
13.3 
Stratification Factors ..............................................................................................44 
13.4 
Interim Monitoring Plan ........................................................................................45 
13.5 
Analysis of Primary Endpoints ..............................................................................45 
13.6 
Analysis of Secondary Endpoints ..........................................................................45 
13.7 
Reporting and Exclusions ......................................................................................46 
14. 
PUBLICATION PLAN .....................................................................................................46 
REFERENCES ..............................................................................................................................47 
APPENDIX A 
PERFORMANCE STATUS CRITERIA ..................................................49 


1 
 
 
1. OBJECTIVES 
 
1.1 
Study Design 
 
This is a Phase I/II, single center study designed to evaluate the safety and efficacy of ulocuplumab 
combined with ibrutinib in symptomatic patients with CXCR4 mutated WM. The phase I part of 
the study is designed to identify the maximum dose or maximum tolerated dose (if a dose-limiting 
toxicity is identified) of ulocuplumab to be combined with ibrutinib.  The dose of ulocuplumab 
will be escalated during the Phase I portion, and the fixed FDA approved dose of ibrutinib (420 
mg/day) for treatment of symptomatic WM patients will be used. The Phase I part of the study will 
be followed by a phase II part designed to assess in an expanded population of patients the clinical 
safety, tolerability, and efficacy of uloculplumab using the maximum dose or maximum tolerated 
dose (if a dose-limiting toxicity is identified) derived from the Phase I portion of the study and 
ibrutinib at 420 mg/day.   
 
Treatment will be comprised of ibrutinib administered orally starting day 1 of cycle 1 for 47 cycles, 
along with ulocuplumab administered intravenously weekly during Cycle 1, and then every other 
week for Cycles 2-6. A 3+3 Phase I design will be employed for 3 dose levels, and 20 additional 
patients will be recruited at the maximum dose or maximum tolerated dose (if a dose-limiting 
toxicity is identified) for the Phase II dose expansion.  After the first six participants are accrued 
to the Phase II cohort, enrollment will be held to conduct a DSMC safety analysis of the first two 
cycles of treatment. 
  
A Screening visit will be conducted within 30 days prior to 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 will be performed during screening, and MYD88 and CXCR4 
mutation status will be determined. Research samples to determine CXCR4 expression on WM 
cells will also be obtained at the screening visit or within 90 days prior to Cycle 1 Day 1. CT 
scanning of the chest, abdomen and pelvis must 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, SGOT (AST), SGPT (ALT), alkaline phosphatase), magnesium, beta 
2-microglobulin, von Willebrand panel, coagulation profile, serum and protein electrophoresis 
with quantification of immunoglobulins (IgM, IgG, IgA) and immunofixation studies, 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 
ulocuplumab based on a 3+3 Phase I study design shown in Figure 1, with expansion to Phase II 
with recruitment of 20 additional participants.  Three dose levels of ulocuplumab will be evaluated 
(Table 1). Three patients will be enrolled into the initial dose cohort. If no dose limiting toxicity 


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(DLT) is observed after cycle 1 & 2 in any of these subjects, the trial will proceed to enroll 
additional subjects into the next higher dose cohort. If one subject develops a DLT at a specific 
dose, an additional three subjects will be enrolled into that same dose cohort. Development of 
DLTs in more than 1 of 6 subjects in a specific dose cohort will be deemed that the MTD has been 
exceeded, and further dose escalation will not be pursued. All patients will receive ibrutinib at 420 
mg orally per day beginning day 1 of cycle 1 for 47 cycles. 
 
Ulocuplumab will be administered on day 1 + 2 days weekly for cycle 1 (Days 1, 8, 15, 22), then 
day 1 + 2 and day 15 + 2 for cycles 2-6. Participants will be evaluated for tolerance and response 
on the first day they receive treatment for each cycle beginning with cycle 2, at the end of treatment 
which will occur 4 weeks + 1 week after the last administered therapy, and every 12 weeks + 1 
week thereafter as long as the participant remains on study.  Participants will be eligible to continue 
therapy and remain on study so long as they do not have unacceptable toxicity or demonstrate 
progressive disease. 
 
Response criteria updated at the Sixth International Workshop on Waldenström’s 
macroglobulinemia (Owen et al, BJH 2013) will be used to assess response, stable disease, and 
progressive disease. 
 
Bristol-Myers Squibb, the study supporter and manufacturer of ulocuplumab, terminated the 
development of ulocuplumab on 3/29/19.  Due to this, the Phase 2 portion of this study was never 
opened. BMS continued to supply drug for this study until 7/1/2020.  The Sponsor-Investigator 
halted enrollment on this study after the 3rd participant in the Phase 1 cohort #3 was accrued.  All 
participants enrolled were able to complete planned ulocuplumab dosing, and participants then 
continued on commercial ibrutinib monotherapy.   
 
The Sponsor-Investigator has decided to discontinue all study therapy and follow-up procedures 
for all participants remaining on the study as of 12/31/22.   
 
1.2 
Primary Objectives 
 
• Phase I:  To determine the maximum dose or maximum tolerated dose (if a dose-limiting 
toxicity is identified) of ulocuplumab with ibrutinib in symptomatic patients with CXCR4 
mutated WM.  
• Phase II:  To determine the major response rate (>50% reduction in disease burden) in 
patients with CXCR4 mutated WM.  
 
1.3 
Secondary Objectives 
 
• Phase II: To determine the time to minor and major response, as well as time to progression 
(TTP) in symptomatic patients with CXCR4 mutated WM.  
• Phase II:  To determine the best overall response rate (ORR) (>25% reduction in disease 
burden) and Very Good Partial Response (>90% reduction in disease burden)/Complete 
Response (VGPR/CR) of ibrutinib combined with ulocuplumab in symptomatic patients 
with CXCR4 mutated WM. 


NCI Protocol #: N/A 
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2. BACKGROUND 
 
2.1 
Study Disease 
 
Waldenström’s macroglobulinemia (WM) 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 and the C-terminal domain of 
CXCR4 in WM (Treon et al, 2012; Hunter et al, 2014; Treon et al, 2015a). In WM cells, mutated 
MYD88 triggers NFkB activation via two divergent pathways involving Bruton’s tyrosine kinase 
(BTK) and IRAK1/IRAK4 (Yang et al, 2013). Ibrutinib is an orally administered, small molecule 
inhibitor of BTK, which triggers apoptosis of mutated MYD88 expressing WM cells. In a 
multicenter prospective study, 63 symptomatic previously treated WM patients received single 
agent ibrutinib. The median prior therapies for these patients was 2 (range 1-9), and 40% were 
refractory to their prior therapy. Patients received ibrutinib (420 mg) until progression or 
unacceptable toxicity (Treon et al, 2015b). Post-therapy, at best response, median serum IgM 
levels (used to measure disease burden) declined from 3,520 to 880 mg/dL; hemoglobin rose from 
10.5 to 13.8 g/dL; and the bone marrow disease involvement declined from 60% to 25% (p<0.01 
for all comparisons). The median time to a minor response (>25% reduction in serum IgM) was 4 
weeks, and to a major (>50% reduction in serum IgM) was 8 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, 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 (>6 months) in comparison to 
patients with the MYD88L265PCXCR4WT genotype (Figure 1; Treon et al, 2015b). 
 




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Figure 2. Impact of MYD88 and CXCR4 mutation status on serial serum IGM and hemoglobin 
levels in previously treated, rituximab-refractory WM patients. Taken from Dimopoulos et al, 
2016. 
 
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, 2014; Cao et al, 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, 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 




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with lenalidomide [25 mg/d/21 days of a 28 day cycle] plus low dose dexamethasone [40 mg/week] 
and monitored for incidence of dose limiting toxicities (DLTs) within Cycle 1 (42 Days) of study 
treatment. For the Bor-Dex group, also starting on Day 15, ulocuplumab was administered in 
combination with bortezomib (1.3 mg/m2 on Days 1, 4, 8, 11 of a 21 day cycle] plus 
dexamethasone [days 1,2,4,5,8,9,11,12] and monitored for incidence of DLT(s) within Cycle 1 (35 
Days) of study treatment. For the expansion phase, subjects received 10mg/kg ulocuplumab 
monotherapy on Days 1 and 8 followed by weekly doses in combination with Len-Dex (28-day 
cycles). Subjects were assessed at day 14 and after every cycle by IMWG criteria. 
 
Forty-four subjects were evaluated on this study (median age, 59.5 yrs; range, 44-77). The median 
number of prior therapies was 4, (range, 1-9), with 76% of subjects having received ≥ 3. Subjects 
had received bortezomib in 93% of the cases, lenalidomide in 86%, thalidomide in 30%, 
carfilzomib in 20% and pomalidomide in 11%. Thirty subjects in escalation received ulocuplumab 
alone and in combination with Len-Dex : One subject in the U-Bor-Dex group experienced a DLT 
in which there was delayed platelet recovery to ≤ Grade 1 or baseline which resulted in a delay of 
dosing of ≥ 21 days. Ulocuplumab was escalated to a maximum of 10 mg/kg without reaching 
MTD in monotherapy or in combination therapy. Twenty-one subjects were treated in expansion 
phase. There were no grade 4 toxicities with ulocuplumab monotherapy and Grade 3 toxicities 
with monotherapy included thrombocytopenia (6.5%), anemia (4.3%), respiratory infections 
(4.3%), femur fracture (4.3%), lymphopenia (2.2%), neutrophil count decreased (2.2%), platelet 
count decreased (2.2%) and cerebrovascular accident (2.2%). The safety profile of ulocuplumab 
with Len-Dex or Bor-Dex was similar to either combination alone. Two subjects (4.5%) presented 
reversible G2 infusion reactions. The overall response rate (≥ PR) for all subjects in escalation and 
expansion was 50% (22/44), including 1 CR, 6 VGPR and 15 PR. The ORR by group was 55.1 % 
(16/29) and 40% (6/15) for U-Len-Dex and U-Bor-Dex, respectively. Furthermore, the ORR in 
expansion with 10 mg/kg U-Len-Dex was 57% (12/21) with 4 VGPRs and 8 PRs. Eight subjects 
in this expansion group had at least SD with a mean duration of 159 days (range, 46-437 days), 
resulting in 95% of subjects with clinical benefit. A median 2-fold mobilization of leukocytes into 
the peripheral circulation was reported after each infusion of ulocuplumab at 3 and 10 mg/kg. 
Samples showed rapid mobilization of leukocytes at 2 hours post-ulocuplumab with a partial 
decrease at 3-4 days post-administration without reaching baseline. Mobilization of plasma cells 
was also documented in some subjects. The results of this study showed that the blockade of the 
CXCR4-CXCL12 axis by ulocuplumab was safe and associated with a high response rate in 
combination with Len-Dex in patients with relapsed/refractory myeloma who previously received 
lenalidomide and bortezomib.  
 
2.3 
Other Agent Ibrutinib 
Ibrutinib is a selective, irreversible inhibitor of Bruton’s Tyrosine Kinase (BTK) that is approved 
by the U.S. FDA and the European Medicines Agency for the treatment of symptomatic WM. 
Activated BTK binds to MYD88, and triggers NFkB signaling. Ibrutinib potently inhibits BTK 
with a median inhibitory concentration of 0.5 nM. Ibrutinib also potently inhibits HCK at a median 
inhibitory concentration of 5 nM, a SRC family member that is triggered by mutated MYD88 and 
transactivates BTK, AKT, and ERK1/2 that support the growth and survival of WM cells (Yang 
et al, 2016).   
Ibrutinib (IMBRUVICA®) is approved by the U.S. Food and Drug Administration (FDA) for the 


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treatment of : 1) mantle cell lymphoma (MCL) in patients who have received at least one prior 
therapy based on overall response rate, 2) chronic lymphocytic leukemia (CLL) including patients 
with17p deletion or a TP53 mutation, and 3) patients with symptomatic WM (Treon et al, 2015). 
Ibrutinib pharmacokinetics 
Following oral administration of ibrutinib at doses of 420, 560, and 840 mg/day, exposure to 
ibrutinib increased as doses increased with substantial intersubject variability.  The mean half-life 
(t1/2) of ibrutinib across 3 clinical studies ranged from 4 to 9 hours, with a median time to maximum 
plasma concentration (Tmax) of 2 hours.  Taking into account the approximate doubling in mean 
systemic exposure when dosed with food and the favorable safety profile, ibrutinib can be dosed 
with or without food.  Ibrutinib is extensively metabolized primarily by cytochrome 
P450 (CYP) 3A4. The on-target effects of metabolite PCI-45227 are not considered clinically 
relevant. Steady-state exposure of ibrutinib and PCI-45227 was less than 2-fold of first dose 
exposure. Less than 1% of ibrutinib is excreted renally. Ibrutinib exposure is not altered in patients 
with creatinine clearance (CrCl) >30 mL/min. Patients with severe renal impairment or patients on 
dialysis have not been studied. Following single dose administration, the AUC of ibrutinib 
increased 2.7-, 8.2- and 9.8-fold in subjects with mild (Child-Pugh class A), moderate (Child-Pugh 
class B), and severe (Child-Pugh class C) hepatic impairment compared to subjects with normal 
liver function.  A higher proportion of Grade 3 or higher adverse reactions were reported in patients 
with B-cell malignancies (CLL, MCL and WM) with mild hepatic impairment based on NCI organ 
dysfunction working group (NCI-ODWG) criteria for hepatic dysfunction compared to patients 
with normal hepatic function 
Clinical experience with ibrutinib 
Ibrutinib is an orally administered agent. The first human Phase 1 study (PCYC-04753) was 
designed to evaluate the initial safety, tolerability, and pharmacokinetic and pharmacodynamic 
properties of ibrutinib in participants with recurrent B cell lymphoma. In this clinical setting a 
useful adverse event profile was obtained.  
 
PCYC-04753 Study 
PCYC-04753 was a multicenter Phase 1 study that included subjects with CLL, MCL and WM 
and constituted the first in-human trial of ibrutinib. The objectives included studying the safety 
profile of ibrutinib, identifying the maximum tolerated dose and optimal dosing schedule, and 
characterizing efficacy, pharmacokinetics, and pharmacodynamics. A minimum of 6 subjects per 
cohort received 1 of 5 escalating dose levels of ibrutinib between 1.25 and 12.5 mg/kg for 28 
consecutive days in a 35-day cycle, with the objective of escalating 3 dose levels above that which 
achieved full BTK occupancy based on the fluorescent probe assay. Two additional cohorts 
received a continuous ibrutinib dose of 8.3 mg/kg without a 7-day rest and a fixed continuous dose 
of 560 mg/day. 
Summary of Safety Data from PCYC-04753 and Monotherapy Trials  
Pooled safety data for a total of 1071 subjects treated with ibrutinib monotherapy from 9 studies 
in B-cell malignancies, which includes subjects from 2 randomized-control studies who crossed 
over from comparator treatment or placebo to receive ibrutinib monotherapy, are summarized 
below. The most frequently reported treatment-emergent adverse events (TEAEs) in subjects 
receiving ibrutinib as monotherapy (N=1071) as summarized below. 


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Most frequently reported 
TEAEs >10%   
Most frequently reported 
Grade 3 or 4 TEAEs >2%  
Most frequently reported 
Serious TEAEs >1%  
Diarrhea 
Neutropenia 
Pneumonia 
Fatigue 
Pneumonia 
Atrial fibrillation 
Nausea 
Thrombocytopenia 
Febrile neutropenia 
Cough 
Anemia 
Pyrexia 
Anemia 
Hypertension   
 
Pyrexia 
Atrial fibrillation 
 
Neutropenia  
 
 
For more detailed information refer to the current version of the IB. 
Clinical Efficacy 
The outcome of patients with B-cell malignancies on ibrutinib has been published (Advani et al, 
2012). Responses have been observed in all histologies dosed to date, including CLL/SLL, MCL, 
ABC DLBCL and WM patients who received ibrutinib treatment at dose of up to 560 mg a day. 
Among 50 evaluable subjects across all B-cell histologies, Advani et al (2012) reported an overall 
response rate of 60%, with 7 complete responses (CRs) and 23 partial responses (PRs). A 
fluorescent probe assay demonstrated complete active-site occupancy of BTK by ibrutinib in 
subjects given doses of 2.5 mg/kg or higher. 
A multicenter, prospective study of single agent ibrutinib investigated the safety and efficacy of 
ibrutinib in relapsed or refractory WM patients (Treon et al, 2015b). The median number of prior 
therapies for these patients was 2 (range 1-9), and 40% of patients were refractory to their previous 
therapy. Seventy-eight percent of patients had a moderate-high WM IPSS prognostic score. Post 
therapy, the median serum IgM levels for all 63 patients declined from 3,520 to 880 mg/dL at best 
response (p<0.01). Pre-therapy, 46/63 (73.0%) patients had a serum IgM >3,000 mg/dL; following 
treatment, at best response, 6/63 (9.5%) patients had a serum IgM >3,000 mg/dL (p<0.01). Median 
BM involvement decreased from 60% to 25% (p<0.01), while hemoglobin increased from a 
median of 10.5 to 13.8 g/dL at best response (p<0.01). Responses included very good partial 
response (n=10); partial response (n=36); and minimal response (n=11) for overall and major 
responses of 90.5% (95% CI 80.4%-96.4%) and 73.0% (95% CI 60.3-83.4%), respectively. The 
median time to at least minor and partial responses were 4 and 8 weeks, respectively. Overall 
responses were similar regardless of baseline age (<65 vs. >65 years), ECOG status (0 vs. >1), 
pre-therapy Waldenström’s macroglobulinemia International Prognostic Scoring System (IPSS) 
score, serum β2-microglobulin levels (<3.0 vs. >3.0 mg/L), hemoglobin (<11 vs. >11 g/dL), serum 
IgM (<4,000 vs. >4,000 mg/dL), BM disease involvement (<50% vs. > 50%), prior relapsed or 
refractory status, and prior lines of therapy (1-3 vs. >3), as well as for major responses across most 
of the baseline subgroups (Treon et al, 2015b). 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, 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 (>6 months) in comparison to patients with the 


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MYD88L265PCXCR4WT genotype (Figure 1; Treon et al, 2015b). 
 
CT-defined adenopathy (>1.5 cm) was present in 37 patients at baseline. Serial imaging for 35 
patients showed decreased or resolved (n=25; 67.6%); stable (n=9; 24.3%); or increased (n=1; 
n=2.9%) adenopathy. Two patients came off study before repeat imaging was required. Among 7 
patients with CT-defined splenomegaly (>15 cm), spleen size was decreased (n=4; 57.1%), stable 
(n=2; 28.6%), or not evaluable (n=1; 14.3%) following elective splenectomy. Nine patients 
(14.3%), 3 with positive anti-MAG antibodies, received ibrutinib for progressive IgM-related 
peripheral sensory neuropathy. All responded, and subjective improvements in peripheral sensory 
neuropathy occurred in 5, and remained stable in 4 during the treatment course. Symptomatic 
hyperviscosity related to progressive disease that required plasmapheresis prompted start of 
ibrutinib in 4 patients. All responded, and none required additional plasmapheresis by the end of 
Cycle 2. One patient required plasmapheresis for acquired Factor VIII deficiency. He responded, 
and did not require further plasmapheresis. The spontaneous bleeding events that prompted therapy 
also resolved. With a median on treatment duration of 19.1 (range 0.5-29.7) months, 43 patients 
(68.3%) remained on therapy. Reasons for treatment discontinuation included non-response (n=1); 
progressive disease (n=7); treatment-aggravated thrombocytopenia (n=1); hematoma after BM 
biopsy (n=1); prolonged drug hold for infection unrelated to ibrutinib (n=1); myelodysplasia/acute 
myeloid leukemia associated with baseline 5q- deletion related to prior therapies (n=1); disease 
transformation possibly related to prior nucleoside analogue therapy (n=2); antineoplastic therapy 
for rectal carcinoma (n=1); ibrutinib incompatible medication (n=1), patient decision to use 
commercially sourced ibrutinib (n=2), travel difficulties (n=1), and alternative therapy (n=1). The 
estimated progression-free and overall survival at 24 months was 69.1% (95% CI 53.2%-80.5%) 
and 95.2% (95% CI 86.0-98.4%), respectively. For patients with progressive disease, the median 
time to progression was 9.6 (range: 3.5 – 19.4) months if transformation cases were censored, and 
9.5 (range: 3.5 – 19.4) months if transformation events were included. Subset analysis showed that 
>3 prior lines of therapy, high pre-therapy IPSS score, and MYD88WTCXCR4WT mutation status 
associated with inferior progression-free survival.  
 
In a prospective, multicenter, open-label substudy within a randomized, placebo-controlled, phase 
3 study of ibrutinib and rituximab in WM (PCYC 1127, see below), 31 WM patients refractory to 
rituximab and requiring treatment received oral ibrutinib 420 mg daily until progression or 
unacceptable toxicity (NCT02165397). Endpoints included progression-free survival (PFS), 
overall survival (OS), overall response rate (ORR), and hemoglobin. The median age was 67 years 
(range 47-90); 42% had high-risk disease per the International Prognostic Scoring System 
Waldenström Macroglobulinemia, median number of prior therapies was 4 (range 1-7), and all 
were rituximab-refractory. At a median follow-up of 18.1 months, the ORR was 90% (major 
response rate, 71%), and estimated 18-month PFS and OS rates were 86% and 97%, respectively. 
Rapid clinical improvement was observed after four weeks of ibrutinib, with a median IgM 
decrease of 48% and median hemoglobin increase from baseline of >1g/dL, improving further 
over time. These clinical outcomes correlated with improvements in validated patient-reported 
outcomes. Common grade ≥3 adverse events (AEs) included neutropenia (13%), hypertension 
(10%), anemia, thrombocytopenia, and diarrhea (6% each). No IgM flare, atrial fibrillation, or 
major bleeding was observed. Five (16%) patients discontinued ibrutinib: 3 due to progression and 
2 due to AEs (gastrointestinal AL amyloidosis and diarrhea); while 84% continued on ibrutinib at 
the time of reporting (Dimopoulos et al, 2016). 


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In an ongoing phase III randomized study (PCYC 1127; NCT02165397), 181 symptomatic WM 
patients that included treatment naïve, and previously treated patients were randomized in a 1:1 
ratio to receive the monoclonal antibody rituximab at 375 mg/m2 IV weekly for 4 weeks, followed 
by a second 4-weekly course 3-months later, and either ibrutinib 420 mg daily or matching placebo 
until progressive disease (PD) or unacceptable toxicity. Key inclusion criteria include WM with 
documented PD or no response (stable disease) to last treatment if previously treated; symptomatic 
disease requiring treatment per the 2ndInternational Workshop on WM; and adequate hematologic, 
hepatic, and renal function. Exclusion criteria include CNS involvement and clinically significant 
cardiovascular disease. The primary endpoint is progression-free survival assessed by an 
independent review committee. Secondary endpoints are ORR, overall survival, hematologic 
improvement, time to next treatment, and safety. Enrollment is complete and study results are 
awaited. 
 
2.4 
Rationale 
 
CXCR4 is expressed on WM cells (Ngo et al, 2008, Rocarro et al, 2014) and dysregulation of 
CXCR4 path signaling is common in WM (Hunter et al, 2016). Up to 40% of WM patients harbor 
a somatic activating mutation that supports tumor growth and survival, as well as drug resistance 
against many agents used to treat WM in response to its ligand CXCL12 (Hunter et al, 2014; Cao 
et al, 2014; Rocarro et al, 2014; Cao et al, 2015). CXCR4 mutations are almost always expressed 
in WM patients with mutated MYD88, and are associated with loss of genes that regulate MYD88 
signaling (Hunter et al, 2016). Gene overexpression of CXCL12 has also been observed in WM 
cells regardless of CXCR4 mutation status, and contributes to enhanced CXCR4 signaling (Hunter 
et al, 2016). The use of CXCR4 antagonists may therefore offer a targeted approach to therapy of 
WM patients with WHIM-like somatic mutations. It is thus hypothesized that ulocuplumab will 
improve overall and major responses, and response kinetics to ibrutinib in symptomatic patients 
with CXCR4 mutated WM.  
 
2.5 
Correlative Studies Background 
 
In most WM patients, CXCR4 mutations are subclonal with an estimated median cancer cell 
fraction of 40-50%, though the transcriptional signature remains relatively homogeneous despite 
the subclonal nature of CXCR4 mutations in WM (Hunter et al, 2016; Xu et al, 2016). CXCR4 
mutated patients also show loss of regulatory genes that regulate MYD88 signaling (Hunter et al, 
2016). Furthermore, the presence of CXCR4 WHIM mutations confers enhanced activation of 
AKT and ERK (Cao et al, 2014; Cao et al, 2015). Bone marrow aspirate (approximately 45cc) will 
therefore be collected at the baseline screening visit, on day 1 of cycle 2 (phase 1 participants 
only), at the completion of cycle 6 following the last ulocuplumab infusion, at year 1, and thereafter 
every year until study completion. Bone marrow lymphoplasmacytic cells will be genotyped for 
MYD88 and CXCR4 at baseline to determine eligibility, and at every BM sampling for the cancer 
cell fraction of mutated CXCR4 cells determined by next generation (whole exome) sequencing; 
ii) wild-type and mutated CXCR4 transcriptional signature determined by transcriptome analytsis; 
and iii) CXCR4, CXCR7 cell surface expression, pAKT, and pERK determined by multicolor flow 
cytometry.  
 


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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 Waldenstrom’s Macroglobulinemia and meeting criteria 
for treatment using consensus panel criteria from the Second International Workshop on 
Waldenstrom’s macroglobulinemia (Kyle et al, 2003) or have high risk disease with an 
serum IgM level of 6,000 mg or higher (Gustine et al, 2016).  
 
3.1.2 MYD88 and CXCR4 mutated disease (determined by Treon laboratory or molecular 
diagnostics laboratory). 
 
3.1.3 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. 
 
3.1.4 Age ≥ 18 years 
 
3.1.5 ECOG performance status <2 (see Appendix A.). 
 
3.1.6 To establish eligibility, participants must have adequate organ and marrow function as 
defined below: 
− 
Absolute neutrophil count 
≥ 1,000/uL independent of growth factor support within 
7 days of screening 
− 
Platelets 
≥ 75,000/uL independent of platelet transfusions within 
7 days of screening 
− 
Hemoglobin 
≥ 8 g/dL 
− 
Total bilirubin 
≤ 1.5 mg/dL or < 2 mg/dL if attributable to hepatic  
                                               infiltration by neoplastic disease or Gilbert’s syndrome 
− 
AST(SGOT)/ALT(SGPT) 
≤ 2.5 × institutional upper limit of normal 
− 
Creatinine 
≤ 2 mg/dL 
3.1.7 Not on any active therapy for other malignancies with the exception of topical therapies 
for basal cell or squamous cell cancers of the skin. 
 
3.1.8 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 28 days after discontinuation from the study.  Men must 
agree to use a latex condom during sexual contact with a FCBP even if they have had a 
successful vasectomy.  FCBP must be referred to a qualified provider of contraceptive 
methods if needed.  FCBP must have a negative serum pregnancy test at screening. 
 
3.1.9 Able to adhere to the study visit schedule and other protocol requirements. 
 


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3.1.10 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. 
 
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 Treatment with strong CYP3A4/5 inhibitors or inducers 
 
3.2.4 Prior exposure to ibrutinib or ulocuplumab 
 
3.2.5 With the exception of low-dose aspirin, subjects enrolled in this study should not take 
concomitant medications that durably inhibit platelet function including marine oil tablets.  
For such medications a wash-out period of ≥ 7 days is required prior to starting treatment.  
Agents which inhibit platelet function transiently or inhibit coagulation by other 
mechanisms are restricted (e.g. use with caution).  Medications that directly and durably 
inhibit platelet function include aspirin containing combinations, clopidogrel, 
dipyridamole, tirofiban, epoprostenol, eptifibatide, cilostazol, abciximab, ticlopidine, 
cilostazol. 
 
3.2.6 Participants should not take drugs that directly and durably inhibit coagulation with the 
exception of warfarin (coumadin) and heparin including low-molecular-weight heparin 
(LMWH), including enoxaparin, tinzaparin, etc. 
 
3.2.7 Participants enrolled in this study should not take concomitant medications that are 
considered to have a risk of Torsades de Pointes (category 1 on http://www.qtdrugs.org/medical-
pros/drug-lists/drug-lists).  For such medications a wash-out period of >7 days is required prior 
to starting treatment. 
 
3.2.8 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. 
 
3.2.9 Known CNS lymphoma. 
 
3.2.10 New York Heart Association classification III or IV heart failure. 
 
3.2.11 Known history of Human Immunodeficiency Virus (HIV), active infection with Hepatitis 
B Virus (HBV), and/or Hepatitis C Virus (HCV). 
 


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3.2.12 Lactating or pregnant women. 
 
3.2.13 Grade > 2 toxicity (other than alopecia) continuing from prior anti-cancer therapy. 
 
3.2.14 Inability to swallow capsules 
 
3.2.15 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.  
 
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 
N/a 
 
4.4 
Registration Process for Other Investigative Sites 
N/a. 
 
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 
participant’s malignancy.   
 


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5.1 
Treatment Regimen 
 
Treatment will be administered in four-week cycles. Treatment will be comprised of ibrutinib 
administered orally starting day 1 of cycle 1 for 47 cycles, along with ulocuplumab administered 
intravenously weekly during Cycle 1, and then every other week for Cycles 2-6. A 3+3 Phase I 
design will be employed for 3 dose levels, and 20 additional patients will be recruited at the 
maximum dose or maximum tolerated dose (if a dose-limiting toxicity is identified) for the Phase 
II dose expansion. 
 
Bristol-Myers Squibb, the study supporter and manufacturer of ulocuplumab, terminated the 
development of ulocuplumab on 3/29/19.  Due to this, the Phase 2 portion of this study was never 
opened. BMS continued to supply drug for this study until 7/1/2020.  The Sponsor-Investigator 
halted enrollment on this study after the 3rd participant in the Phase 1 cohort #3 was accrued.  All 
participants enrolled were able to complete planned ulocuplumab dosing, and participants then 
continued on commercial ibrutinib monotherapy.   
 
The Sponsor-Investigator has decided to discontinue all study therapy and follow-up procedures 
for all participants remaining on the study as of 12/31/22.   
 
Each cycle is four weeks. Ibrutinib will be administered continuously for 47 cycles. Ulocuplumab 
will be administered weekly on days 1, 8, 15, and 22 (+ 2 days for each dose) for Cycle 1, then 
every other week on days 1 and 15 (+ 2 days) for Cycles 2-6. For the Phase I portion, a 3+3 design 
will be used following the dosing schema in Table 1. 
 
Table 1. Cohort dosing 
Dose Level 
Ibrutinib 
Ulocuplumab Cycle 1 
Ulocuplumab Cycles 2-6 
Cohort 1 –Starting dose 
420mg PO DQ 
400 mg weekly 
800 mg every other week 
Cohort 2  
420mg PO DQ 
800 mg weekly 
1200 mg every other week 
Cohort 3 
420mg PO DQ 
800 mg weekly  
1600 mg every other week 
 
The MTD or highest administered dose informed from the Phase I portion of the study will be used 
in Phase II portion of the study.  
 
Participants will be pre-medicated with 10mg of oral dexamethasone and 20mg of oral famotidine 
(or equivalent for either agent) 8-18 hours prior to each dose of ulocuplumab, in addition to 30-60 
minutes before each treatment.  
 
Regimen Description 
Agent1 
Premedications; Precautions 
30-60 minutes before 
ulocuplumab infusion 
Dose 
Route 
Schedule 
Cycle 
Length 


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Ulocuplumab 1. Diphenhydramine 25-50 mg 
IV or PO 
2. Acetaminophen 650 mg 
orally 
3. Corticosteroids (10 mg of 
IV dexamethasone or 
equivalent) 
4. Famotidine (or equivalent) 
20 mg PO or IV* 
Refer to Table 1. Cohort 
Dosing 
IV 
Cycle: 1 Days 1, 8, 
15, and 22 
+ 2 days 
Cycles 2-6: Days 1 
and 15 
+ 2 days 
28 days (4 
weeks) 
 
Ibrutinib 
 Not applicable 
420mg  
PO 
QD (outpatient) 
28 days (4 
weeks) 
1 The order of administration of Ibrutinib and Ulocuplumab does not matter. 
*Oral famotidine or equivalent may be given in the event of drug shortages or formulary changes. 
 
Reported adverse events and potential risks are described in Section 7.  Dose modifications are 
described in Section 6.  No investigational or commercial agents or therapies other than those 
described below may be administered with the intent to treat the participant's malignancy.  
 
5.2 
Pre-Treatment Criteria 
 
C1D1 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 Day 1 of all cycles: 
• No grade 3 or 4 nausea, vomiting, or diarrhea (if persistent despite optimal antiemetic 
and/or antidiarrheal therapy) 
• No non-hematologic grade 3 toxicities 
• Neutrophil count > 750/uL (growth factor permitted to retreat) 
• Platelet count > 50,000 uL (platelet transfusion permitted to retreat)  
• Hemoglobin > 8 g/dL 
 
5.3 
Treatment Administration 
 
5.3.1 
 Ulocuplumab  
 
Ulocuplumab (400mg, 800mg, 1200mg, or 1600mg flat dose) will be administered as a single 60 
minute intravenous infusion.  Participants should be observed for one hour after the completion of 
every infusion. 
 
Ulocuplumab will be administered 30-60 minutes after pre-medications on Day 1, 8, 15, and 22 of 
Cycle 1 (+ 2 days for each dose), and Days 1 and 15 for Cycles 2-6 (+ 2 days for each dose). 
 
Vital signs (blood pressure, temperature, heart rate, respiratory rate) will be obtained before 
infusion, every 15 minutes (+ 5 minutes) during the infusion period, and at 15, 30, and 60 minutes 
(+ 5 minutes) after the completion of infusion.   
 
Since ulocuplumab contains only human protein sequences, it is unlikely to be immunogenic and 
to induce infusion or hypersensitivity reactions.  However, if such a reaction were to occur, it 


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might manifest with fever, chills, rigors, headache, rash, pruritis, arthralgias, hypo or hypertension, 
bronchospasm, or other symptoms.   
 
For Grade 1 symptoms, i.e. mild reaction for which infusion interruption is not indicated, and 
intervention is not indicated: 
 
Patient will remain at the clinic and monitored until there is recovery from symptoms. Continuation 
of infusion as before can proceed until infusion is completed. Information on prophylactic pre-
medications is provided in Section 5.7.1. 
 
For Grade 2 symptoms, i.e. moderate reaction that requires infusion interruption, and that 
necessitates intervention such as antihistamines, non-steroidal, or anti-inflammatory agents 
(NSAIDs), narcotics, corticosteroids, or intravenous fluids. Patients will remain at the clinic and 
monitored until there is recovery from symptoms. Infusion may be restarted at 50% of the original 
infusion rate when symptoms resolve. If no further complications occur after 30 minutes, the rate 
may be increased to 100% of the original infusion rate. Subject should be monitor closely at this 
time. If symptoms recur, then the infusion will be stopped and no further ulocuplumab will be 
administered at that visit. The amount of study drug infused must be recorded on the case report 
form (CRF). Patient will be monitored until recovery from symptoms.  
 
For prolonged Grade 3 or Grade 4 symptoms, i.e. severe reactions that are severe or not rapidly 
responsive to symptomatic medication and/or interruption of infusion, or recurrence of symptoms 
following initial improvement, study drug should be terminated. An intravenous infusion of 
normal saline, and support as follows can be considered by the treating clinician: bronchodilators, 
epinephrine 0.2 to 1 mg of a 1:1,000 solution for subcutaneous administration, 0.3 mg of a 1:1,000 
solution for intramuscular administration, or 0.1 to 0.25 mg of a 1:10,000 solution injected slowly 
for i.v. administration, and/or diphenhydramine 50 mg i.v. with methylprednisolone 100 mg i.v. 
(or equivalent), as needed. The subject should be monitored until the treating clinician is 
comfortable that symptoms will not recur. Ulocuplumab will be permanently discontinued. 
Investigators should follow their institutional guidelines for the treatment of anaphylaxis, and 
treating clinician should if possible remain at bedside and monitor the subject until recovery from 
symptoms.  
 
In the case of late occurring hypersensitivity symptoms (e.g., appearance of a localized or 
generalized pruritus within 1 week after treatment), symptomatic treatment may be given (e.g., 
oral antihistamine, or corticosteroids).  
 
Product description and storage information is described in Section 8. 
 
5.3.2 Ibrutinib Administration 
 
Ibrutinib 420 mg will be prescribed per the FDA package label, administered orally once daily for 
47 cycles. The capsules should be taken around the same time each day with 8 ounces 
(approximately 240 mL) of water. The capsules should be swallowed intact and subjects should 
not attempt to open capsules or dissolve them in water. The use of strong CYP3A 
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study (see section 5.7.3).  
 
If a dose of ibrutinib is not taken at the scheduled time, it can be taken as soon as possible within 
6 hours, with a return to the normal schedule the following day. The subject should not take extra 
capsules to make up the missed dose.  
Participants will be treated with ibrutinib for 47 cycles or until progression, unacceptable toxicity, 
or decision to withdraw from the trial. Dose reductions due to toxicity will be permitted on 
information seen in Section 6. 
 
Ibrutinib will be self-administered, and participants will be instructed to write in a diary daily, 
documenting that the drug was taken. Participants will be instructed to take the study drug at 
approximately the same time each day, ideally at least 30 minutes before eating or at least 2 hours 
after a low-fat meal. Participants will also be instructed on how to complete the diary. Participants 
will be reminded that dietary habits around the time of ibrutinib intake should be as consistent as 
possible throughout the study. If a dose is missed, study drug may be taken up to 6 hours after the 
scheduled time with a return to the normal schedule the following day.  If it has been greater than 
6 hours, ibrutinib should not be taken on that date, and the patient should take the next ibrutinib 
dose at the scheduled time the next day.  The missed dose will not be made up and must be returned 
at the next scheduled visit. The patient will be instructed to document missed drug doses in the 
study diary.  Furthermore, they will be instructed to call the PI or research nurse if vomiting occurs. 
If the pills are vomited, this should be noted on the patient diary, but a replacement dose should 
not be taken that day. All dosages prescribed and dispensed to the participant, and all dose changes 
during the study must be recorded. 
5.4 
Definition of Dose-Limiting Toxicity (DLT) for Ulocuplumab (Phase I only) 
 
The following will be considered a DLT if occurring during the 1st & 2ndCycle of Therapy: 
• > Grade 4 hematologic toxicity (anemia, neutropenia, or thrombocytopenia) 
• Any grade 5 hematologic or non-hematologic toxicity 
• Any grade 4 non-hematologic toxicity, including vomiting or diarrhea 
• Any other > Grade 3 adverse event not due to underlying disease, except for Grade 3 
infection, easily reversible asymptomatic laboratory abnormalities, and nausea, vomiting, 
or diarrhea controlled by medications.   
o Grade 3 vomiting or diarrhea can only be excluded if the participant does not 
require total parenteral nutrition (TPN), tube feeding, or hospitalization, and the 
toxicity resolves to less than grade 3 within 72 hours. 
o Reversible asymptomatic laboratory abnormalities may be excluded only if they 
are correctable to <grade 3 within 72 hours. 
 
The following will NOT be considered a DLT: 
• An IgM flare, which is commonly observed with antibody therapy in WM patients and may 
require plasmapheresis 
• Lymphocytosis, or mobilization of leukocytes which often occurs as a consequence of 
CXCR4 antagonism 
• Lymphopenia, which is an intended consequence of therapy 
• A < Grade 2 infusion reaction 


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Management and dose modifications associated with the above adverse events attributed to 
ulocuplumab are outlined in Section 6. 
 
Dose escalation will proceed within each cohort according to the following scheme.  Dose-
limiting toxicity (DLT) is defined above.   
 
Number of Participants with DLT at a 
Given Dose Level 
Escalation Decision Rule 
0 out of 3 
Enter 3 participants at the next dose level. 
>2 
Dose escalation will be stopped.  This dose level will be declared 
the maximally administered dose (highest dose administered).  
Three (3) additional participants will be entered at the next lowest 
dose level if only 3 participants were treated previously at that dose. 
1 out of 3 
Enter at least 3 more participants at this dose level. 
• If 0 of these 3 participants experience DLT, proceed to the next 
dose level. 
• If 1 or more of this group suffer DLT, then dose escalation is 
stopped, and this dose is declared the maximally administered 
dose.  20 additional participants will be entered at the next lowest 
dose level. 
≤1 out of 6 at highest dose level below the 
maximally administered dose 
This is generally the recommended phase 2 dose.  
 
5.5 
Definition of Maximum Tolerated Dose (MTD) for Ulocuplumab (from Phase I) 
 
The MTD is defined as the highest combination drug dosage not causing medically unacceptable, 
dose-limiting toxicity (DLT) in more than 33% of the treated participants in the first cycle and 
second cycle of treatment. Adverse events and laboratory abnormalities that are considered DLTs 
are defined in Section 5.4. The MTD or maximum dose from Phase I portion of the study will be 
used in the phase II part of the study. 
 
5.6 
Ulocuplumab Dose for Phase II Part of Study 
 
The MTD or maximum dose from Phase I portion of the study will be used in the phase II part of 
the study. After the first six participants are accrued to the Phase II cohort, enrollment will be held 
to conduct a DSMC safety analysis of the first two cycles of treatment.  The DSMC will determine 
if there have been excessive dose reductions or delays which require an amendment to the Phase 
II ulocuplumab dose level. 
 
5.7 
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 


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visit, the investigator will ask the participant about any new medications he/she is or has taken 
after the start of the study drug. 
 
5.7.1 Prophylactically Prescribed Medication 
 
All prophylactic premedication administration is mandatory.  Participants will be pre-medicated 
with 10mg of oral dexamethasone and 20mg of oral famotidine (or equivalent for either agent) 8-
18 hours prior to each dose of ulocuplumab.  The following premedications should be administered 
within 30-60 minutes prior to administration of ulocuplumab: 
• IV or oral diphenhydramine 25-50 mg 
• Acetaminophen 650 mg orally 
• Corticosteroids (10 mg of IV dexamethasone or equivalent) 
• Famotidine (or equivalent) 20 mg PO or IV 
 
5.7.2 Permitted Treatments 
 
Subjects may receive DVT prophylaxis (if needed) with LMWH, warfarin (coumadin), or similar. 
All anticoagulants, and/or aspirin should be held in case the platelet count is < 50,000 mm3. 
5.7.3 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 ulocuplumab 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. 
• Medications that are generally considered to have a risk of causing “Torsades de Pointes” 
(Category 1 on http://www.qtdrugs.org/medical-pros/drug-lists/drug-lists). Subjects must 
have a washout period of > 7 days prior to first dose of investigational product. Caution is 
warranted when administering ulocuplumab to subjects taking drugs associated with 
prolongation of QTc listed in Category 2: Drugs with Possible Risk of Torsades de Pointes. 
• Medications that Durably Inhibit Platelet Function: 
With the exception of low-dose aspirin, subjects enrolled in this study should not take 
concomitant medications that durably inhibit platelet function. For such medications, a 
wash-out period of ≥ 7 days is required prior to starting treatment. Medications that directly 
and durably inhibit platelet function include aspirin-containing combinations, clopidogrel, 
dipyridamole, tirofiban, dipyridamole, epoprostenol, eptifibatide, cilostazol, abciximab, 
ticlopidine, cilostazol should be avoided. 
• Medications that Inhibit Coagulation: With the exception of heparin including low-
molecular-weight heparin (LMWH) (enoxaparin, tinzaparin, etc), or Factor X inhibitors, 
subjects should not take drugs that directly and durably inhibit coagulation. 
• Supplements such as fish oils and vitamin E preparations should be avoided. 


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CYP3A- Inhibitors/Inducers 
Ibrutinib is metabolized primarily by CYP3A. Avoid co-administration with strong CYP3A4 or 
moderate CYP3A inhibitors and consider alternative agents with less CYP3A inhibition. 
• If a strong CYP3A inhibitor (eg, ketoconazole, indinavir, nelfinavir, ritonavir, saquinavir, 
clarithromycin, telithromycin, itraconazole, nefazadone, or cobicistat) must be used, 
withhold ibrutinib treatment for the duration of inhibitor use.  
• If a moderate CYP3A inhibitor (eg, voriconazole, erythromycin, amprenavir, aprepitant, 
atazanavir, ciprofloxacin, crizotinib, darunavir/ritonavir, diltiazem, fluconazole, 
fosamprenavir, imatinib, verapamil, amiodarone, or dronedarone) must be used, reduce 
ibrutinib to 140 mg PO QD for the duration of the inhibitor use. Avoid grapefruit and 
Seville oranges during ibrutinib/placebo treatment, as these contain moderate inhibitors of 
CYP3A. 
• No dose adjustment is required in combination with mild inhibitors.  
Avoid concomitant use of strong CYP3A inducers (eg, carbamazepine, rifampin, phenytoin, and 
St. John’s Wort). Consider alternative agents with less CYP3A induction. 
No chronic treatment with systemic steroids (at dosages equivalent to prednisone > 20 mg/day for 
more than 14 days) or other immunosuppressive agents should be used. Topical or inhaled 
corticosteroids are allowed. 
5.8 
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 
47 cycles or until one of the following criteria applies: 
 
• 
Disease progression. 
• 
Intercurrent illness that prevents further administration of treatment. 
• 
Unacceptable adverse event(s) based on study team determination. 
• 
Participant demonstrates an inability or unwillingness to comply with treatment 
administration and/or documentation requirements for ibrutinib. 
• 
Participant decides to withdraw from the protocol therapy. 
• 
General or specific changes in the participant's condition render the participant 
unacceptable for further treatment in the judgment of the treating investigator. 
• 
Unacceptable toxicity requiring discontinuation of Ibrutinib 
• 
Withdrawal of subject consent.  
 
Participants meeting criteria for disease progression but deemed by the investigator to be clinically 
benefiting from ibrutinib will be permitted to continue on protocol therapy at the PI’s discretion.  
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 


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participant.  An ODQ Treatment Ended/Off Study Form will be filled out when a participant is 
removed from protocol therapy. This form can be found on the DF/HCC website at 
http://www.dfhcc.harvard.edu/research/clinical-research-support/document-library-forms-sops-
etc/. 
 
In the event of unusual or life-threatening complications, treating investigators must immediately 
notify the Study Chair Steven Treon at 617-470-7064 or the PI, Jorge J. Castillo at 617-632-3352.  
 
The Sponsor-Investigator has decided to discontinue all study therapy and follow-up procedures 
for all participants remaining on the study as of 12/31/22.   
 
 
5.9 
Duration of Follow Up 
 
Participants will be followed for up to 24 months after completion of protocol therapy, or until 
termination from study, disease progression, initiation of new anti-neoplastic therapy, or death.  
Participants removed from protocol therapy for unacceptable adverse event(s) will be followed 
until resolution of the adverse event to at least grade 1 or less, or stabilization of the adverse event. 
The Sponsor-Investigator has decided to terminate all follow-up as of 12/31/22.   
 
5.10 
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 
• Study termination as of 12/31/22 
 
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 and modifications will be made using the following recommendations. Toxicity 
assessments will be done using the CTEP Version 4 of the NCI Common Terminology Criteria for 
Adverse Events (CTCAE) which is identified and located on the CTEP website at: 
http://ctep.cancer.gov/protocolDevelopment/electronic applications/ctc.htm.  
 
In the case of toxicity, appropriate medical treatment should be used (including transfuions, 
cytokine growth factors, anti-emetics, anti-diarrheals, etc.) as medically indicated. 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 


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resolved or is deemed irreversible. 
 
For patients who are unable to tolerate the protocol-specified dosing schedule, treatment 
interruption(s) and dose adjustment(s) are permitted. Adverse event attribution to ibrutinib, 
ulocuplumab or both agents should be determined before treatment interruptions and dose 
adjustments are made.  For non-hematologic toxicities attributable to ulocuplumab, but not to 
ibrutinib, ibrutinib dosing may be continued. 
 
Dosing of ibrutinib and ulocuplumab will both be held for any of the following hematologic 
conditions: 
• Absolute neutrophil count (ANC) <500/uL 
• Platelet count <50,000/uL 
• Hemoglobin <8 g/dL 
 
Protocol therapy may be re-started as follows: 
• Recovery of ANC to >750 uL for ulocuplumab, and >500/uL for ibrutinib 
• Recovery of Platelet count to >50,000/uL 
• Recovery of Hemoglobin to >8 g/dL 
• Recovery of non-hematologic toxicity to grade 1 or less 
 
Dosing of ibrutinib will be held for any of the following ibrutinib-related conditions: 
• Grade 3 non-hematological toxicity 
• Grade >2 atrial fibrillation. Consider the risks and benefits of restarting and continuing 
ibrutinib treatment. If clinically indicated, the use of concomitant antiarrythmics, rate 
control medications, cardiac ablation, or the use of warfarin, non-warfarin or vitamin k 
antagonist anticoagulants agents may be considered to prevent or control ibrutinib related 
atrial fibrillation   
 
If administration of ibrutinib must be interrupted because of unacceptable toxicity, ulucuplomab 
should also be held. Resumption of ibrutinib treatment should be handled as follows:   
• 1st Occurrence: Retreat at dose level 1 (or dose level -1 if in the opinion of the principal 
investigator this is in subject’s best interest). 
• 2nd Occurrence: Retreat at Dose level -1  
• 3rd Occurrence: Retreat at Dose level -2  
• 4th Occurrence: Discontinue ibrutinib 
 
If administration of ibrutinib must be interrupted because of unacceptable toxicity, drug dosing 
will be interrupted or modified according to rules described in Table 6-1.  
 
Dose re-escalations of ibrutinib will not be permitted once dose reduced to next lower dose level 
unless done for concurrent treatment with CYP3A inhibitors (section 5.7.3). Dose reductions are 
permitted down to dose level -2 in Table 6-1 before a patient is taken off study. If a participant 
requires a dose delay of ibrutinib for > 28 days, then the participant will be taken off study. 
 


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Table 6-1. Ibrutinib Dose Modification Guidelines 
 
Dose Level 
Dose and Schedule 
1 
420 mg po qD 
 
-1 
280 mg po qD 
 
-2 
140 mg po qD 
 
 
Participants who must permanently discontinue Ibrutinib administration will be removed from 
protocol therapy. 
 
Ulocuplomab should be held if ibrutinib is held (as noted above). Dosing of ulocuplumab should 
also be held for any of the following ulocuplumab-related conditions: 
• Grade 3 non-hematological toxicity 
 
If administration of ulocuplumab must be interrupted because of unacceptable toxicity, unless only 
delayed due to ibrutinib associated toxicity, resumption of treatment should be handled as follows:   
• 1st Occurrence: Retreat at current dose (or dose level -1 if in the opinion of the principal 
investigator this is in subject’s best interest). 
• 2nd Occurrence: Retreat at Dose level -1  
• 3rd Occurrence: Retreat at Dose level -2  
• 4th Occurrence: Retreat at Dose level -3  
• 5th Occurrence: Discontinue ulocuplumab 
 
Dose level reduction(s) or termination for ulocuplumab will follow the rules described in Table 6-
2, 6-3, or 6-4.  
 
Dose re-escalations of ulocuplumab will not be permitted once dose reduced to next lower dose 
level. Dose reductions are permitted per Table 6-2, 6-3, or 6-4 before a patient is taken off study. 
If a participant requires a dose delay of ibrutinib for > 28 days, then the participant will be taken 
off study. 
 
If administration of ulocuplumab must be interrupted because of unacceptable toxicity, drug 
dosing will be interrupted or modified according to rules described in Table 6-2, 6-3, and/or 6-4. 
Treatment with ulocuplumab may be delayed and schedules adjusted if holding ulocuplumab is 
necessary.  Ibrutinib therapy can be continued throughout ulocuplumab hold period unless the 
adverse event may also be related to ibrutinib. In such situations, treatment hold and/or dose 
modifcations may be made for both drugs per Table 6-1 (for ibrutinib) and Table 6-2, 6-3, & 6-4 
(for ulocuplumab).  
 
Dose hold and de-escalation for ulocuplumab for the Phase II portion of the study will follow the 
rules for the cohort deemed to represent the maximum dose or MTD from the Phase I part of the 
study and shown in Table 6-2, 6-3, & 6-4. If a participant requires a dose delay of ulocuplumab 


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for > 28 days, then ulucuplomab will be discontinued. For participants permanently discontinuing 
ulocuplumab, ibrutinib therapy may be continued alone for study duration.  
 
Table 6-2.  Ulocuplumab Dose Modification Guidelines Cohort 1 
 
Cohort dose 
level 1 
Ulocuplumab 
Dose Level 1 
Dose level -
1 
Dose level -
2 
Cycle 1 
 
400mg 
200mg 
STOP 
Cycle 2-6  
800mg 
400mg 
200mg 
 
Table 6-3 Ulocuplumab Dose Modification Guidelines Cohort 2 
 
Cohort dose 
level 2 
Ulocuplumab 
Dose Level 1 
Dose level -
1 
Dose level -
2 
Dose level -
3 
Cycle 1 
 
800mg 
400mg 
200mg 
STOP 
Cycle 2-6  
1200mg 
800mg 
400mg 
STOP 
 
Table 6-4 Ulocuplumab Dose Modification Guidelines Cohort 3 
 
Cohort dose 
level 3 
Ulocuplumab 
Dose Level 1 
Dose level -
1 
Dose level -
2 
Dose level -
3 
Dose Level -4 
Cycle 1 
 
800mg 
400mg 
200mg 
STOP 
- 
Cycle 2-6  
1600mg 
1200mg 
800mg 
400mg 
STOP 
 
 
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, 
2004, Ghobrial et al, Cancer 2004). Such abrupt increases can prompt symptomatic hyperviscosity 
in patients with high serum IgM levels and can contribute to worsening of IgM related morbidity 
such as cryoglobulinemia, cold agglutinemia, and demyelinating neuropathy (Treon et al, 2015). 
Plasmapheresis is therefore used to treat symptomatic IgM flares, as well as prophylax in patients 
with high serum IgM levels (>4,000 mg/dL). Following plasmapheresis, serum IgM levels will 
return to steady state in 4-5 weeks. As such WM patients will be inevaluable for response purposes. 
It is recommended patients with symptomatic hyperviscosity or a pre-treatment serum IgM level 
>4,000 mg/dL undergo plasmapheresis before treatment with ulocuplumab. Treatment with 
ulocuplumab may be delayed for up to two weeks if plasmapheresis is warranted. Close serial 
monitoring of serum IgM levels (at least weekly) is recommended for all participants during cycle 
1, and at least every other week during cycles 2-6.  For purposes of dose limiting toxicity, an IgM 
flare will not count given the expected nature of the flare with antibody therapy in WM patients. 
 






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Cardiac  
Atrial fibrillation and atrial flutter have been reported in subjects treated with ibrutinib, particularly 
in subjects with cardiac risk factors, hypertension, acute infections, and a previous history of atrial 
fibrillation.  
Cytopenias  
Treatment-emergent Grade 3 or 4 cytopenias (neutropenia, thrombocytopenia, and anemia) were 
reported in subjects treated with ibrutinib.  
Diarrhea  
Diarrhea is the most frequently reported non-hematologic AE with ibrutinib monotherapy and 
combination therapy. Other frequently reported gastrointestinal events include nausea, vomiting, 
and constipation. These events are rarely severe. Should symptoms be severe or prolonged, follow 
the protocol dose modification guidelines (see Section 6).  
Infections  
Fatal and non-fatal infections have occurred with ibrutinib therapy. At least 25% of subjects with 
MCL and 35% of subjects with CLL had Grade 3 or greater infections per NCI Common 
Terminology Criteria for Adverse Events (CTCAE). The most commonly reported infections 
include pneumonia, cellulitis, urinary tract infection and sepsis. Although causality has not been 
established, cases of progressive multifocal leukoencephalopathy (PML) have occurred in patients 
treated with ibrutinib. 
Non-Melanoma Skin Cancer  
Non-melanoma skin cancers have occurred in patients treated with ibrutinib.  Monitor patients 
for the appearance of non-melanoma skin cancer. 
Rash  
Rash has been commonly reported in subjects treated with either single agent ibrutinib or in 
combination with chemotherapy. In a randomized Phase 3 study (PCYC-1112-CA), rash occurred 
at a higher rate in the ibrutinib arm than in the control arm. Most rashes were mild to moderate in 
severity. 
Lymphocytosis and Leukostasis  
Leukostasis  
There were isolated cases of leukostasis reported in non-WM subjects treated with ibrutinib. A 
high number of circulating lymphocytes (>400,000/µL) may confer increased risk.  
Lymphocytosis 
Upon initiation of treatment, a reversible increase in lymphocyte counts (ie, ≥50% increase from 
baseline and an absolute count >5000/µL), often associated with reduction of lymphadenopathy, 
has been observed in most subjects with CLL/ small lymphocytic lymphoma (SLL) treated with 
ibrutinib. This effect has also been observed in some subjects with MCL treated with ibrutinib. 
This observed lymphocytosis is a pharmacodynamic effect and should not be considered 
progressive disease in the absence of other clinical findings. In both disease types, lymphocytosis 


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typically occurs during the first few weeks of ibrutinib therapy (median time 1.1 weeks) and 
typically resolves within a median of 8.0 weeks in subjects with MCL and 18.7 weeks in subjects 
with CLL/SLL.  
A large increase in the number of circulating lymphocytes (eg, >400,000/ul) has been observed in 
non-WM subjects. Lymphocytosis was uncommon in subjects with WM treated with ibrutinib, 
and was typically <5,000/ul.  
Tumor Lysis Syndrome 
There have been reports of tumor lysis syndrome (TLS) events in non-WM subjects treated with 
single-agent ibrutinib or in combination with chemotherapy. Subjects at risk of tumor lysis 
syndrome are those with comorbidities and/or risk factors such as high tumor burden prior to 
treatment, increased uric acid (hyperuricemia), elevated lactate dehydrogenase (LDH), bulky 
disease at baseline, and preexisting kidney abnormalities.  
Interstitial Lung Disease (ILD) 
Cases of interstitial lung disease (ILD) have been reported in patients treated with ibrutinib. 
Monitor patients for pulmonary symptoms indicative of ILD.  
Other Malignancies 
All new malignant tumors including solid tumors, skin malignancies and hematologic 
malignancies will be reported for the duration of study treatment and during any protocol-specified 
follow-up periods including post-progression follow-up for overall survival. If observed, enter data 
in the corresponding eCRF. 


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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-


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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.  
 
7.3.2 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.  
 
7.3.3 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). 
 
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. 
 
 
 


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7.5 
Expedited Reporting to BMS Worldwide Safety 
 
All Serious Adverse Events (SAEs) that occur following the subject’s written consent to participate 
in the study through 30 days of discontinuation of dosing must be reported to BMS Worldwide 
Safety. 
• The FDA Medwatch form should be used to report SAEs.  The BMS protocol ID number 
must be included on whatever form is submitted by the Sponsor/Investigator. 
• Following the subject’s written consent to participate in the study, all SAEs, whether 
related or not related to study drug, are collected, including those thought to be associated 
with protocol-specified procedures. The investigator should report any SAE occurring after 
these time periods that is believed to be related to study drug or protocol-specified 
procedure.  
SAEs and pregnancies must be reported to BMS within 24 hours of learning of the event regardless 
of causality. SAEs must be recorded on BMS or an approved form; pregnancies must be reported 
on a Pregnancy Surveillance Form. 
A serious AE (SAE) is any untoward medical occurrence that at any dose: 
a) results in death 
b) is life-threatening (defined as an event in which the subject was at risk of death at the 
time of the event; it does not refer to an event which hypothetically might have caused 
death if it were more severe) 
c) requires inpatient hospitalization or causes prolongation of existing hospitalization (see 
NOTE below) 
d) results in persistent or significant disability/incapacity 
e) is a congenital anomaly/birth defect 
f) is an important medical event (defined as a medical event(s) that may not be immediately 
life-threatening or result in death or hospitalization but, based upon appropriate medical 
and scientific judgment, may jeopardize the subject or may require intervention [e.g., 
medical, surgical] to prevent one of the other serious outcomes listed in the definition 
above.) Examples of such events include, but are not limited to, intensive treatment in an 
emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions 
that do not result in hospitalization.) Potential drug induced liver injury (DILI) is also 
considered an important medical event. (See Section 6.6 for the definition of potential 
DILI.) 
g) Suspected transmission of an infectious agent (eg, any organism, virus or infectious 
particle, pathogenic or non-pathogenic) via the study drug is an SAE. 
h) Although pregnancy, overdose and cancer are not always serious by regulatory definition, 
these events must be handled as SAEs. (See Section 6.1.1 for reporting pregnancies). 


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NOTE: 
The following hospitalizations are not considered SAEs in BMS clinical studies: 
• a visit to the emergency room or other hospital department < 24 hours, that does not 
result in admission (unless considered "important medical event" or event life 
threatening) 
• elective surgery, planned prior to signing consent 
• admissions as per protocol for a planned medical/surgical procedure 
• routine health assessment requiring admission for baseline/trending of health status (eg, 
routine colonoscopy) 
• medical/surgical admission for purpose other than remedying ill health state and was 
planned prior to entry into the study. Appropriate documentation is required in these 
cases admission encountered for another life circumstance that carries no bearing on 
health status and requires no medical/surgical intervention (eg, lack of housing, 
economic inadequacy, care-giver respite, family circumstances, administrative). 
SAE Email Address:  Worldwide.Safety@BMS.com 
SAE Facsimile Number:  609-818-3804 
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 BMS (or 
designee) using the same procedure used for transmitting the initial SAE report.  
All SAEs should be followed to resolution or stabilization. 
 
7.6 
Routine AE reporting to BMS  
 
All treatment emergent AEs (including severity grade, action taken, and outcome) will be 
communicated to BMS on a quarterly basis. 
 
7.7 
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.  
 
7.8 
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. 
 








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8.2 
Ibrutinib 
 
8.2.1 Description 
 
Ibrutinib 
is 
1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-
piperidinyl]-2-propen-1-one and has a molecular weight of 440.50 g/mole (anhydrous basis). 
Ibrutinib exhibited 18% to 23% oral bioavailability in rats and 7% to 11% oral bioavailability in 
dogs. The mean terminal half-life of ibrutinib after oral administration ranged from 1.7 to 3.1 hours 
in mice, 1 to 4.7 hours in rats, and 3.3 to 6.4 hours in dogs. Preliminary results suggest a 1.5- to 
2.5-hour half-life of ibrutinib in humans. The effects of renal and/or hepatic impairment on drug 
clearance are not known at this time. In vitro studies have indicated that ibrutinib is metabolized 
extensively by cytochrome P450 (CYP) 3A4. 
 
8.2.2 Form 
 
The structure of ibrutinib is:  
 
 
 
 
 
 
 
 
 
 
 
 
Ibrutinib is a white to off-white crystalline solid. Ibrutinib has a single chiral center and is the R-
enantiomer. Ibrutinib product is manufactured for Pharmacyclics LLC by a contract manufacturer.  
 
Ibrutinib PO Hard Gelatin Capsule is an oral formulation containing micronized ibrutinib and the 
following compendial excipients: microcrystalline cellulose (NF); croscarmellose sodium (NF); 
sodium lauryl sulfate (NF); may contain magnesium stearate (NF). The 140 mg strength contains 
140 mg of the active ingredient, ibrutinib, adjusted for water content and purity in a size 0, white, 
hard gelatin capsule. Capsules are packaged in 60-cc high-density polyethylene (HDPE) bottles 
with an induction seal and a child resistant screw top cap. Each bottle is distributed by 
Pharmacyclics LLC. The number of capsules per bottle is indicated on the label.   
 
Ibrutinib is also available in tablets in 140mg, 280mg, and 420mg strengths.  Each 140mg tablet 
is a yellow green to green round tablet debossed with “ibr” on one side and “140” on the other 
side.  Each 280mg tablet is a purple oblong tablet debossed with “ibr” on one side and “280” on 
the other side.  Each 420mg tablet is a yellow green to green oblong tablet debossed with “ibr” on 
one side and “420” on the other side. 
 


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8.2.3 Storage and Stability 
Ibrutinib should be stored according to the package insert. 
 
8.2.4 Handling 
N/a.  Ibrutinib will be commercially supplied. 
 
8.2.5 Availability 
Ibrutinib is considered standard of care for this patient population.  It will be commercially sourced 
and charged to patient insurance.  
 
8.2.6 Administration 
Ibrutinib should be self-administered daily by the participant according to the package insert. 
 
8.2.7 Ordering 
Ibrutinib is commercially available. 
 
8.2.8 Accountability 
The investigator or designee will comply with all institutional commercial drug SOPs. 
 
8.2.9 Destruction and Return 
N/A. 
 
9. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
9.1 
Biomarker Studies 
 
9.1.1 Laboratory Correlative Studies 
 
Bone marrow aspirate (approximately 45cc) will therefore be collected at the baseline screening 
visit, on day 1 of cycle 2 (phase I participants only), at the completion of cycle 6 following the last 
ulocuplumab infusion, at year 1, and thereafter every year until study completion. Bone marrow 
lymphoplasmacytic cells will be genotyped for MYD88 and CXCR4 at baseline to determine 
eligibility, and at every BM sampling for the cancer cell fraction of mutated CXCR4 cells 
determined by next generation (whole exome) sequencing; ii) wild-type and mutated CXCR4 
transcriptional signature determined by transcriptome analytsis; and iii) CXCR4, CXCR7 cell 
surface expression, pAKT, and pERK determined by multicolor flow cytometry.  
 
 
 
 
 
 
 
 
 




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* Physical exam, vital signs, laboratory tests, 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, every 15 minutes during the infusion (+5 minutes), and 15, 30, and 60 minutes post 
infusion (+ 5 minutes). 
 
1  More 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 on days 1 of cycle 12, 24, 36, and 
off-treatment assessment for participants who had extramedullary disease at baseline (i.e. 
lymph nodes 15 mm or greater, spleen >15 cm, or other documented extramedullary site of 
WM disease). 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.  CT scans will also be done 
at the completion of Cycle 6 on Day 15 (+/- 2 days).  Scans will also be repeated to confirm a 
complete response if the participant has no detectable monoclonal protein and had extramedullary 
disease (as noted above) at baseline and at the discretion of the investigator. 
 
3Bone marrow biopsy and aspiration will be done during the screening visit or within 90 days prior 
to Cycle 1 Day 1, and on days 1 of cycle 6, 12, 24, 36, and off-treatment assessment. Bone marrow 
biopsy and aspiration will also be done at the completion of Cycle 6 on Day 15 (+/- 2 days).  Up 
to 45 additional cc of aspirate will be collected (if collectable) at these sampling times for 
laboratory correlative studies specified in section 9.1.1. A bone marrow aspirate only will be 
collected on day 1 of cycle 2 for laboratory correlative studies per 9.1.1 from participants on the 
Phase I part of the study only. Bone marrow biopsy and aspiration may also be performed to 
confirm complete response, or progression, and study samples may be collected at this time to 
perform laboratory corollary studies per section 9.1.1 
 
4For women of childbearing potential only, a serum pregnancy test is required at screening. 
 
5Participants still on commercial ibrutinib as of study termination on 12/31/22 are not required to 
complete the Off Treatment visit and will not enter follow-up. 
 
6All follow-up will be terminated as of 12/31/22.  
 


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11. MEASUREMENT OF EFFECT 
 
11.1.1 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. 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.) 
 
11.1.2 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. For participants on active therapy who are on 
a drug hold for > 7 days, serum IgM levels will be considered unevaluable for response assessment. 
Patient must be on study drug for >2 consecutive weeks to be considered eligible for serum IgM 
response assessment. 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 
the absence of new or increasing adenopathy or splenomegaly and/or other progressive signs or 
symptoms of WM. 


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Overall Response Rate (ORR): Includes patients who achieved MR, PR, VGPR and CR. 
 
11.1.1 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).  
 
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 
 
CTRIO/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 CTRIO/ODQ according to the schedule set by the CTRIO/ODQ. 
 
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 
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.  
 
After the first six participants are accrued to the Phase II cohort, enrollment will be held to conduct 
a DSMC safety analysis of the first two cycles of treatment. 
12.3 
Multicenter Guidelines 
 
Not applicable. 


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12.4 
Collaborative Agreements Language 
 
Not applicable. 
 
13. STATISTICAL CONSIDERATIONS 
 
This is a phase I/II, dose-escalating, single-arm, open-label prospective study aimed at evaluating 
the safety of ulocuplumab, an anti-CXCR4 monoclonal antibody, in symptomatic patients with 
CXCR4 mutated WM. As a phase I study, response and/or survival outcomes will not be taken 
into account for sample size purposes. Regarding toxicity, assuming that an adverse event 
associated with study drug has a true incidence of 10%, with an estimated sample size of 38 
patients (maximum population to be enrolled), the likelihood of observing at least 1 adverse event 
would be at least 90% 
 
13.1 
Study Design/Endpoints 
 
This is a phase I/II, dose-escalating, single-arm, open-label prospective study aimed at evaluating 
the safety of ibrutinib combined with ulocuplumab, an anti-CXCR4 monoclonal antibody, in 
patients with symptomatic CXCR4 mutated WM. Toxicity will be graded according to the 
Common Terminology Criteria for Adverse Events (CTCAE version 4.0), which is available at 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE 4.03 2010-06-14 QuickReference 8.5x11.pdf.  
 
The following will be considered a DLT if occurring during the 1st or 2nd Cycle of Therapy 
• > Grade 4 hematologic toxicity (anemia, neutropenia, or thrombocytopenia) 
• Any grade 5 hematologic or non-hematologic toxicity 
• Any grade 4 non-hematologic toxicity, including vomiting or diarrhea 
• Any other > Grade 3 adverse event not due to underlying disease, except for Grade 3 
infection, easily reversible asymptomatic laboratory abnormalities, and nausea, vomiting, 
or diarrhea controlled by medications.   
o Grade 3 vomiting or diarrhea can only be excluded if the participant does not 
require total parenteral nutrition (TPN), tube feeding, or hospitalization, and the 
toxicity resolves to less than grade 3 within 72 hours. 
o Reversible asymptomatic laboratory abnormalities may be excluded only if they 
are correctable to <grade 3 within 72 hours. 
 
The following will NOT be considered a DLT 
• An IgM flare, which is commonly observed with antibody therapy in WM patients and may 
require plasmapheresis. 
• Lymphocytosis, or mobilization of leukocytes which often occurs as a consequence of 
CXCR4 antagonism. 
• Lymphopenia, which is an intended consequence of therapy. 
• A < Grade 2 infusion reaction. 
 
The maximum tolerated dose (MTD) will be the dose below that which produced a DLT or the 
maximum dose allowed by protocol (1600 mg) if no DLT was observed. The MTD will be then 


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be used for the phase II portion of the study. 
Dose escalation will be as follows, for a maximum accrual of 18 patients: 
 
Number of Participants with DLT at a 
Given Dose Level 
Escalation Decision Rule 
0 out of 3 
Enter 3 participants at the next dose level. 
>2 
Dose escalation will be stopped.  This dose level will be declared 
the maximally administered dose (highest dose administered).  
Three (3) additional participants will be entered at the next lowest 
dose level if only 3 participants were treated previously at that 
dose. 
1 out of 3 
Enter at least 3 more participants at this dose level. 
• If 0 of these 3 participants experience DLT, proceed to the next 
dose level. 
• If 1 or more of this group suffer DLT, then dose escalation is 
stopped, and this dose is declared the maximally administered 
dose.  20 additional participants will be entered at the next 
lowest dose level. 
≤1 out of 6 at highest dose level below the 
maximally administered dose 
This is generally the recommended phase 2 dose.  
 
13.2 
Sample Size, Accrual Rate and Study Duration 
 
A maximum of 18 patients will be accrued for the phase I study.   
 
A maximum of 20 evaluable patients will be accrued for the phase II study. To be evaluable for 
response, patients must have one cycle of therapy. Patients inevaluable for response will be 
replaced. Assuming an H0 of major response rate of 50% vs. an H1 of 80%, a sample of 20 patients 
would have a power of 80% with an alpha of 0.04 to detect a difference. If 15 patients or more 
obtain a major response, then the study would be a success, if 14 patients or fewer obtain a major 
response, then the study would be a failure and the combination should not continue further 
evaluation.  Sample size and power estimation were obtained using the binomial method (STATA 
version 13). 
 
Accrual time will be approximately 12-18 months, at a rate of 2-3 patients per month. Patients will 
be followed for the duration of time on active protocol therapy (47 cycles), and then 2 additional 
years after completion of cycle 47. Participants will be followed for up to 24 months after 
completion of protocol therapy, or until termination from study, disease progression, initiation of 
new anti-neoplastic therapy, or death. Participants removed from protocol therapy for unacceptable 
adverse event(s) will be followed until resolution of the adverse event to at least grade 1 or less, 
or stabilization of the adverse event. 
 
13.3 
Stratification Factors 
 
No stratification factors will be applied for either the Phase I or Phase II portion of the study.   


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13.4 
Interim Monitoring Plan 
 
The study will be monitored by the DFCI Data Safety Monitoring Committee (DSMC). The 
DSMC will meet at least two times a year and more often if needed (e.g., for safety review). For 
each meeting, the study will be reviewed for safety and progress toward completion. Copies of the 
toxicity reports prepared by the DSMC meetings will be distributed to the Principal Investigator. 
The Principal Investigator will then distribute to subinvestigators. Any DSMC recommendations 
for changes to the study will be distributed to the Principal Investigator and then circulated to sub- 
investigators by the Principal Investigator. No interim analysis of the outcome data is planned.  
After the first six participants are accrued to the Phase II cohort, enrollment will be held to conduct 
a DSMC safety analysis of the first two cycles of treatment.  The DSMC will determine if there 
have been excessive dose reductions or delays which require an amendment to the Phase II 
ulocuplumab dose level. 
 
13.5 
Analysis of Primary Endpoints 
 
The primary objective of the Phase I portion of the protocol is to determine the MTD of 
ulocuplumab combined with ibrutinib. The maximum tolerated dose (MTD) will be the dose that 
produces a DLT or the maximum dose allowed by protocol (1600 mg) if no DLT is observed 
(see section 13.1). 
 
Participants from the Phase II portion of the protocol will be included 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. 
 
Primary analyses will be performed in FAS population and will include calculating the 
proportion of patients having a major response (PR or better).  Confidence intervals (95%) 
around these point estimates will be presented.   
 
13.6 
Analysis of Secondary Endpoints 
 
The Per-Protocol Analysis Set (PPS) is defined as all participants from the FAS set who 
complete the study and are deemed to be protocol-compliant.  To be protocol-compiant, a 
participant must not have any major protocol deviations during the study period.  Protocol 
deviations will be identified prior to database lock and will be listed in the clniical study report.  
The PPS will be used for secondary assessment of efficacy endpoints. 
 
Secondary analyses will be performed in both the FAS and PPS populations.  There are no 
secondary endpoints for the Phase I portion of the protocol.  For the Phase II participants the 
time to response, both major (PR or better) and minor response will be estimated using Kaplan 
Meier methodology with median time plus 25th and 75th percentile time to response along with 
95% confidence intervals being provided, as appropriate.  Time to progression (TTP) will also be 
estimated using Kaplan Meier methodology.  Best overall response and Very Good Partial 
Response (>90% reduction in disease burden)/ CR (complete response) will be estimated in both 


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the FAS and PPS populations involving calculating the proportion of patients having an overall 
response (MR or better).  Confidence intervals (95%) around these point estimates will be 
presented. 
 
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 who have received at least one cycle of therapy are eligible for response 
assessment. Inevaluable patients for response will be replaced. All conclusions will be based on 
evaluable participants.  
 
14. PUBLICATION PLAN 
 
Interim study results may be presented at a major scientific meeting (American Society of 
Hematology, the International Workshop on WM or the International Conference on Malignant 
Lymphoma) once the Phase I portion of the study is completed. Once the Phase II portion is 
completed, a final study report will be presented at a major meeting. 
 
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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REFERENCES 
 
Cao Y, Hunter ZR, Liu X, et al. The WHIM-like CXCR4S338X somatic mutation activates AKT 
and ERK, and promotes resistance to ibrutinib and other agents used in the treatment of 
Waldenstrom’s Macroglobulinemia. Leukemia 2014; [Epub ahead of print].  
 
Cao Y, Hunter ZR, Liu X, Xu L, Yang G, Chen J, Tsakmaklis N , et al. CXCR4 WHIM-like 
frameshift and nonsense mutations promote ibrutinib resistance but do not supplant MYD88L265P 
directed survival signaling in Waldenstrom macroglobulinaemia cells. 
 
Dimopoulos MA, Trotman J, Tedeschi A, et al. Single agent ibrutinib in rituximab-refractory 
patients with Waldenström’s macroglobulinemia: Results from a multicenter, open-label phase 3 
substudy (iNNOVATETM). Lancet Oncol 2016; manuscript in press.  
 
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. 
 
Ghobrial IM,  Perez R,  Baz R, Richardson PG,  Anderson KC,  Sabbatini P, et al. Phase Ib study 
of the novel anti-CXCR4 antibody ulocuplumab (BMS-936564) in combination with lenalidomide 
plus low-dose dexamethasone, or with bortezomib plus dexamethasone in subjects with relapsed 
or refractory multiple myeloma. Blood 2014; 124: Abstract 3483. 
 
Gustine JN, Meid K, Manning R, Dubeau T, Ghobrial IM, Treon SP, Castillo JJ. The high risk of 
symptomatic hyperviscosity in patients with high serum IgM levels can be used to support 
initiation of treatment in Waldenström macroglobulinemia. Proc. 9th International Workshop on 
Waldenstrom’s Macroglobulinemia. 2016; Amsterdam, The Netherlands. 
 
 
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. 
 
Hunter ZR, Xu L, Yang G, Tsakmaklis N, Vos JM, Liu X, Chen J, et al. Transcriptome sequencing 
reveals a profile that corresponds to genomic variants in Waldenström macroglobulinemia. Blood. 
2016; 128(6):827-38. 
 
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. 
 


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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, Jiminez 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, Branagan AR, Hunter ZR, Santos D, Tournilhac O, Anderson KC. Paradoxical increases 
in serum IgM and viscosity levels following rituximab in Waldenstrom's macroglobulinemia. Ann. 
Oncol. 2004; 15(10):1481-3. 
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. 
Treon SP. How I treat Waldenström macroglobulinemia. Blood 2015; 126(6):721-32. 
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, Buhrlage S, Tan L, et al. HCK is a survival determinant transactivated by mutated 
MYD88, and a direct target of ibrutinib. Blood 127:3237-52, 2016. 
 
 
 
 
 


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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.