A Phase 2 Study of Acalabrutinib, Umbralisib, and Ublituximab (AU2) in Relapsed and Previously Untreated CLL Patients
Phase: PHASE2
Conditions: Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma, Relapsed Chronic Lymphocytic Leukemia, Refractory Chronic Lymphocytic Leukemia
Sponsor: Jennifer R. Brown, MD, PhD

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NCI Protocol #: N/A
DF/HCC Protocol #: 20-394 
TITLE: A Phase 2 Study of Acalabrutinib, Umbralisib and Ublituximab in Relapsed and Previously 
Untreated CLL Patients
Coordinating Center:
Dana-Farber Cancer Institute
Principal Investigator (PI):
Jennifer R. Brown, MD, PhD
Dana-Farber Cancer Institute
Jennifer_Brown@dfci.harvard.edu
Other Investigators:
Matthew S. Davids, MD, MMSc
Dana-Farber Cancer Institute
Matthew_Davids@DFCI.HARVARD.EDU
Statistician: 
Svitlana Tyekucheva, PhD
Dana-Farber Cancer Institute
svitlana@jimmy.harvard.edu
 
NCI-Supplied Agent: N/A
Other Agents: Acalabrutinib (CALQUENCE®, ACP-196) – Acerta Pharma; Umbralisib (TGR-1202) 
– TG Therapeutics, Inc.; Ublituximab (TG-1101) – TG Therapeutics, Inc.
IND #: 150694
IND Sponsor: Jennifer R. Brown, MD, PhD 
TG Therapeutics, Inc. Tracking Number:  U2-NTG-013
Protocol Version # / Version Date: Version 6.1 / 28 March 2023

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SCHEMA
Informed 
consent and 
confirmation of 
eligibility for 
study 
treatment
Enrollment to 
Cohort 1: 
Participants with 
relapsed disease 
(30 patients)
Enrollment to 
Cohort 2:
Participants with 
previously 
untreated disease
(30 patients)
Assessment 
of 
treatment 
response
Assessment 
of 
treatment 
response
Treatment with 
acalabrutinib & 
umbralisib 
beginning C1D1, 
ublituximab 
beginning C7D1
(1 cycle = 28 days)
Treatment 
continues 
for a 
maximum 
of 24 cycles
Treatment 
continues 
for a 
maximum 
of 24 cycles
Treatment with 
acalabrutinib & 
umbralisib 
beginning C1D1, 
ublituximab 
beginning C7D1
(1 cycle = 28 days)
Participants 
followed post-
treatment for a 
maximum of 5 
years
Participants 
followed post-
treatment for a 
maximum of 5 
years

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TABLE OF CONTENTS
SCHEMA..........................................................................................................................................2
1.
OBJECTIVES.............................................................................................................................7
1.1
Study Design............................................................................................................7
1.2
Primary Objective....................................................................................................7
1.3
Secondary Objectives...............................................................................................7
1.4
Exploratory Objectives ............................................................................................7
2.
BACKGROUND.........................................................................................................................8
2.1
Study Disease and Rationale....................................................................................8
2.2
Umbralisib (TGR-1202).........................................................................................10
2.3
Ublituximab (TG-1101).........................................................................................16
2.4
Acalabrutinib (CALQUENCE®, ACP-196) .........................................................20
2.5
Umbralisib and Ibrutinib ± Ublituximab ...............................................................22
2.6
Correlative Studies Background ............................................................................23
2.7
Eligibility Criteria..................................................................................................25
2.8
Exclusion Criteria ..................................................................................................26
2.9
Inclusion of Women and Minorities ......................................................................29
3.
REGISTRATION PROCEDURES................................................................................................29
3.1
General Guidelines for DF/HCC Institutions ........................................................29
3.2
Registration Process for DF/HCC Institutions.......................................................30
3.3
General Guidelines for Other Investigative Sites ..................................................30
3.4
Registration Process for Other Investigative Sites.................................................30
4.
TREATMENT PLAN.................................................................................................................31
4.1
Treatment Regimen................................................................................................31
4.2
Pre-Treatment Criteria ...........................................................................................32
4.3
Agent Administration.............................................................................................33
4.4
General Concomitant Medication and Supportive Care Guidelines......................36
4.5
Criteria for Taking a Participant Off Protocol Therapy.........................................40
4.6
Duration of Follow Up...........................................................................................41
4.7
Criteria for Taking a Participant Off Study ...........................................................41
5.
DOSING DELAYS/DOSE MODIFICATIONS ..............................................................................41
5.1
Dose Delays ...........................................................................................................41
5.2
Dose Modifications................................................................................................42
5.3
Toxicity Management............................................................................................43
5.4
Overdose ................................................................................................................48
5.5
Withdrawal of Umbralisib and Ublituximab .........................................................48
6.
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS..................................................48
6.1
Expected Toxicities................................................................................................48
6.2
Adverse Event Characteristics...............................................................................52
6.3
Serious Adverse Event Reporting..........................................................................52
6.4
Adverse Events of Special Interest (AESI)............................................................54
6.5
Adverse Event Reporting.......................................................................................55

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6.6
Reporting to the Food and Drug Administration (FDA) .......................................56
6.7
Reporting to Hospital Risk Management...............................................................56
6.8
Routine Adverse Event Reporting .........................................................................56
7.
PHARMACEUTICAL INFORMATION.......................................................................................57
7.1
Acalabrutinib maleate............................................................................................57
7.2
Umbralisib..............................................................................................................58
7.3
Ublituximab ...........................................................................................................60
8.
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES.............................................................63
8.1
BH3 Profiling.........................................................................................................63
8.2
Genomic Analyses .................................................................................................64
8.3
Adaptive ClonoSEQ Assay....................................................................................64
8.4
T Cell Profiling ......................................................................................................64
8.5
Additional Prognostic Tests...................................................................................65
8.6
Correlative Study Sample Collection Summary....................................................65
9.
STUDY CALENDAR.................................................................................................................66
10. MEASUREMENT OF EFFECT ..................................................................................................75
10.1
Imaging Evaluations ..............................................................................................75
10.2
Bone Marrow Biopsy / Aspirate ............................................................................75
10.3
Response Criteria...................................................................................................76
10.4
Definitions..............................................................................................................77
10.5
Response Review...................................................................................................77
11. DATA REPORTING / REGULATORY REQUIREMENTS .............................................................78
11.1
Data Reporting.......................................................................................................78
11.2
Data Safety Monitoring..........................................................................................78
11.3
Multi-Center Guidelines ........................................................................................78
12. STATISTICAL CONSIDERATIONS.............................................................................................79
12.1
Study Design..........................................................................................................79
12.2
Sample Size, Accrual Rate and Study Duration ....................................................79
12.3
Interim Monitoring Plan ........................................................................................79
12.4
Analysis of Primary Endpoints..............................................................................80
12.5
Analysis of Secondary and Exploratory Endpoints ...............................................80
12.6
Reporting and Exclusions ......................................................................................81
13. PUBLICATION PLAN...............................................................................................................81
REFERENCES..................................................................................................................................83
APPENDIX A: PERFORMANCE STATUS CRITERIA...........................................................................86
APPENDIX B: HEPATITIS B SEROLOGIC TEST RESULTS...................................................................87
APPENDIX C: DANA-FARBER/HARVARD CANCER CENTER MULTI-CENTER DATA SAFETY 
MONITORING PLAN ......................................................................................................................88
INTRODUCTION............................................................................................................................88
1.1
Purpose...................................................................................................................88

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2
GENERAL ROLES AND RESPONSIBILITIES.............................................................................88
2.1
External Site .........................................................................................................88
3
DF/HCC REQUIREMENTS FOR MULTI-CENTER PROTOCOLS................................................89
3.1
Protocol Revisions and Closures.........................................................................89
3.2
Informed Consent Requirements .......................................................................89
3.3
IRB Re-Approval .................................................................................................90
3.4
DF/HCC Multi-Center Protocol Confidentiality ..............................................90
3.5
Participant Registration......................................................................................90
3.6
Data Management................................................................................................92
3.7
Protocol Reporting Requirements......................................................................92
4
MONITORING: QUALITY CONTROL......................................................................................93
4.1
Ongoing Monitoring of Protocol Compliance...................................................93
4.2
Monitoring Reports .............................................................................................93
4.3
Accrual Monitoring .............................................................................................93
5
AUDITING: QUALITY ASSURANCE........................................................................................94
5.1
DF/HCC Internal Audits.....................................................................................94
5.2
Audit Notifications...............................................................................................94
5.3
Audit Reports .......................................................................................................94
5.4
External Site Performance..................................................................................94
APPENDIX D: NEW YORK HEART ASSOCIATION CLASSIFICATION.................................................95
APPENDIX E: IWCLL 2018 HEMATOLOGIC TOXICITY GUIDELINES.................................................96
APPENDIX F: ACALABRUTINIB DRUG DIARY..................................................................................97
APPENDIX G: UMBRALISIB DRUG DIARY.....................................................................................101

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LIST OF TABLES
Table 1: Umbralisib Food Effect PK Parameters .........................................................................14
Table 2: Umbralisib Formulation Effect.......................................................................................15
Table 3: PK results after the 1st (150 mg), 4th (450 mg) & 8th (450 mg) ublituximab infusion ...19
Table 4: Regimen Description......................................................................................................31
Table 5: Ublituximab Infusion Rate Cycle 7 Days 1 and 2...........................................................34
Table 6: Ublituximab Infusion Rate Cycle 7 Days 8 and 15.........................................................35
Table 7: Ublituximab Infusion Rate Cycles 8 – 12 Day 1.............................................................35
Table 8: Acalabrutinib Dose Adjustments for Concomitant Administration of CYP Agents1 ....37
Table 9: Umbralisib Dose Reductions..........................................................................................42
Table 10: Acalabrutinib Dose Reductions1,2................................................................................42
Table 11: Hematologic Toxicity Management1 ...........................................................................43
Table 12: Non-Hematologic Toxicity Management ....................................................................44
Table 13: Acalabrutinib Expected Toxicities ...............................................................................48
Table 14: Umbralisib Expected Toxicities....................................................................................49
Table 15: Ublituximab Expected Toxicities .................................................................................50
Table 16: Composition of Umbralisib Drug Product ...................................................................58
Table 17: Ublituximab Dilutions for Cycle 7 Day 1 & Day 2........................................................62
Table 18: Ublituximab Dilutions for Cycle 7 Day 8 & Beyond.....................................................62
Table 19: Correlative Sample Collection Schedule......................................................................65
Table 20: Study Calendar for All Participants, Cycles 1 - 12........................................................67
Table 21: Study Calendar for Participants in CR Cycles 13 - 37...................................................69
Table 22: Study Calendar for Participants with Recurrence/Relapse after Discontinuation of 
Therapy ........................................................................................................................................70
Table 23: Study Calendar for Participants NOT in CR Cycles 13 - 24 ..........................................72
Table 24: Response Definition Following Treatment of CLL Participants...................................75
Table 25: Accrual Targets.............................................................................................................78
Table 26: Grading Scale For Hematological Toxicity in CLL Studies1 ..........................................95

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1.
OBJECTIVES
1.1
Study Design
An open label, non-randomized phase 2 trial assessing the combination of acalabrutinib, 
umbralisib, and ublituximab in adult participants with chronic lymphocytic leukemia (CLL). 
Participants will be enrolled to one of two treatment cohorts:

Cohort 1: Participants with relapsed disease

Cohort 2: Participants who are treatment naïve
1.2
Primary Objective

Assess the rate of complete remission (CR) after 24 cycles of treatment with 
acalabrutinib, umbralisib, and ublituximab in previously untreated and relapsed CLL 
patients per 2018 IW-CLL criteria.1 
1.3
Secondary Objectives

Determine the rates of partial remission (PR) and complete remission with incomplete 
count recovery (CRi) after 24 cycles of therapy. 

Evaluate the median progression-free survival (PFS), time to next treatment (TTNT), and 
overall survival (OS), as well as the rates at 2 years, 3 years, and 5 years.

Assess the rates of CR with bone marrow minimal residual disease (MRD)-negativity, 
peripheral blood MRD-negativity, and correlation between blood and bone marrow 
MRD-negativity after 6, 12, and 24 cycles of treatment.

Determine the rate of early therapy discontinuation and time to clinical progression.

Evaluate the association between established CLL prognostic factors (including FISH 
cytogenetics, somatic mutations and IGHV mutation status) and treatment response.

Confirm the safety and tolerability of the combination.
1.4
Exploratory Objectives

Explore the association between novel CLL prognostic factors (including somatic 
mutations such as SF3B1, TP53, NOTCH1, and other mutations in the BCR/NFκB 
pathway) and rates of MRD-negativity, CR, PR, PFS, and OS.

Perform BH3 profiling and explore rates of MRD-negativity, CR, PR, PFS, and OS.

Assess the development and kinetics of BTK, PLCG2 and CARD11 somatic resistance 
mutations.

Evaluate MRD measurements by flow cytometry as compared to those of the Adaptive 
ClonoSEQ sequencing technology after 12 cycles and at the primary response (24 cycle) 
endpoint.

Assessment of baseline and on study levels of newly identified biomarker indicators of 
response and resistance.

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
Characterization of T-cell phenotype of patients treated with the combination and 
comparison to previous patients treated with single agent umbralisib. 
2.
BACKGROUND
2.1
Study Disease and Rationale 
CLL is the most common leukemia in Western countries, with about 19,000 new cases per year 
in the US. Most patients are over 70 years old at diagnosis, and over 75 when first treated. At 
this age multiple comorbidities and prescription medications are common, thereby limiting 
treatment choices in this population and making time-limited oral therapy for CLL appealing.2
CLL patients are divided according to their prognostic factors, and specifically, by the mutation 
status of the immunoglobulin heavy-chain rearrangement (IGHV), chromosomal abnormalities, 
and specific somatic mutations. Patients with deletion of the short arm of chromosome 17 
(del17p) and/or a mutated TP53 are at the highest risk. They tend to have more steadily 
progressing disease, a shorter interval before first therapy and a reduced response rate to 
standard chemoimmunotherapy (CIT).3  Patients with unmutated IGHV also have a more rapid 
progression to therapy than those with mutated IGHV, typically with good response but with 
continuous relapse and reduced durability after chemoimmunotherapy. 
Treatment, especially for older patients or those with any of the higher risk markers, is 
increasingly based on novel targeted therapies, mainly Bruton tyrosine kinase (BTK) and PI3K 
inhibitors, that usually at least partially overcome these poor prognostic factors. Although most 
CLL patients respond to these targeted agents, in both the first line and relapsed setting the CR 
rate is modest (about 10%) and the drugs are given indefinitely.4,5 MRD-negativity, which is an 
independent predictor for survival in CLL after CIT or venetoclax, is seldom achieved with BCR 
inhibitor monotherapy.6 Moreover, each drug has its own unique toxicity profile, in part due to 
off-target effects.7 Ibrutinib, the first FDA approved BTK inhibitor and most widely used 
targeted small-molecule-agent in CLL, increases bleeding risk (up to 5% high-grade bleeding) 
and the incidence of atrial fibrillation (up to 16% at 18 months) and hypertension (25% and 
rising at 36 months).8Idelalisib, a first-generation PI3Kδ inhibitor, has a characteristic 
autoimmune toxicity profile, mainly colitis, hepatitis and pneumonitis.5,9 
Targeting the B-cell receptor pathway with either inhibitors of BTK or PI3Kδ is highly effective 
for the treatment of CLL. However, deep remissions are uncommon, and drug resistance with 
single-agent therapy can occur. In vitro studies support the effectiveness of combining PI3Kδ 
and BTK inhibitors in CLL.10 Combination treatment for dual blockade of pathways downstream 
of BCR could increase the effectiveness of each single agent, enable lower dose administration 
thus minimizing side effects, and potentially prevent drug-resistance. The combination of 
ibrutinib and idelalisib has been shown to synergistically inhibit in-vitro BCR-controlled 
adhesion in both mantle cell lymphoma (MCL) cell lines and primary MCL and CLL cells. This is a 
crucial mechanism of cell survival and likely explains the surge in lymphocytosis after BTK/PI3K-
inhibitor administration.10 This combination may increase initial lymphocytosis even further, 

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although this would not be clinically meaningful. The combination of acalabrutinib, a highly 
specific BTK inhibitor, with a different PI3K inhibitor (ACP-319) in a CLL mouse model resulted in 
significantly larger reductions in tumor burden and survival compared to single-agent therapy. 
It also reduced phosphorylation of pathways downstream of NF-kB signaling.11. Our group has 
recently combined ibrutinib with umbralisib and found that the combination was tolerable, 
with encouraging PFS and an early suggestion of higher CR rate.12 
Ublituximab is a type I, chimeric, glycoengineered anti-CD20 monoclonal antibody that causes 
increased ADCC activity against B cells and shows activity as a single-agent in relapsed NHL and 
CLL patients, with an overall response rate of 50%.13 A phase 2 study of its combination with 
ibrutinib in 45 patients with relapsed CLL showed a 90% PR rate at 6 months, due to clearance 
of lymphocytosis that is usually seen with ibrutinib alone. The combination was well tolerated. 
The most common AEs were infusion-related reactions (IRRs), diarrhea, fatigue, nausea, and 
rash. Grade 3/4 AEs were mainly hematological (7-11% cytopenias) and IRRs, and 9% of subjects 
discontinued study due to AEs.14 
Previous phase 1 studies of umbralisib, a PI3K inhibitor highly selective for the δ isoform, and 
ublituximab in relapsed refractory NHL and CLL have demonstrated that the combination is well 
tolerated.15 A recent phase 1/2 trial combining ibrutinib, umbralisib and ublituximab has 
established that the triplet is also well tolerated and can be given at the full phase 2/3 doses of 
each drug (see Section 2.5).16 
There had been some concern that ibrutinib would interfere with anti-CD20 antibodies’ activity. 
In-vitro data suggested that the off-target inhibition of ITK by ibrutinib would lead to decreased 
NK-mediated ADCC with rituximab17 which was largely overcome with the Fc engineered 
obinutuzumab. However, this has not been shown in-vivo, and ublituximab is more similar to 
obinutuzumab. Moreover, ibrutinib was shown to downregulate CD20 expression in samples 
from patients’ blood. Ex-vivo, tumor cells from patients on ibrutinib were less susceptible to 
anti-CD20 mAb-mediated complement-dependent-cytotoxicity (CDC), although opsonization by 
the complement protein C3d, which targets cells for phagocytosis, was relatively maintained. 
Interestingly, ibrutinib significantly inhibited trogocytosis, which is a major contributor to 
antigen loss and tumor escape during mAb therapy.18,19 While the significance of these data are 
conflicting and unclear, clinical trials combining ibrutinib with anti-CD20 antibodies have shown 
no evidence of antagonism, although it is unclear that the antibody significantly increases CR 
rates when given early in therapy, nor does rituximab increase PFS.20,21 
Acalabrutinib is a second-generation FDA approved BTK inhibitor that is highly specific for BTK. 
While a head-to-head comparison study has not been done, clinical data reported from 
separate clinical trials have indicated acalabrutinib is likely typically better tolerated by patients 
and has fewer off-target side effects than ibrutinib, including less cardiac toxicity.22 
Incorporating the more specific next-generation kinase inhibitors in therapy shows marked 
activity with less off-target activity. 

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Furthermore, recent in-vitro data suggests that acalabrutinib, as opposed to ibrutinib, has 
favorable activity against CLL cells together with CD20 antibodies, and does not mitigate ADCC, 
likely because it is a much more specific inhibitor of BTK.23 A later antibody administration, 
when disease is already reduced, is also employed here, as it should lead to more favorable 
antibody pharmacokinetics and perhaps better clearance of residual disease.  This hypothesis 
has some support from an ASH abstract presented in 2018, which suggested that delayed 
administration of obinutuzumab with ibrutinib resulted in a significantly higher CR rate than 
early obinutuzumab administration.24
We therefore plan to build on the prior phase 1 experience with ibrutinib-umbralisib and 
ibrutinib, umbralisib, ublituximab, by substituting acalabrutinib in a phase 2 study of the three-
drug combination. From data available from separate clinical studies, acalabrutinib appears to 
be better tolerated than ibrutinib so this should not cause any unexpected toxicity. This study 
targeting less heavily pretreated patients will better establish the efficacy of the combination as 
measured by CR rate and PFS in untreated CLL patients and early relapsed patients.
The trial will have another two novel therapeutic approaches. First, ublituximab administration 
will be delayed in an attempt to improve its ability to clear residual bone marrow disease at a 
point when significant cytoreduction has already occurred and the half-life of the antibody 
should be prolonged. Second, treatment will be given for only 12 – 24 cycles, thus mitigating 
long-term adverse events and potentially reducing selection pressure for resistant clones. 
Patients who are not heavily pre-treated, especially those who are treatment-naïve, may 
benefit from a long drug-free period before they progress, at which time they could 
theoretically receive the same regimen again. 
2.2
Umbralisib (TGR-1202)
Umbralisib is a highly-specific and orally available phosphoinositide-3-kinase (PI3K) delta (δ) 
inhibitor with nanomolar inhibitory potency, and high selectivity over the alpha, beta, and 
gamma Class I isoforms of PI3K.  The PI3Ks are a family of enzymes involved in various cellular 
functions, including cell proliferation and survival, cell differentiation, intracellular trafficking 
and immunity.  The delta isoform of PI3K is highly expressed in cells of hematopoietic origin, 
and strongly upregulated, and often mutated in various hematologic malignancies.  
2.2.1
Preclinical Evaluations of Umbralisib 
The potency of umbralisib against the human and mouse δ isoform of PI3K was 
evaluated in a homogeneous time resolved fluorescence (HTRF) based enzyme assay in the 
presence of ATP at its Km value (100 μM) (Umbralisib Investigator Brochure). Selectivity 
over the other three isoforms, namely, α, β, and γ was also determined. 25-27 
Data demonstrated the specificity of umbralisib towards PI3Kδ with >1000, 50 and 48-fold 
selectivity over α, β, and γ, respectively in an enzyme-based assay, indicating that the primary 
mode of action of this compound is via inhibition of the δ isoform.

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Figure 1: Umbralisib Potency Against 
Human and Mouse PI3K Isoforms
PI3K isoforms 
(Human)
IC50 (nM)

>10,000

1,116

1,065

22.23
Proliferation of immortalized leukemic cells representative of various indications was 
determined by a MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assay 
(Umbralisib Investigator Brochure). Cells were incubated with umbralisib for different time-
periods (72 -96 h) based on their doubling time. Data demonstrated the ability of umbralisib 
to inhibit leukemic cell proliferation albeit with different potencies based on the cell type.
Overall, a 50% growth inhibition for majority of B, T, and monocytic cell lines was achieved 
at a concentration between 0.5 -7.5 μM of umbralisib.
Subsequent to cell viability, the effect of umbralisib on AKT phosphorylation (Umbralisib 
Investigator Brochure) was determined. AKT, a serine threonine kinase, mediates the 
downstream effects of PI3K activity and modulates several cell processes including survival 
and growth. Reduction of phosphorylated AKT by umbralisib in representative cell lines was 
determined by Western blotting using a phospho-AKT (Ser473) antibody.
FIGURE 2: REDUCTION OF PAKT BY 
UMBRALISIB IN CELL LINES BY WESTERN 
BLOTTING
In vivo efficacy of umbralisib was confirmed in a subcutaneous mouse MOLT-4 xenograft 
model. Oral administration of 150 mg/kg/QD over a 25-day period resulted in a significant 
delay in tumor growth.

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FIGURE 3: UMBRALISIB IN VIVO 
EFFICACY
2.2.2
Toxicology
To assess the safety and toxicity of umbralisib a 28-day repeat dose study with a 14-day 
recovery period was conducted in CD-1 mice and beagle dogs, to evaluate the potential 
reversibility of findings and to support the use in humans.  Umbralisib was administered orally 
in order to mimic the planned mode of clinical administration.      
Once daily oral administration of umbralisib was tolerated in mice at free base dose levels of 50 
and 150 mg/kg/day.  Increases in liver weights, microscopic findings in the liver and the 
increases in serum cholesterol, and female only ALT, AST, and GGT levels were observed at 750 
mg/kg/day of free base (the highest dose tested) and were considered adverse. The no-
observed-adverse-effect level (NOAEL) was considered to be 150 mg/kg/day in mice. 
Once daily oral administration by capsule of umbralisib was well tolerated in dogs at levels of 
50 and 150 mg/kg/day.  The gastrointestinal tract, based on clinical signs, was the target organ 
system.  Based on effects on body weight and the incidence and severity of emesis and 
diarrhea, the NOAEL was considered to be 150 mg/kg/day (114.5 mg/kg/day as free base) in 
this species.
Refer to the Umbralisib Investigator’s Brochure (IB) for detailed information on toxicology 
studies conducted to date.
2.2.3
Clinical Development of Umbralisib 
2.2.3.1
Single-Agent in Subjects with Relapsed or Refractory Hematologic Malignancies
Umbralisib was evaluated in a single-agent Phase I dose-escalation study (Study TGR-1202-101; 
NCT01767766) in subjects with relapsed and refractory hematologic malignancies. There were 
90 subjects enrolled and eligible for safety evaluation, and 73 subjects evaluable for efficacy in 
the modified intention to treat population.  The median age was 64 years (range 51-72), 63% 
male, median number of prior therapies was 3, and 49% of subjects were refractory to their 
most recent prior therapy.  Histological diagnoses included; CLL (n=24), FL (n=22), DLBCL (n=16), 
HL (n=11), MCL (n=6), MZL (n=5), WM (n=2), HCL and TCL (n=1 each).  The majority of subjects 
(58%) had received 3 or more prior therapies.   

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Patients were enrolled in a 3+3 dose-escalation design starting at 50 mg QD with subsequent 
cohorts evaluating doses as high as 1800 mg QD.  In an effort to further improve the oral 
bioavailability of umbralisib, the particle size of the drug product was reduced through a 
micronization process, resulting in greater absorption when tested in a bioequivalence 
crossover study in healthy subjects. This micronized formulation was introduced into dose 
escalation at 200 mg QD and dosed as high as 1800 mg QD.  The maximum tolerated dose 
(MTD) was 1200 mg QD of the micronized formulation, with 800 mg of this formulation 
selected as the recommended phase 2 dose based on changes in tumor burden correlated with 
dose-proportional plasma exposure.  Intra-subject dose escalation rules allowed subjects 
enrolled into the study in early cohorts to increase their dose of umbralisib as subsequent 
higher cohorts cleared safety evaluation.  The most common treatment-emergent adverse 
events irrespective of causality were diarrhea (in 39 [43%] of 90 subjects), nausea (38 [42%]), 
and fatigue (28 [31%]).  The most common grade 3 or 4 adverse events were neutropenia (in 12 
[13%] subjects), anemia (eight [9%]) and thrombocytopenia (six [7%]).  Serious adverse events 
considered at least possibly related to umbralisib occurred in seven subjects: pneumonia in 
three (3%) subjects, lung infection in one (1%), febrile neutropenia in one (1%), and colitis in 
two (2%), one of whom also had febrile neutropenia.  Both cases of colitis occurred above the 
recommended phase 2 dose.  No time-related trends in toxicity were noted.  See the umbralisib 
investigator’s brochure for a complete overview of the umbralisib side effect profile.  
Dosing of umbralisib initially occurred in the fasting state, but was transitioned mid-study to fed 
state dosing, with subjects instructed to take umbralisib with food.  All dosing of umbralisib is 
now conducted using the micronized formulation and in the fed state.  
Among 73 subjects in the modified intention-to-treat population, which included subjects who 
received at least 800 mg per day of the original formulation or any dose of the micronized 
formulation and had at least one response assessment, 53 (73%) had reductions in disease 
burden, including 33 (45%) subjects with reductions of 50% or more, of which three (4%) were a 
complete response and 30 (41%) were a partial response.  In subjects with relapsed or 
refractory CLL, 17 (85%) of 20 achieved an objective response, with ten (50%) achieving an 
objective response per 2008 IWCLL criteria, seven (35%) achieving a partial response with 
lymphocytosis, and the remaining three (15%) achieving stable disease.  Of eight assessable 
subjects with CLL who had high-risk cytogenetic features, six (75%) had a response, of whom 
two (25%) had a partial response with lymphocytosis, and the remainder had stable disease.  In 
subjects with follicular lymphoma, nine (53%) of 17 subjects achieved an objective response, 
including two (12%) who achieved a complete response; the remainder had a partial 
response.  In subjects with diffuse large B-cell lymphoma, four (31%) of 13 achieved an 
objective response and two (15%) further subjects achieved stable disease.  Responses for the 
other subject subgroups were Hodgkin lymphoma: one complete response, four stable disease, 
four progressive disease; marginal zone lymphoma: one partial response, four stable disease; 
Waldenström’s macroglobulinemia: two stable disease; and mantle cell lymphoma: one partial 
response, four stable disease, and one progressive disease.  In a post-hoc exploratory analysis, 
tumor reductions in most subjects with indolent lymphoma and CLL treated with umbralisib 

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tended to improve over time.  The mean duration of response was 13.4 months (95% CI 7.7–
19.1) in 16 subjects in the CLL cohort, 6.4 months (4.5–17.3) in four subjects in the DLBCL 
cohort, and 9.3 months (3.6–15.1) in nine subjects in the follicular lymphoma cohort.  In a post-
hoc exploratory analysis of progression-free survival, median progression-free survival was 24.0 
months (95% CI 7.4 months–not reached) in 20 subjects with CLL, and 16 months (9.2 months–
not reached) in 24 subjects with indolent non-Hodgkin lymphoma (follicular lymphoma, 
Waldenström’s macroglobulinemia, and marginal zone lymphoma).  Overall, umbralisib was 
well tolerated and displayed promising signs of clinical activity at the higher dosing cohorts.  
Umbralisib monotherapy is being studied in a registration directed trial in various NHL subtypes 
(Study UTX-TGR-205 [UNITY-NHL]; NCT02793583).
2.2.3.2
Healthy Subject Pharmacokinetic Studies
In parallel with the Phase 1 single-arm, dose-escalation study in patients with relapsed or 
refractory hematologic malignancies; two healthy subject, crossover, bioequivalence 
pharmacokinetics studies have been completed. The first pharmacokinetic study was a Phase 
1 drug-food interaction study with a single 200 mg oral dose of umbralisib in healthy 
volunteers followed by a second single dose Phase 1 pharmacokinetic study evaluating the 
absorption, distribution, metabolism and excretion characteristics of two different oral 
formulations of 200 mg umbralisib (original formulation vs. micronized formulation) in 
healthy volunteers.
2.2.3.3
Food Effect
Study TGR-1202-PK 101 was two-period, randomized, two-way crossover, drug-food, drug-
gender interaction study in 24 healthy subjects (12 males and 12 females) to assess the mean 
plasma umbralisib concentration over time following a single oral dose of 200 mg of umbralisib 
under fasting and fed condition using the original formulation. In general, administration of 
umbralisib under fed conditions results in a higher rate of exposure relative to when the 
product was given under fasting conditions.
The statistical comparisons of umbralisib pharmacokinetic parameters under fasted and fed 
condition are shown below.
Table 1: Umbralisib Food Effect PK Parameters
Geometric LS 
Parameters
Fasting
Fed
% Geometric Mean 
Ratio
Confidence 
Interval
AUC0-t (ng∙hr/mL)
6029.87
9692.02
160.73
140.25 – 184.21
AUC0-inf (ng∙hr/mL)
8391.35
14047.17
167.40
141.59 – 197.92
Cmax (ng/mL)
176.78
483.15
273.31
234.04 – 319.17
Food increased both the extent and rate of exposure of umbralisib. The extent (AUC0-t) and 
total extent (AUC0-inf) of exposure increased by 61% and 67%, respectively, when umbralisib 

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was administered under fed conditions compared to fasting conditions. The peak plasma levels 
of umbralisib increased by over 173% when umbralisib was administered with food.
Using these mean values, a 334 mg oral dose of umbralisib under fasted condition can be 
extrapolated to be equivalent to an oral dose of 200 mg of umbralisib under fed conditions in 
terms of exposure based on AUC0-inf.
2.2.3.4
Formulation Effect
Study TGR-1202-PK 102 was a two-period, randomized, two-way cross over, relative 
bioavailability and pharmacokinetic bioequivalence study with two different drug product 
formulations of umbralisib. In this study, umbralisib was administered under fasted 
conditions in 24 healthy subjects (12 males and 12 females) to assess the mean plasma 
umbralisib concentration over time following a 200 mg single dose of the original drug 
product formulation and modified (micronized) drug product formulation of umbralisib. The 
mean rate and extent of exposure to umbralisib were higher following administration of the 
micronized drug product formulation compared to the original drug product formulation as 
mean concentrations were higher throughout most of the sampling interval.
Table 2: Umbralisib Formulation Effect
Geometric LS Means
Parameters
Original 
Formulation
Micronized Formulation
% Geometric 
Mean Ratio
Confidence 
Interval
AUC0-t (ng∙hr/mL)
5906.11
9439.82
159.83
149.43 – 170.95
AUC0-inf (ng∙hr/mL)
7715.67
12378.19
160.43
146.49 – 175.70
Cmax (ng/mL)
166.20
371.70
223.65
202.33 – 247.20
The micronized drug product formulation increased both the extent and rate of exposure of 
umbralisib under fasted conditions. The extent (AUC0-t) and total extent (AUC0-inf) of 
exposure both increased by 60%, respectively, following administration of the modified drug 
product formulation relative to original drug product formulation. The Peak plasma (Cmax) 
levels of umbralisib increased by over 124% following administration of the micronized drug 
product formulation relative to original drug product formulation under fasted conditions.
Using these mean values, a 320 mg oral dose of umbralisib in the original formulation under 
fasted condition can be extrapolated to be equivalent to an oral dose of 200 mg of the original 
formulation umbralisib under fasted conditions in term of exposure based on AUC0-inf.
The improved exposure seen with the micronized formulation of umbralisib was confirmed in 
patients in the Phase 1 dose escalation as well. The chart below illustrates the pre-dose 
plasma concentrations of umbralisib on Day 1 of Cycle 2 in patients administered equivalent 
doses of either the initial formulation in the fasting state or the micronized formulation in the 
fed state.

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2.3
Ublituximab (TG-1101)
Ublituximab is a novel third generation chimeric anti-CD20 monoclonal antibody bioengineered 
for potent activity, exhibiting a unique glycosylation profile with a low fucose content, designed 
to induce superior antibody-dependent cytotoxicity (ADCC).  Ublituximab exhibits competitive 
complement-dependent cytotoxicity (CDC), on par with rituximab, and has also been 
demonstrated to induce programmed cell death (PCD) upon binding to the CD20 antigen on B-
lymphocytes.  Ublituximab has a unique protein sequence, and targets epitopes on CD20 not 
targeted by rituximab or ofatumumab, both currently approved anti-CD20 antibodies.28
2.3.1
Pre-Clinical Development Of Ublituximab
2.3.1.1
In-Vitro Activity
In an in-vitro assay using B-CLL cells from patient donors, ublituximab demonstrated an 
enhanced ability to kill CLL cells compared to rituximab.  Ublituximab demonstrated improved 
Fcγ receptor IIIA (FcγRIIIA)/CD16 binding and FcγRIIIA dependent effector functions compared 
to rituximab.  Additionally, ublituximab induced higher in vitro ADCC against CLL cells, and a 
higher FcγRIIIA mediated interleukin-2 (IL2) production by FcγRIIIA+ Jurkat cells.29 Ublituximab 
demonstrated high ADCC against both patient-derived CLL cells and NHL cell lines.  
Ublituximab’s engagement to FcγRIIIA triggers a stronger NK cell cytotoxicity against CLL as 
compared to rituxan (in vitro) despite CD20 density, likely related to the glycosylation pattern.29 
2.3.2
In Vivo Activity
The antitumor effect of ublituximab was compared to that of rituximab with chemotherapy in 
follicular lymphoma (FL), and mantle cell lymphoma (MCL) xenograft murine models.  Single 
agent ublituximab demonstrated dose-related anti-tumor activity with 100% tumor growth 
inhibition in the FL xenograft at a dose of 100mg/kg, and a superior tumor growth delay (21 
days) compared to rituximab. Ublituximab also demonstrated superior anti-tumor activity 
compared to rituximab against MCL xenografts at all dose levels.28

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2.3.2.1
Toxicology
In single-dose and repeat dose toxicology studies performed under GLP, ublituximab displayed 
a safety profile similar to what might be expected for anti-CD20 monoclonal antibodies. Single 
administration of up to 100 mg/kg ublituximab in cynomolgus monkeys was well tolerated, with 
no local irritation with intravenous administration.  Genotoxicity studies (Ames test) showed 
that ublituximab was not mutagenic.  Monkeys that received a single injection of 0.3 mg/kg of 
ublituximab developed an anti-ublituximab response, whereas anti-ublituximab antibodies 
were not detected in the animals which received 10 or 100 mg/kg (see Ublituximab Investigator 
Brochure).
2.3.3
Clinical Development of Ublituximab
Ublituximab has been studied in a variety of patient populations, both as a single agent, and in 
combination with other agents, with over 1,000 patients having received ublituximab therapy 
to date across all studies. Two Single-Agent Phase I/Ib trials have been conducted with 
ublituximab treating both NHL and CLL patients.  Further, following demonstration of safety and 
tolerability in these early single agent studies, Phase I and II combination studies were 
undertaken with a variety of agents.  Given the number of patients who have received 
ublituximab in early-phase trials, the safety and side effect profile of the agent is well 
characterized.  Summaries of the single-agent experience are provided below as well as data 
with use of ublituximab in combination with ibrutinib.
In a two part, first-in human dose escalation study (protocol CD20-0703), patients with relapsed 
or refractory CLL  received one weekly infusion of single agent ublituximab for 4 doses in a 3+3 
dose escalation design through 5 sequential dose levels.  Part II of the study was a dose-
confirmation component which used an initial dose of 150 mg followed by 7 doses of 450 mg 
(total dose 3300 mg) – the clinical summary will focus on the Part II part of the study as the 
dose is more relevant to the clinical application used in current clinical studies.  In Part II, 12 
patients were enrolled at 9 centers in France and followed for 12 months. Demographic data 
for the 12 patients enrolled in the study were as follows.  The median age was 69.5 years [62–
77]; median time from diagnosis to inclusion was 10.4 years [4.0–23.6] and median prior 
therapies was 3 [1–8].  Seven patients (58%) received at least one prior rituximab-containing 
regimen.  The median lymphocyte bone marrow infiltration was 85% [40–94].
Most frequent drug-related adverse events (AE’s) reported were infusion related reactions (IRR) 
(75% of the patients, including 33% of patients with Grade 3 IRR).  Other Grade 3/4 AE’s > 10% 
included: neutropenia (67%) and increase ALT/AST (17%).  All AEs were reversible 
spontaneously or with supportive care intervention.  None of the reported adverse events were 
considered as a dose-limiting toxicity according the judgment of the study Safety Committee.  
Therefore, the maximum tolerated dose was not reached in this study.  Significant blood 
lymphocyte depletion was observed in all patients:  median lymphocyte count at baseline was 
46.6 (x109/l); after 1 month (M1) = 1.5 (↓94%); M4=1.4 (↓91%) and M6=2.0 (↓89%). No cases 
of serum anti-ublituximab antibodies were detected at any time point. 

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Clinical response was based on the criteria established by the National Cancer Institute (NCI)-
Working Group updated in 2008. All patients but one received the planned 8 infusions without 
any dose reduction--one patient was prematurely withdrawn due to a concomitant secondary 
leukemia unrelated to ublituximab therapy.  Response was evaluated at month 4 for the 11 
evaluable patients, with an initial response rate of 64% (7/11) with a confirmed response at 
month 6 in 5/11 patients (45%) patients (all PRs).  Four of the 11 patients achieved stable 
disease.  At the 1 year follow-up, no responders had progressed, demonstrating all confirmed 
responses were durable despite no ublituximab maintenance therapy.  The median 
progression-free survival (PFS) was not reached at the 12 month follow-up.30
A phase I trial of ublituximab (Study TG-1101-101; NCT01647971) was subsequently undertaken 
in subjects with B-cell lymphoma or CLL who were relapsed or refractory to a prior rituximab 
containing regimen.  This trial utilized a 3+3 design, assessing dose levels of 450, 600, 900, and 
1200 mg. Patients with CLL/SLL received treatment on days 1, 8 and 15 during cycles 1 and 2 
(28-day cycles) followed by maintenance ublituximab on day 1 of cycles 3–6, then every 3 
months for a maximum of 2 years.  Patients with NHL were treated with the same schedule 
except for the omission of the Cycle 2 doses.  For CLL subjects, Cycle 1 Day 1 infusions were split 
(up to 150 mg administered on Day 1 and up to 750 mg administered on Day 2).  No dose-
limiting toxicities (DLTs) were observed, hence no MTD was identified.  There was no significant 
difference in the overall number of AEs among the four dose cohorts.  There appeared to be no 
difference in ORR between 900 and 1200 mg, with a slightly higher incidence of hematological 
AEs observed (grade 3 neutropenia, anemia, and thrombocytopenia) at the 1200-mg dose 
level.  Hence, 900 mg was selected as the recommended phase 2 dose.
All 35 subjects enrolled were evaluable for safety.  IRRs occurred in 14 (40%) subjects and were 
more prevalent among subjects with CLL.  The majority of IRRs occurred on C1D1, with only 5 
occurring on subsequent cycles.  No episodes of grade ≥ 3 IRR were reported.  All IRRs were 
manageable with infusion interruptions, and all subjects recovered without 
repercussion.  Other common AEs included fatigue (37%), pyrexia (29%) and diarrhea 26%, 
which were all grade 1 or 2 except for 1 subject with grade 3 fatigue.  Laboratory abnormalities 
included neutropenia (14%; grade 3/4, 14%), thrombocytopenia (6%; grade 3/4, 6%) and 
anemia (11%; grade 3/4, 6%).  No infections were associated with grade 3/4 neutropenia, and 
no bleeding accompanied thrombocytopenia.  See the ublituximab investigator’s brochure for a 
complete overview of the ublituximab side effect profile.
Among response evaluable subjects, the ORR was 44% (11/25) and 50% (3/6) in subjects with 
NHL and CLL, respectively.  Of 6 evaluable CLL subjects, 5 (83%) had an absolute lymphocyte 
count (ALC) > 4.0 x 109/l at study entry (range 3.055–165.996 x 109/l).  A rapid depletion in 
circulating lymphocytes was observed in all 6 CLL subjects, with most subjects achieving a > 50% 
reduction within 7 days of the first infusion, and all 6 CLL subjects achieved an ALC < 4.0 x 109/l 
within the first cycle.  Among 12 follicular lymphoma subjects, 5 subjects responded (42%) 
including 2 CRs (17%) and 3 PRs (25%).  Of 7 MZL subjects, there were 5 responders (71%) 
including 2 CRs (29%) and 3 PRs (43%). 

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2.3.3.1
Pharmacokinetics
After infusion of ublituximab (previously known as LFB-R603) at a 150 mg dose followed by 
seven weekly injection infusions at 450 mg, results suggested non-linear pharmacokinetics with 
respect to dose (450 mg vs. 150 mg) and time (week 4 vs. week 8) and more than proportional 
increase of Cmax and AUC∞ due to a clearance decrease.  The volume of distribution at steady 
state was small (~5 L), approximately equal to blood volume.   These non-linear 
pharmacokinetics may be explained by binding of ublituximab to its target, with a large 
component of target-mediated elimination after the first dose that is decreased after 
subsequent infusions due to a reduction in the available target.  However, limited data for each 
dose level cohort and considerable variability in baseline patient characteristics, particularly in 
terms of tumor burden, make firm conclusions difficult.
A summary of non-compartmental PK parameters after the first, the fourth and the eighth 
infusion of ublituximab are presented in the table below.
Table 3: PK results after the 1st (150 mg), 4th (450 mg) & 8th (450 mg) ublituximab infusion
PK
Parameters a
1st Infusion
150 mg  (Day 1)
4th Infusion
450mg  (Day 22)
8th Infusion
450 mg  (Day 50)
N
12
11
11
Cmax (mg/L)
23.4 ± 11.2
168.6 ± 61.8
220.5 ± 141.9
tmax (h)
9.0 (5.0-30.3)
5.00 (3.1-52.0)
5.1 (3.1-23.5)
AUC∞ (mg.h/L)
732.1 ± 590
17890 ± 17730*
50760 ± 74460
t1/2term (h)
13.43± 10.2
80.7 ± 58.5*
147.8 ± 133.8
CL (mL/h)
424.2 ± 389.3
57.69 ± 42.91
38.62 ± 26.63
Vd/Vdss, (L)
4.8 ± 2.1
4.9 ± 2.3*
5.7 ± 3.3
a mean ± SD, tmax: median (range) , with respect to the start of infusion                                             
*Accurate determination not possible
Concentration was still measurable in at least one patient of the cohort up to day 169. Values 
for Cmax and AUC increased from the first to the eighth infusion whereas t1/2 term decreased.
2.3.3.2
Ublituximab in Combination with Umbralisib
The combination of ublituximab and umbralisib (TGR-1202) is currently under evaluation in 
registration trials in CLL and various B cell NHL histologies.  Preliminary results of an ongoing 
Phase I/Ib study in patients with relapsed or refractory NHL and CLL have been reported.31  In 
early cohorts, patients received ublituximab on days 1, 8 and 15 of Cycles 1 & 2, then on day 1 
of Cycles 4, 6, 9, and 12.  In later cohorts, the ublituximab administration schedule was 
amended to infusions on days 1, 8, and 15 of Cycle 1, followed by Day 1 of Cycles 2 through 6.  
CLL patients receive Cycle 1, Day 1 infusions split over Days 1 and 2.  TGR-1202 is taken once 
daily until patients are removed from study as per the protocol. A 3+3 dose-escalation design is 
being utilized to evaluate sequentially higher doses of the combination agents.

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As of December 1, 2015, 71 patients have been enrolled and are evaluable for safety, with 58 
patients evaluable for efficacy.  The median age was 65 years (range 26 – 86), 47 Male/24 
Female, with histologies as follows: 24 DLBCL, 19 CLL/SLL, 19 FL, 6 MZL, 2 MCL, and 1 patient 
with Richter’s Transformation.  Patients had a median of 3 prior therapies, and 58% were 
refractory to prior therapy.  
Among the 71 patients evaluable for safety, nausea was the most prevalent adverse event 
(46%), followed by diarrhea (44%), fatigue (41%), neutropenia (30%), and infusion related 
reaction (25%).  Seven patients had their dose of TGR-1202 reduced due to various adverse 
events.  IRR and neutropenia were managed through dose delays, with 1 CLL patient having a 
neutropenia related dose delay which met the criteria for a DLT, necessitating enrollment of 
additional CLL patients into Cohort 1.  Overall 8% of patients have discontinued TGR-1202 due 
to an adverse event.  
Sixteen DLBCL patients treated with ublituximab + TGR-1202 were treated with therapeutic 
doses, amongst whom, the overall response rate was 31% with three patients experiencing a 
complete remission as confirmed by independent review. Amongst the five patients who 
responded, three had GCB subtype, while the other two patients subtype was not known.  
Overall, the preliminary data suggests the combination of ublituximab and TGR-1202 is well 
tolerated and active in patients with relapsed or refractory hematologic malignancies.  The 
combination of ublituximab and umbralisib is in registration directed trials in CLL (Study UTX-
TGR-304 [UNITY-CLL]; NCT02612311), and various NHL subtypes, (Study UTX-TGR-205 [UNITY-
NHL]; NCT02793583).  See the latest Investigator’s Brochure for updated information regarding 
the clinical development of ublituximab and umbralisib as single-agents or in combination.
2.4
Acalabrutinib (CALQUENCE®, ACP-196)
Acalabrutinib is a small-molecule inhibitor of BTK. Acalabrutinib and its active metabolite, ACP-
5862, form a covalent bond with a cysteine residue in the BTK active site, leading to inhibition 
of BTK enzymatic activity. BTK is a signaling molecule of the B cell antigen receptor (BCR) and 
cytokine receptor pathways. In B cells, BTK signaling results in activation of pathways necessary 
for B-cell proliferation, trafficking, chemotaxis, and adhesion. In non-clinical studies, 
acalabrutinib inhibited BTK mediated activation of downstream signaling proteins CD86 and 
CD69 and inhibited malignant B-cell proliferation and survival.
Acalabrutinib first received FDA approval in 2017 for the treatment of mantle cell lymphoma 
(MCL) in patients who have received at least one prior therapy. Please refer to the FDA package 
insert and acalabrutinib Investigator’s Brochure (IB) for full background information.

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2.4.1
Key Risks Associated with Acalabrutinib Include the Following
2.4.1.1
Hemorrhage
Serious hemorrhagic events, including central nervous system, respiratory, and 
gastrointestinal hemorrhage, have been reported in clinical trials with acalabrutinib; 
some of these bleeding events resulted in fatal outcomes. Grade 3 or higher 
bleeding events, including gastrointestinal, intracranial, and epistaxis have been 
reported in 2% of patients. Overall, bleeding events including bruising and petechiae 
of any grade occurred in approximately 50% of patients with hematological 
malignancies. 
The mechanism for hemorrhage is not well understood. Acalabrutinib may further 
increase the risk of hemorrhage in patients receiving antiplatelet or anticoagulant 
therapies and patients should be monitored for signs of bleeding. Consider the 
benefit-risk of withholding acalabrutinib for 3-7 days pre- and post-surgery 
depending on the surgery and the risk of bleeding.  
2.4.1.2
Infection
Serious infections (bacterial, viral or fungal), including fatal events and opportunistic 
infections, have been reported in clinical studies with acalabrutinib.  The most 
frequently reported Grade 3 or 4 infection was pneumonia.  Across the acalabrutinib 
clinical development program (including subjects treated with acalabrutinib in 
combination with other drugs), cases of hepatitis B virus (HBV) reactivation 
(resulting in liver failure and death in 1 case) and cases of progressive multifocal 
leukoencephalopathy have occurred in subjects with hematologic malignancies.  
Monitor patients for signs and symptoms of infection and treat as medically 
appropriate.
2.4.1.3
Cytopenias
Treatment-emergent Grade 3 or 4 cytopenias including neutropenia, anemia, and 
thrombocytopenia have occurred in clinical studies with acalabrutinib.   Subjects 
should be closely monitored as appropriate.
2.4.1.4
Second Primary Malignancies
Events of second primary malignancies, including non-skin carcinomas, have been 
reported in clinical studies with acalabrutinib.  The most frequently reported second 
primary malignancy was skin cancer.  Advise protection from sun exposure. 

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2.4.1.5
Atrial Fibrillation
Events of atrial fibrillation/flutter have been reported in clinical studies with 
acalabrutinib, particularly in subjects with cardiac risk factors, hypertension, 
diabetes mellitus, acute infections, and a previous history of atrial fibrillation. The 
mechanism for atrial fibrillation is not well understood.    
2.5
Umbralisib and Ibrutinib ± Ublituximab
Our group studied the doublet combination of umbralisib and ibrutinib in a phase 1 study of 
patients with relapsed or refractory CLL or mantle cell lymphoma (NCT02268851).12 A total of 
42 participants were analyzed for safety and efficacy, 21 of whom had CLL. CLL participants 
enrolled to the dose escalation received treatment with ibrutinib at 420 mg and umbralisib at 
400, 600, or 800 mg. No DLTs were observed and an MTD was not reached. An expansion 
cohort of 12 CLL patients received treatment with ibrutinib at 420 mg and umbralisib at 800 
mg. Toxicities were manageable and consistent with expected adverse events for both agents. 
The most common adverse events of any grade among all participants were diarrhea (n = 22, 
52%), infection (n = 21, 50%), nausea (n = 18, 43%), neutropenia (n = 17, 40%), fatigue (n = 16, 
38%), thrombocytopenia (n = 10, 33%), hyperglycemia (n = 12, 29%), anemia (n = 8, 27%), 
transaminitis (n = 10, 24%), and dizziness (n = 9, 21%). Nineteen CLL participants (90%) 
experienced a response, defined as CR, PR, or PR with lymphocytosis. Six (29%) participants 
achieved CR and 13 (62%) PR. Median PFS and OS were not reached, with 2-year OS 95% and 2-
year PFS 90%.12
The triplet combination of ublituximab, umbralisib and ibrutinib was previously evaluated as 
part of a phase 1 trial in participants with advanced B-cell malignancies (NCT02006485).16 
Umbralisib, ublituximab and ibrutinib were administered to a total of 46 participants. The 
recommended dose for the combination was umbralisib at 800 mg orally once daily, ibrutinib 
orally once daily at either 420 mg for CLL participants or 560 mg for non-Hodgkin lymphoma 
participants (the FDA recommended dose for the respective diagnoses), and ublituximab at 900 
mg IV on days 1, 8, and 15 of cycle 1, day 1 of cycles 2 – 6, and day 1 of cycles 9 and 12. The 
regimen was well tolerated, an MTD was not reached. The most common adverse events of any 
grade were diarrhea (n = 27, 37%), fatigue (n = 23, 50%), infusion-related reaction (n = 20, 43%), 
dizziness (n = 17, 37%), nausea (n = 17, 37%), cough (n = 16, 35%), insomnia (n = 15, 33%), 
neutropenia (n = 15, 33%), pyrexia (n = 15, 33%), thrombocytopenia (n = 13, 28%), and 
peripheral edema (n = 12, 26%). Grade 3/4 adverse events were infrequent, the most common 
being neutropenia (n = 10, 22%) and cellulitis (n = 6, 13%). Four patients (9%) experienced 
grade 3 diarrhea, no grade 4 diarrhea was reported. No deaths due to treatment-related 
adverse events were reported.16 
A total of 44 participants were evaluable for response, including 18 CLL participants. Among 
those 18, 8 (44%) achieved a CR and 10 (56%) achieved a PR. Nine CLL participants were 
analyzed for MRD, 7 (78%) had no MRD, 3 (33%) achieved CR, and 4 (44%) achieved PR. The 
median duration of response for CLL or small lymphocytic leukemia participants was 22.7 

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months (IQR 8.6 – 25.9), median PFS in all participants was 38.2 months, and median PFS in CLL 
participants was not reached.16
2.6
Correlative Studies Background
2.6.1
BH3 Profiling
This study will incorporate a laboratory technique known as BH3 profiling, which is a functional
assay we previously developed that detects the proximity of malignant cells to the threshold of
apoptosis (what we call ‘priming’) through physiologic interrogation of BCL-2 family members.32 
To perform a BH3 profile, we add individual BH3-only peptides to gently permeabilized primary 
CLL cells and use fluorescence activated cell sorting (FACS) to determine the amount of 
mitochondrial depolarization induced by each peptide, as measured by cytochrome c release. 
We previously found that in a small, heterogeneously treated cohort of CLL patients, increased 
priming was associated with improved clinical response.33 Building on these initial studies, we 
will incorporate BH3 profiling into this clinical trial to determine whether priming predicts 
degree of clinical response in this larger, homogeneously treated patient population.
2.6.2
Genomic Markers
We will perform whole exome sequencing (WES) on CLL cells and normal tissue from patients at 
baseline to evaluate for somatic mutations that may confer drug sensitivity and resistance. Our 
group and others have recently identified recurrent somatic mutations in the CLL genome 
which appear to associate with prognosis; these include NOTCH1 and SF3B1.34 At present, 
whether other recurrent mutations associate with prognosis is less clear. Our group has also 
recently found that the presence of subclonal driver mutations was associated in retrospective 
analysis with time to next treatment.35 In this trial, we will assess all of these recently described 
mutations as well as the presence of a subclonal driver mutation as potential predictors of 
response and PFS. We will also bank samples at time of relapse for repeat analysis by WES to 
assess for the acquisition of resistance mutations and evaluate established CLL prognostic 
markers such as cytogenetics by FISH, TP53 mutation presence, IGHV status, and ZAP-70 status, 
and will determine whether these factors are associated with response.
2.6.3
Single Cell Sequencing Studies
Next generation sequencing (NGS) techniques have the potential for revolutionizing the 
treatment of CLL by allowing the detection of minimal residual disease or resistance mutations 
at levels below the sensitivity of current assays. We have previously explored the utility of 
measuring undetectable MRD using a targeted deep sequencing panel.  Here we will again 
evaluate that technology and will consider using single cell DNA sequencing and RNA 
sequencing to identify the presence of oncogenic mutations, resistance mutations, and 
transcriptomic profiles of circulating CLL cells at various time points during the course of 
therapy. We will also retain plasma samples collected at the same time to explore the utility of 
cell-free DNA (cfDNA) analysis, making use of an orthogonal assay to verify or expand upon 

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results obtained from single cell sequencing.
2.6.4
ClonoSEQ NGS 
In addition to our prior work exploring the utility of targeted sequencing for somatic mutations, 
we have also explored the utility of NGS targeting the B cell receptor.  Specifically, Adaptive, 
Inc. has an assay known as ClonoSEQ, in which a baseline sample of genomic DNA is extracted 
from tumor cells, amplified using locus-specific primer sets for IGH and IGK rearrangements, 
and sequenced.  This sequence is then used to assess for undetectable MRD with a sensitivity as 
high as 10-6.  Once a patient achieves an undetectable MRD state, a peripheral blood sample 
can be examined to determine whether tumor DNA again becomes detectable. 

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PARTICIPANT SELECTION
2.7
Eligibility Criteria 
2.7.1
Confirmed diagnosis of chronic lymphocytic leukemia (CLL) or small lymphocytic 
lymphoma (SLL) per International Workshop on CLL (iwCLL) 2018 criteria.1
2.7.2
Participants must have an indication for treatment as defined by iwCLL 2018 criteria.1 
2.7.3
Participants must have measurable disease, defined as lymphocytosis > 5,000 / µL, or 
palpable or CT measurable lymphadenopathy ≥ 1.5 cm, or bone marrow involvement ≥ 
30%. 
2.7.4
For enrollment to Cohort 1: Participants must have relapsed or refractory disease as per 
iwCLL 2018 criteria,1 and must have received no more than 2 prior lines of anti-cancer 
therapy. 
2.7.5
For enrollment to Cohort 2: Participants must have previously untreated disease (i.e. 
must not have received any prior systemic therapy for CLL or SLL).
2.7.6
Age ≥ 18 years. Because no dosing or adverse event data are currently available on the 
use of umbralisib, acalabrutinib, and ublituximab in participants < 18 years of age and 
CLL is extremely rare in this population, children are excluded from this study.
2.7.7
ECOG performance status ≤ 2 (Karnofsky ≥ 60%, see Appendix A).
2.7.8
Participants must have adequate organ and marrow function as defined below:
Total bilirubin
≤ 1.5 × institutional upper limit of normal (ULN) (unless 
due to hemolysis or Gilbert’s disease, in which ≤ 3 × 
institutional ULN is acceptable)
AST (SGOT) and ALT (SGPT)
≤ 2.5 × institutional ULN, OR
AST (SGOT) and ALT (SGPT)
≤ 5 × institutional ULN if there is hemolysis or 
documented disease involvement in the liver
Calculated creatinine clearance 
≥ 30 mL/min (as calculated by the Cockcroft-Gault 
formula)
Platelet count
≥ 50,000/mcL, unless there is bone marrow involvement 
with disease
PT-INR or aPTT
≤ 2 × institutional ULN
Absolute neutrophil count (ANC)
≥ 750 mm3
Hemoglobin (Hgb)
> 8 g/dL

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2.7.9
Participants with known history or current symptoms of cardiac disease, or history of 
treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac 
function using the New York Heart Association Functional Classification.  To be eligible 
for this trial, participants should be class 2B or better.
2.7.10 The effects of umbralisib, acalabrutinib, or ublituximab on the developing human fetus 
are unknown.  For this reason and because anti-cancer agents are known to be 
teratogenic, women of child-bearing potential and men must agree to use highly 
effective methods of contraception (see Section 5.4). Should a woman become 
pregnant or suspect she is pregnant while she or her partner is participating in this 
study, she should inform her treating physician immediately.  Men and women treated 
on this protocol must agree to use highly effective contraception prior to the study, for 
the duration of study participation, and 4 months after completion of umbralisib, 
acalabrutinib, or ublituximab administration.
2.7.11 Ability to understand and the willingness to sign a written informed consent document.
2.7.12 Ability to swallow and retain oral medication.
2.7.13 Participants must be able to receive prophylactic anti-pneumocystis jiroveci pneumonia 
(PJP) and anti-viral therapy, see Section 5.4.
2.8
Exclusion Criteria
2.8.1
Participants with progressive or refractory disease while receiving either a BTK inhibitor 
or PI3K inhibitor.  Prior exposure to either a BTK inhibitor, PI3K inhibitor, or both is 
acceptable as long as the participant’s disease did not progress during active therapy 
with the agent(s). 
2.8.2
Participants who have undergone a major surgical procedure within 28 days of the first 
dose of study drug. If a participant had major surgery greater than 28 days prior to the 
first dose of study drug, they must have recovered adequately from any adverse event 
and/or complications from the intervention prior to the first dose (as judged by the 
treating investigator).
2.8.3
For enrollment to Cohort 1: For enrollment to Cohort 1: receipt of prior BTK inhibitor 
treatment or any other anti-cancer therapy (e.g. chemotherapy, immunotherapy, 
radiation, biologic therapy or any investigational agent) within five half-lives or 21 days, 
whichever is shorter, of the first dose of study drug. 
2.8.4
Participants who are receiving any other investigational agents.
2.8.5
History of prior allogeneic stem cell transplant.

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2.8.6
History of autologous hematologic stem cell transplant within 6 months of the first dose 
of study drug.
2.8.7
Participants with known Richter’s transformation, or histological transformation from 
CLL to large cell lymphoma. 
2.8.8
Participants with known CNS involvement, because of their poor prognosis and because 
they often develop progressive neurologic dysfunction that would confound the 
evaluation of neurologic and other adverse events. Participants with no known history 
of CNS leukemia are not required to undergo CT scan or lumbar puncture (LP) for trial 
eligibility unless the participant is symptomatic as judged by the treating investigator.
2.8.9
Participants with uncontrolled autoimmune hemolytic anemia (AIHA) or idiopathic 
thrombocytopenic purpura (ITP).
2.8.10 Participants with active clinically significant bleeding or history of bleeding diathesis 
(e.g., hemophilia or von Willebrand disease).
2.8.11 Participants requiring or receiving anticoagulation with warfarin or equivalent vitamin K 
antagonists (other anticoagulants are permitted).
2.8.12 Participants with a history of significant cerebrovascular disease/event within 6 months 
before the first dose of study drug, including stroke or intracranial hemorrhage.
2.8.13 Participants with uncontrolled intercurrent illness, including but not limited to: unstable 
angina pectoris, cardiac arrhythmia, or poorly controlled and clinically significant 
atherosclerotic vascular disease (including patients who required angioplasty, cardiac or 
vascular stenting within 6 months prior to the first dose of study agent), myocardial 
infarction within 6 months of screening, congestive heart failure, or patients with Class 3 
or 4 cardiac disease as defined by the New York Heart Association Functional 
Classification (Appendix D). Note: participants with controlled, asymptomatic atrial 
fibrillation are permitted to enroll on study.  Concomitant use of medication known to 
cause QT prolongation or torsades de pointes should be used with caution and at 
investigator discretion.  
2.8.14 Individuals with a history of a different malignancy are ineligible with the following 
exceptions: individuals who have been treated and are disease-free for a minimum of 2 
years prior to study enrollment, or individuals who are deemed by the treating 
investigator to be at low risk for disease recurrence. Additionally, individuals with the 
following cancers are eligible if diagnosed and curatively treated within the past 2 years: 
basal or squamous cell carcinomas of the skin, and breast or cervical carcinomas in situ.  
Prostate cancer on observation, with stable PSA for 6 months, is also eligible.

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2.8.15 Participants who require ongoing immunosuppressive therapy including systemic 
corticosteroids (prednisone or equivalent ≤ 10 mg daily is permitted). Topical, inhaled, 
and ophthalmologic steroids are permitted.
2.8.16 Participants with a history of inflammatory bowel disease (e.g. Crohn’s disease or 
ulcerative colitis).
2.8.17 Participants with irritable bowel syndrome (IBS) with greater than 3 loose stools per day 
at baseline.
2.8.18 Participants with evidence of ongoing systemic bacterial, fungal, or viral infection, 
except localized fungal infections of the skin or nails. NOTE: participants may be 
receiving prophylactic antiviral or antibacterial therapies at the treating investigator’s 
discretion. Use of anti-pneumocystis and antiviral prophylaxis is required, see Section 
5.4.
2.8.19 Participants with a known history of progressive multifocal leukoencephalopathy (PML).
2.8.20 Participants with evidence of chronic active Hepatitis B (HBV, not including patients with 
prior hepatitis B vaccination or positive serum Hepatitis B antibody), chronic active 
Hepatitis C infection (HCV), active cytomegalovirus (CMV), or known history of human 
immunodeficiency virus (HIV):

If HBc antibody is positive or the patient has a known history of hepatitis B, the 
subject must be evaluated for the presence of HBV DNA by PCR (see Appendix 
B). Subjects with a known history of hepatitis B and a positive HBc antibody but a 
negative HBV DNA by PCR are eligible if on suppressive therapy.  Subjects with 
no known history of hepatitis B, with positive HBc antibody and negative HBV 
DNA by PCR, are eligible but serial monitoring of HBV DNA by PCR is required, 
see Section 5.4.  Subjects with positive HBV DNA by PCR are not eligible.

Participants with positive HBsAg are to be excluded.

If HCV antibody is positive, the subject must be evaluated for the presence of 
HCV RNA by PCR. Subjects with positive HCV antibody and negative HCV RNA by 
PCR are eligible. Subjects with positive HCV RNA by PCR are not eligible.

If the subject is CMV IgG or CMV IgM positive, the subject must be evaluated for 
the presence of CMV DNA by PCR. Subjects who are CMV IgG or CMV IgM 
positive but who are CMV DNA negative by PCR are eligible, anti-viral prophylaxis 
should be considered per treating investigator discretion.
2.8.21 History of allergic reactions attributed to study drugs including active product or 
excipients, or compounds of similar chemical or biologic composition to acalabrutinib, 
umbralisib, or ublituximab, including participants with a history of anaphylaxis 
(excluding infusion-related reactions) in association with previous anti-CD20 
administration.

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2.8.22 Participants requiring concomitant treatment with any medications or substances that 
are strong inhibitors or inducers of CYP3A4 at the time of study enrollment.  Because 
the lists of these agents are constantly changing, it is important to regularly consult a 
frequently-updated medical reference.  As part of the enrollment/informed consent 
procedures, the participant will be counseled on the risk of interactions with other 
agents, and what to do if new medications need to be prescribed or if the participant is 
considering a new over-the-counter medicine or herbal product.
2.8.23 Participants requiring concomitant treatment with proton pump inhibitors (e.g., 
omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or 
pantoprazole) at the time of study enrollment. Note: participants receiving proton pump 
inhibitors who switch to H2-receptor antagonists or antacids prior to the first dose of 
study medication are eligible.
2.8.24 Participants with psychiatric illness/social situations that would limit compliance with 
study requirements.
2.8.25 Pregnant women are excluded from this study because acalabrutinib, umbralisib, and 
ublituximab are anti-cancer agents with the potential for teratogenic or abortifacient 
effects.  Because there is an unknown but potential risk for adverse events in nursing 
infants secondary to treatment of the mother with acalabrutinib, umbralisib, or 
ublituximab, breastfeeding must be discontinued prior to the initiation of study 
treatment. A negative serum pregnancy test is required for women of childbearing 
potential within 3 days prior to Cycle 1 Day 1.
2.9
Inclusion of Women and Minorities
Both men and women of all races and ethnic groups are eligible for this trial.
3.
REGISTRATION PROCEDURES
3.1
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 any protocol-specific therapy or 
intervention. Any participant not registered to the protocol before protocol-specific therapy or 
intervention 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-specific therapy and/or intervention. 
Issues that would cause treatment delays should be discussed with the Principal Investigator 
(PI) of the registering site. If the subject does not receive protocol therapy following 

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registration, the subject must be taken off study in the CTMS (OnCore) with an appropriate date 
and reason entered.  
3.2
Registration Process for DF/HCC Institutions
Applicable DF/HCC policy (REGIST-101) must be followed.  
3.3
General Guidelines for Other Investigative Sites
Eligible participants will be entered on study centrally at the Dana-Farber Cancer Institute by 
the Study Coordinator or Project Manager.  The required forms can be found in Section 4.4.
Following registration, participants should begin protocol therapy within 5 days. Issues that 
would cause treatment delays should be discussed with the Principal Investigator (PI).  If the 
subject does not receive protocol therapy following registration, the subject must be taken off-
study in the CTMS (OnCore) with an appropriate date and reason entered.  
3.4
Registration Process for Other Investigative Sites
To register a participant, the following documents should be completed by the participating site 
and e-mailed to the Study Coordinator/Project Manager:

Signed participant consent form

HIPAA authorization form

DFCI eligibility checklist

Screening provider note including the medical/surgical history, ECOG performance 
status, vital signs, and physical exam findings

Copies of laboratory reports and clinical information confirming satisfaction of 
eligibility criteria.
The participating site will then e-mail the Study Coordinator or Project Manager to verify 
eligibility.  The Study Coordinator/Project Manager will follow DF/HCC policy (REGIST-101) and 
register the participant on the protocol.  The Study Coordinator/Project Manager will e-mail the 
participant study number, and if applicable the dose treatment level, to the participating site.  
The Study Coordinator/Project Manager may also contact the participating site and verbally 
confirm registration
NOTE: Registration can only be conducted during the regular business hours of 8:30 AM to 
4:30 PM Eastern Standard Time Monday through Friday, holidays excluded. Same day 
treatment registrations will only be accepted with prior notice and discussion with the DF/HCC 
Project Manager or Study Coordinator.

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4.
TREATMENT PLAN
4.1
Treatment Regimen
A treatment cycle is defined as 28 consecutive days. Treatment will be administered on an 
outpatient basis.  Reported adverse events and potential risks are described in Section 7.  
Appropriate dose modifications are described in Section 6.  
Participants will receive acalabrutinib at the FDA approved dose of 100 mg by mouth twice daily 
and umbralisib at 800 mg by mouth once daily continuously throughout each treatment cycle. 
Ublituximab will be given IV starting with cycle 7 on days 1, 2, 8, and 15 and cycles 8-12 on day 
1. 
Participants who are in bone marrow and CT confirmed CR at the end of cycle 12 will stop 
dosing with acalabrutinib and umbralisib.. Participants not in CR will continue to cycles 13-24.
Participants will have peripheral blood monitoring for MRD as described in the Study Calendar 
in Section 10. If early relapse or recurrence is detected, the patient will undergo restaging with 
a CT scan and a bone marrow biopsy / aspirate. At the discretion of the treating investigator, 
patients with early relapse not meeting iwCLL criteria for retreatment may resume dosing with 
acalabrutinib and umbralisib until further disease progression, unacceptable toxicity, or other 
criteria are met as described in Section 5.5. The study agents will be resumed at the dose levels 
the participant was receiving prior to discontinuation. Dosing will resume for a maximum of 12 
additional treatment cycles, such that participants may receive a maximum total of 36 cycles of 
study therapy.
Table 4: Regimen Description
Agent
Premedications; Precautions
Dose
Route
Schedule1
Cycle 
Length
Acalabrutinib May be taken with or without food.
100 mg
By 
mouth
Twice Daily
Umbralisib
Take within 30 minutes of a meal.
Participants are required to receive 
prophylactic anti-viral and anti-
pneumocystis jiroveci pneumonia 
(PJP) treatment, refer to Section 5.4.  
800 mg
By 
mouth
Once Daily
28 days

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Table 4: Regimen Description
Agent
Premedications; Precautions
Dose
Route
Schedule1
Cycle 
Length
Ublituximab
Pre-medicate with an antihistamine 
(diphenhydramine 50 mg or 
equivalent) and a corticosteroid 
(dexamethasone 10 – 20 mg or 
methylprednisolone 80 mg or  
equivalent).2,3,4

If oral pre-medication: start 
the ublituximab infusion 45 – 
60 minutes after the ingestion 
of the oral pre-medications

If IV pre-medication: start the 
ublituximab infusion 30 – 35 
minutes after the completion 
of the last pre-medication 
infusion
See 
Section 
5.3.3
IV   
Cycle 7: 
Days 1, 2, 
8, 15
Cycles 8 – 
12: Day 1
1.
Order of administration of the study agents does not matter.
2.
Diphenhydramine must be 50 mg IV on Cycle 7 day 1 and 2, but may be reduced to 25 
mg on subsequent infusions in the absence of infusion related reactions and at 
treating physician discretion.  After the completion of cycle 8, use of corticosteroid 
pre-medication may be discontinued with approval from the sponsor-investigator if 
the participant has not experienced any infusion-related or hypersensitivity reactions.
3.
Administration of oral acetaminophen 650 mg (or equivalent) may be as clinically 
warranted, or in participants who experience fever/pyrexia after the first infusion. 
4.
Infusion-related hypotension may occur, investigators should consider holding anti-
hypertensive medications 12-24 hours prior to and throughout the infusion. Decision 
to withhold anti-hypertensive medication is at the treating investigator’s discretion.
4.2
Pre-Treatment Criteria
4.2.1
Cycle 1, Day 1
If screening laboratory assessments were completed ≤ 72 hours prior to cycle 1 day 1, 
laboratory tests do not need to be repeated on cycle 1 day 1 and the screening laboratory 
values can be used as the cycle 1 day 1 values. If cycle 1 day 1 laboratories are performed, the 
values do not need to re-meet eligibility criteria, participants will be allowed to initiate 
treatment at the treating investigator’s discretion.
4.2.2
Subsequent Cycles 
Management guidelines for toxicities associated with study treatment are located in Section 6.

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4.3
Agent Administration
4.3.1
Acalabrutinib
Acalabrutinib administration instructions:

Acalabrutinib should be administered orally twice daily, approximately every 12 hours.  

If a dose is missed, it can be taken up to 3 hours after the scheduled time with a return 
to the normal schedule with the next dose.  If it has been > 3 hours, the dose should not 
be taken and the participant should take the next dose at the scheduled time.

The tablets should be swallowed intact with water. Participants should not attempt to 
open, crush, chew, or dissolve the tablets.  

Acalabrutinib can be taken with or without food.

If the participant vomits following a dose, the dose should not be re-taken. Instead, the 
participant should proceed with their next scheduled dose as clinically appropriate.

Order of administration of the study agents does not matter.
4.3.2
Umbralisib
Umbralisib administration instructions:

Umbralisib should be administered orally once daily, approximately every 24 hours.  

If a dose is missed, it can be taken up to 12 hours after the scheduled time with a return 
to the normal schedule with the next dose.  If it has been > 12 hours, the dose should 
not be taken and the participant should take the next dose at the scheduled time.

The tablets should be swallowed intact. Participants should not attempt to crush, chew, 
or dissolve the tablets.  

Umbralisib should be taken within 30 minutes of a meal.

If the participant vomits following a dose, the dose should not be re-taken. Instead, the 
participant should proceed with their next scheduled dose as clinically appropriate.

See Section 4.4 for information regarding required anti-viral and anti-PJP prophylaxis.

Order of administration of the study agents does not matter.
4.3.3
Ublituximab
Ublituximab administration instructions:

Ublituximab will be administered as an intravenous (IV) infusion through a dedicated 
infusion line.

Medication and resuscitation equipment must be available per institutional guidelines 
prior to ublituximab administration for the emergency management of potential 
anaphylactic reactions. See hypersensitivity and infusion reaction guidance below.

Ublituximab should not be administered as an IV push or bolus.

Diluted ublituximab should be checked before administration for cloudiness, color, or 
deposits. Ublituximab should not be administered if it does not conform to the 
specifications.

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
It is recommended that ublituximab be administered immediately after dilution.  It 
should NOT be mixed the day before and mixing should only occur once confirmed that 
the patient is eligible for therapy on the day of treatment.

Ublituximab should not be mixed with other medicinal products. 

Ublituximab should only be diluted in 0.9% NaCl before use.

Participants must be pre-medicated with an antihistamine (diphenhydramine 25-50 mg 
or equivalent) and a corticosteroid (dexamethasone 10 – 20 mg or equivalent). Decision 
of using oral or IV pre-medication is at the treating investigator’s discretion except for 
cycle 1 days 1 and 2, when IV pre-medication and diphenhydramine 50 mg are required:
o
If oral pre-medication: start the ublituximab infusion 45 – 60 minutes after the 
ingestion of the oral pre-medications.
o
If IV pre-medication: start the ublituximab infusion 30 minutes (+ 5 minute 
window) after the completion of the last pre-medication infusion.
o
Adjusting antihistamine and corticosteroid doses, adjusting the timing of 
administration and/or additional pre-medications may be used at investigator 
discretion for additional prophylaxis against infusion related reactions. 
o
Administration of oral acetaminophen 650 mg (or equivalent) may be as clinically 
warranted, or in participants who experience fever/pyrexia after the first 
infusion. 

Infusion-related hypotension may occur, investigators should consider holding anti-
hypertensive medications 12 – 24 hours prior to and throughout the infusion. Decision 
to withhold anti-hypertensive medication is at the treating investigator’s discretion.

For patients at risk for tumor lysis syndrome in the opinion of the treating investigator, 
prophylaxis with allopurinol or similar per recommended institutional standards should 
be considered.

Order of administration of the study agents does not matter.

Ublituximab should be administered at the dose, rate, and schedule indicated in the 
tables below.
Table 5: Ublituximab Infusion Rate Cycle 7 Days 1 and 2
Infusion Rate1
Cycle 
7
Ublituximab 
Dose
Total Volume to 
be Infused
Start – 30 
min
30 min – 
1 hr
1 hr – 2 
hrs
2 hrs – 4 
hrs
Day 1
150 mg
250 mL
10 mL/hr
20 mL/hr
35 
mL/hr
100 
mL/hr
Day 2
750 mg
500 mL
10 mL/hr
20 mL/hr
85 
mL/hr
200 
mL/hr
1: A ± 2 minute window is allowable for adjustment of the infusion rate.

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Table 6: Ublituximab Infusion Rate Cycle 7 Days 8 and 15
Infusion Rate1
Cycle 7
Ublituximab 
Dose
Total Volume to be 
Infused
Start – 1 
hr
1 hr – 2 
hrs
2 hrs – 3 
hrs
Day 8, 
15
900 mg
500 mL
50 mL/hr
150 mL/hr
300 mL/hr
1: A ± 2 minute window is allowable for adjustment of the infusion rate.
Table 7: Ublituximab Infusion Rate Cycles 8 – 12 Day 1
Infusion Rate1
Cycle 
Day 
Ublituximab 
Dose
Total Volume to be 
Infused
Start – 30 
min
30 min – 90 
min
1
900 mg
500 mL
200 mL/hr
400 mL/hr
1: A ± 2 minute window is allowable for adjustment of the infusion rate.
4.3.4
Infusion-Related Reaction Guidelines – Ublituximab
Infusion-related reactions (including severe reactions) have been reported with ublituximab 
administration.  Guidelines are provided for patients who experience such reactions. 
Symptomatic infusion reactions may be treated at the discretion of the treating investigator 
and as per institutional standards of practice, including but not limited to: oral acetaminophen 
650 mg (or equivalent), corticosteroids, antihistamines, oxygen, and bronchodilators.  
If an infusion-related reaction is observed at any time during the ublituximab treatment, the 
treating investigator may reduce the infusion flow rate at their discretion.
The following are recommended infusion rate reduction/delay guidelines for patients who 
experience severe Infusion-Related Reactions (IRR’s) that result in treatment interruption.  Final 
decision for infusion rate reduction/delay or discontinuation resides with the treating 
investigator.
If grade 4 anaphylaxis is observed at any point during ublituximab treatment, permanently 
discontinue ublituximab treatment and intervene as per treating investigator discretion and 
institutional standards of practice.
1st or 2nd Infusion Interruption (same day):

Hold infusion and closely monitor patient, institute symptomatic medical management 
until resolution of IRR symptoms.

Following the judgment of the treating investigator, and provided the patient is stable, 
the infusion may be resumed at no more than half the previous rate.

If the patient does not experience any further IRR symptoms, infusion rate escalation 
may resume at the increments and intervals as appropriate for the treatment cycle 
dose.

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3rd Infusion Interruption (same day):

Discontinue infusion for that day – monitor patient for resolution of all symptoms.  
Patient should have all vital signs completed as well as any other standard of care 
procedures completed as warranted by the treating investigator prior to release of 
patient from study site.

Any remaining diluted investigational product should be discarded.
If an ublituximab infusion is discontinued, the next scheduled dose should be administered 
according to the protocol dosing schedule.
4.4
General Concomitant Medication and Supportive Care Guidelines
No investigational or commercial agents or therapies other than acalabrutinib, umbralisib, or 
ublituximab may be administered with the intent to treat the participant's malignancy.
Investigators should use appropriate supportive medications to address toxicities that arise
during the study, including but not limited to anti-emetics, anti-diarrheals, hematopoietic 
growth factors and blood product transfusion.
4.4.1
Umbralisib Prophylactic Anti-Viral Treatment
Participants receiving umbralisib are required to start prophylactic treatment with anti-PJP and 
anti-viral therapy prior to day 1 of treatment.  Choice of PJP and anti-viral prophylaxis is per 
investigator discretion and institutional standard of care, with the following as 
recommendations: 

Anti-viral Prophylaxis:  Valtrex 500 mg daily or Acyclovir 400 mg BID or equivalent. 

PJP Prophylaxis:  Sulfamethoxazole/trimethoprim 800 mg / 160 mg three times per 
week, or 400 mg / 80 mg daily, or if allergic, atovaquone 750 mg twice daily. Dapsone 
100 mg daily may also be used if other agents are contraindicated or unavailable but is 
not recommended. If dapsone is used, be aware that methemoglobinemia is not 
uncommon in CLL patients treated with dapsone.  

Final choice of PJP and anti-viral prophylactic therapy is per treating investigator 
discretion.
Participants should continue prophylactic treatment for at least one year after stopping 
protocol therapy. 
If anti-viral or anti-bacterial prophylaxis is not tolerated, alternate to a different prophylactic 
agent, reduce the dose or modify the schedule for the prophylactic agent, or discontinue 
prophylaxis at the treating investigator’s discretion.
4.4.2
Hepatitis B Monitoring and Anti-Viral Prophylaxis
All participants are required to have testing for hepatitis B surface antigen (HBsAg) and 

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hepatitis B core (HBc) antibody at screening. If HBc antibody is positive, the subject must also 
be evaluated for the presence of hepatitis B viral (HBV) DNA by PCR (see Appendix B). Subjects 
with positive HBc antibody and negative HBV DNA by PCR are eligible, but serial monitoring of 
HBV DNA is required monthly. 
Subjects with a prior history of hepatitis must be closely monitored as clinically 
indicated based on liver tests and any observed signs/symptoms such as jaundice, 
abdominal pain, dyspepsia, dark-colored urine often accompanied by lighter-than-
normal colored stools, nausea, vomiting or fatigue. 
For patients with a prior history of hepatitis B who experience an increase in liver enzymes 
while on study, hold ublituximab immediately and assess for active hepatitis B infection. If 
negative for hepatitis B by viral load testing, ublituximab may be resumed. If reactivation of 
hepatitis B is confirmed, institute hepatitis B antiviral treatment. Ublituximab may be resumed 
at investigator discretion once hepatitis B infection has resolved, with continued monitoring as 
described above. 
Serious or life-threatening reactivation of viral hepatitis may occur in subjects treated with 
acalabrutinib or ublituximab. Use of anti-viral prophylaxis will be permitted at the treating 
investigator’s discretion. Entecavir is the preferred agent for pharmacologic prophylaxis. Use of 
an agent other than entecavir must be discussed with the sponsor-investigator. HBV DNA 
should be monitored every 1-2 months while a patient is receiving pharmacologic prophylaxis. 
If the HBV DNA level becomes detectable, all study medications must be discontinued and 
infectious disease consultation should be obtained.   If a patient completes study therapy while 
taking entecavir, they should remain on entecavir for at least one year after completion of all 
therapy.  If discontinuation of entecavir is considered, patients should have their LFTs and HBV 
DNA level monitored weekly for the first two months.   
4.4.3
CYP Interactions
At the systemic exposure levels expected in this study, acalabrutinib inhibition of CYP 
metabolism is not anticipated. However, acalabrutinib is metabolized by CYP3A. Participants 
who are known to require the concomitant administration of strong inhibitors or inducers of 
CYP3A4 at the time of study entry are excluded from trial participation. The concomitant use of 
strong or moderate inhibitors of CYP3A4, or strong inducers of CYP3A4, should be avoided 
when possible while the participant is receiving treatment with acalabrutinib. If it is medically 
necessary to administer while on study, monitor the participant closely for potential toxicities 
and refer to dose adjustment table below.

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Table 8: Acalabrutinib Dose Adjustments for Concomitant Administration of CYP Agents1
CYP3A
Co-Administered 
Drug
Recommended Acalabrutinib Adjustment
Inhibition
Strong CYP3A4 
Inhibitor
Avoid concomitant use when possible.
If used short-term (e.g. anti-infectives for up to 7 days), 
hold dosing of acalabrutinib.
Inhibition
Moderate CYP3A4 
Inhibitor
100 mg once daily.
Induction
Strong CYP3A4 
Inducer
Avoid concomitant use when possible.
If these inducers cannot be avoided, increase dose to 
200 mg twice daily.
1. To be made in accordance with institutional standards of practice, treating 
investigator judgement, and FDA prescribing information.
 
The in vitro ability of umbralisib acting as a substrate, inhibitor, or inducer of cytochrome P450 
enzymes (CYPs), conjugating enzymes, and transporters was evaluated as per FDA Guidance. 
Except for a P-gp inhibitory potential, the results demonstrated no drug-drug interaction effects 
against major CYPs, conjugating enzymes, and transporters evaluated.  
Ublituximab is a protein and is expected to be metabolically degraded through peptide 
hydrolysis. Based on this expectation, ublituximab is an unlikely candidate for cytochrome 
P450-mediated drug-drug interactions.
4.4.4
Agents that Reduce Gastric Acidity
The effect of agents that reduce gastric acidity (e.g., proton pump inhibitors or antacids) on 
acalabrutinib absorption was evaluated in a healthy volunteer study.  Results from this study 
indicate that subjects should avoid the use of calcium carbonate containing drugs or 
supplements for a period of at least 2 hours before and at least 2 hours after taking 
acalabrutinib.  Use of omeprazole, esomeprazole, lansoprazole or any other proton pump 
inhibitors while taking acalabrutinib is not recommended due to a potential decrease in study 
drug exposure.  However, the decision to treat with proton-pump inhibitors during the study is 
at the treating investigator’s discretion, with an understanding of the potential benefit to the 
subject’s gastrointestinal condition and a potential risk of decreased exposure to acalabrutinib.
Although the effect of H2-receptor antagonists (such as famotidine or ranitidine) on 
acalabrutinib absorption has not been evaluated, if treatment with an H2-receptor antagonist is 
required, the H2-receptor antagonist should be taken approximately 2 hours after an 
acalabrutinib dose.

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4.4.5
Acceptable Forms of Contraception and Pregnancy Guidelines
4.4.5.1
Definition of Females Not of Childbearing Potential 
Females are considered post-menopausal and not of child bearing potential if they have had 12 
months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age 
appropriate, history of vasomotor symptoms) or six months of spontaneous amenorrhea with 
serum FSH levels > 40 mIU/mL and estradiol < 20 pg/mL] or have had surgical bilateral 
oophorectomy (with or without hysterectomy) at least six weeks ago. In the case of 
oophorectomy alone, only when the reproductive status of the woman has been confirmed by 
follow up hormone level assessment is she considered not of child bearing potential.
4.4.5.2
Fertile Males
Fertile males, defined as all males physiologically capable of conceiving offspring, must use a 
condom during treatment and for 4 months after the last dose of study treatment. They should 
also not father a child during this period.
4.4.5.3
Pregnancies
To ensure patient safety, each pregnancy in a patient on study treatment must be reported and 
followed as per the guidelines in Section 7.  
4.4.5.4
Acceptable Contraception
Highly effective methods of contraception (to be used during heterosexual activity) are defined 
as methods that can achieve a failure rate of <1% per year when used consistently and 
correctly.  
Such methods include: 

Combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation, which may be oral, intravaginal, or transdermal 

Progestogen-only hormonal contraception associated with inhibition of ovulation, which 
may be oral, injectable, or implantable

Intrauterine device (IUD) or intrauterine hormone-releasing system (IUS)

Bilateral tubal occlusion

Vasectomy (with medical assessment and confirmation of vasectomy surgical success)

Sexual abstinence (only if refraining from heterosexual intercourse during the entire 
period of risk associated with the study treatments)

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Hormonal contraception may be susceptible to interaction with study or other drugs, which 
may reduce the efficacy of the contraception method.
Abstinence (relative to heterosexual activity) can only be used as the sole method of 
contraception if it is consistently employed during the entire period of risk associated with the 
study treatments as the subject’s preferred and usual lifestyle.  Periodic abstinence (e.g., 
calendar, ovulation, sympto-thermal, and post-ovulation methods) and withdrawal are not 
acceptable methods of contraception.
If a contraceptive method is restricted by local regulations/guidelines, then it does not qualify 
as an acceptable highly effective method of contraception for subjects participating at sites in 
the relevant region.
The following are unacceptable forms of contraception for females of childbearing potential:

Female condom

Natural family planning (rhythm method) or breastfeeding

Fertility awareness

Withdrawal

Cervical shield
4.4.6
Live Virus Vaccines
Live virus vaccines are prohibited beginning 4 weeks prior to the first dose of ublituximab and 
for the duration of ublituximab treatment.
4.5
Criteria for Taking a Participant Off Protocol Therapy
Duration of therapy will depend on individual response, evidence of disease progression and 
tolerance. In the absence of treatment delays due to adverse event(s), treatment may continue 
for a maximum of 24 cycles or until one of the following criteria applies:

Disease progression, with the exception of participants who relapse following 
confirmed CR and treatment discontinuation who are permitted to be re-treated as 
described in Section 5.1

Intercurrent illness that prevents further administration of treatment

Unacceptable adverse event(s)

Participant becomes pregnant or plans to become pregnant

Participant demonstrates an inability or unwillingness to comply with the oral 
medication regimen and/or documentation requirements

Participant decides to withdraw from the protocol therapy

General or specific changes in the participant's condition render the participant 
unacceptable for further treatment in the judgment of the treating investigator

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Participants will be removed from the protocol therapy when any of these criteria apply.  The 
reason for removal from protocol therapy, and the date the participant was removed, must be 
documented in the case report form (CRF). Alternative care options will be discussed with the 
participant.
When a participant is removed from protocol therapy and/or is off of the study, the 
participant’s status must be updated in OnCore in accordance with REGIST-OP-1.
4.6
Duration of Follow Up
Participants will be followed for 30 days after removal from protocol therapy or until death, 
whichever occurs first, for adverse events.  Participants removed from protocol therapy for 
unacceptable adverse event(s) will be followed until resolution or stabilization of the adverse 
event. Following the 30 day follow up period, participants will be followed for a maximum of 5 
years after treatment discontinuation to observe treatment response and survival status. 
4.7
Criteria for Taking a Participant Off Study
Participants will be removed from study when any of the following criteria apply:

Completion of the 5 year follow-up period

Lost to follow-up

Withdrawal of consent for data submission

Death
The reason for taking a participant off study, and the date the participant was removed, must 
be documented in the case report form (CRF). In addition, the study team will ensure the 
participant’s status is updated in OnCore in accordance with REGIST-OP-1.
5.
DOSING DELAYS/DOSE MODIFICATIONS
Dose delays and modifications will be made as indicated in the following table(s). The 
descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 5.0 will be utilized for dose delays and dose modifications of 
non-hematologic toxicity. A copy of the CTCAE version 5.0 can be downloaded from the CTEP 
website
 http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. The iwCLL 2018 
criteria will be used for grading and assessment of hematologic toxicity (Appendix E).1
5.1
Dose Delays
Umbralisib may be held for a maximum of 56 days to allow for recovery of toxicity, and 
acalabrutinib may be held for a maximum of 28 days. Ublituximab may be delayed for a 
maximum of 2 cycles (56 days). Participants requiring a longer delay should be removed from 

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protocol therapy. Participants who are deriving clinical benefit who require a longer hold of any 
of the study agents may be allowed to continue treatment following discussion and agreement 
with the sponsor-investigator.
If attribution of the toxicity is known, study medications may be held independently of each 
other. For example, a participant may continue dosing with acalabrutinib and umbralisib while 
holding ublituximab at the treating investigator’s discretion. If attribution of the toxicity is 
unknown or the combination of study agents may be contributing to the toxicity, all study 
agents must be held. Refer to Section 6.3 for toxicity management guidelines.
In the event of a dose hold due to toxicity, the counting of cycle days and protocol assessment 
schedule will continue without interruption. For example, a participant who holds dosing of 
umbralisib and acalabrutinib on Cycle 4 Day 15 to Cycle 4 Day 18 for toxicity will resume dosing 
on Cycle 4 Day 19 and proceed with their next scheduled clinic visit as previously planned (Cycle 
5 Day 1). Interim visits may be conducted as clinically necessary to manage toxicity; however, 
the cycle will not restart and doses will not be “made up” in the event of dosing delays.
5.2
Dose Modifications
Permitted dose reductions of acalabrutinib and umbralisib are detailed below. Once a 
participant’s dose has been reduced due to toxicity, it may not be re-escalated. If a subject 
requires a dose reduction of umbralisib and further evaluation of the toxicity reveals the event 
was not related to umbralisib, this should be recorded in the medical record and dose re-
escalation to the previous umbralisib dose may be considered at the discretion of the treating 
investigator after consultation with the sponsor-investigator.  No dose reductions of 
ublituximab are permitted. If the participant cannot tolerate the dose of ublituximab, 
ublituximab should be discontinued.
If attribution of the toxicity is known, dose reductions may occur independently of each other. 
For example, the dose of umbralisib may be reduced while maintaining the dose of 
acalabrutinib. If toxicity attribution is unknown or the combination of study agents may 
contribute to the toxicity, both agents must be dose reduced.
Table 9: Umbralisib Dose Reductions
Dose Reduction Level
Umbralisib Dose (Once Daily)
-1
600 mg
-2
400 mg
-3
Discontinue
Table 10: Acalabrutinib Dose Reductions1,2
Dose Reduction Level
Acalabrutinib Dose
-1
100 mg once daily
-2
Discontinue
1. Dose modifications of acalabrutinib may be made in 

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Table 10: Acalabrutinib Dose Reductions1,2
Dose Reduction Level
Acalabrutinib Dose
accordance with the FDA prescribing information.
2. Refer to Section 5.4 for dose modifications for co-
administered CYP3A drugs.
If attribution of the toxicity is known, discontinuation of study medications may also occur 
independently of each other with agreement from the sponsor-investigator. For example, 
participants who cannot tolerate ublituximab may be allowed to continue to receive umbralisib 
and acalabrutinib if the sponsor-investigator provides approval.
5.3
Toxicity Management
Management of toxicity considered at least possibly related to the study agents is detailed in 
the tables below.
Table 11: Hematologic Toxicity Management1
Event Term
Grade
Study Agent Management Guidelines2
Neutrophil 
count 
decreased
Grade 3
Provide supportive care as warranted.
Maintain current dose of umbralisib and acalabrutinib.
For recurrent or persistent Grade 3 neutropenia unresponsive 
to supportive care, reduce umbralisib by one dose level.
Maintain full dose and schedule of ublituximab, if applicable.
Neutrophil 
count 
decreased
Grade 4
Provide supportive care as warranted. Hold dosing of study 
agents until resolution to ≤ Grade 3.
First and second occurrence: resume umbralisib and 
acalabrutinib at the same dose level.
Recurrence after second re-challenge: resume umbralisib and 
acalabrutinib with one dose level reduction.
If applicable, resume ublituximab at full dose and schedule.
Febrile 
neutropenia
≥ Grade 3
Provide supportive care as warranted. Hold study agents until 
resolution.
First occurrence: resume umbralisib and acalabrutinib at the 
same dose level.
Recurrence after re-challenge despite supportive care: reduce 
dose of umbralisib by one dose level.
If applicable, resume ublituximab at full dose and schedule upon 
resolution.

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Table 11: Hematologic Toxicity Management1
Event Term
Grade
Study Agent Management Guidelines2
Platelet count 
decreased3
Grade 3 with 
clinically 
significant 
bleeding
-OR-
Grade 4
Provide supportive care as warranted. 
First occurrence: delay umbralisib and acalabrutinib until Grade 
≤ 3 without clinically significant bleeding; thereafter, resume 
umbralisib and acalabrutinib at the same dose level.
  
Second occurrence: delay umbralisib and acalabrutinib until 
Grade ≤ 3 without clinically significant bleeding; thereafter, 
resume umbralisib and acalabrutinib at next lower dose level 
unless there is a clear alternative explanation for the event.
Delay ublituximab until Grade ≤ 3 without clinically significant 
bleeding; thereafter, resume ublituximab at full dose and 
schedule.
1.
Grading of hematologic toxicity will be per iwCLL 2018 criteria (Appendix E).1 
2.
Management of acalabrutinib may be made in accordance with the FDA prescribing 
information.
3.
If participant receives a platelet transfusion, they will be considered to have grade 4 toxicity 
for that day and the next 2 calendar days regardless of actual platelet count.
Table 12: Non-Hematologic Toxicity Management
Event Terms
CTCAE 
Grade
Study Agent Management Guidelines1
Pulmonary & 
Related 
Infections2
Grade 3
Provide supportive care as warranted.
Maintain acalabrutinib dosing. Hold dosing of umbralisib and 
ublituximab (if applicable) until complete resolution.  Acalabrutinib 
may also be held at the treating investigator’s discretion and SHOULD 
be held for any suspected fungal or opportunistic infections until 
resolution of infection to grade 1 or less. Resume acalabrutinib at the 
same dose level.
If suspicious for a possible drug-related pneumonitis, resume 
umbralisib at next lower dose level. If recurrence after re-challenge, 
permanently discontinue umbralisib.
Upon complete resolution, resume ublituximab at full dose and 
schedule. If recurrence after re-challenge, permanently discontinue 
ublituximab.
Pulmonary & 
Related 
Infections2
Grade 4
Provide supportive care as warranted.
Permanently discontinue umbralisib and ublituximab (if applicable). 

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Table 12: Non-Hematologic Toxicity Management
Event Terms
CTCAE 
Grade
Study Agent Management Guidelines1
Colitis
ANY
Provide supportive care as warranted. Hold dosing of umbralisib and 
ublituximab (if applicable) until resolution. Acalabrutinib may also be 
held at the treating investigator’s discretion.
Upon resolution, resume umbralisib at the next lower dose level. 
Acalabrutinib may be resumed at the same dose level or reduced at 
the treating investigator’s discretion. Resume ublituximab at the same 
dose and schedule.
Liver Toxicity 
Includes: ALT 
(SGPT), AST 
(SGOT), Bilirubin 
increased
Grade 1
Maintain current dose and schedule of umbralisib, acalabrutinib, and 
ublituximab (if applicable).
Assess concomitant medications and risk factors.3 Monitor liver 
function laboratories every 1 – 2 weeks until resolution to baseline.
Liver Toxicity 
Includes: ALT 
(SGPT), AST 
(SGOT), Bilirubin 
increased
Grade 2
Assess concomitant medications and risk factors.3  
First Occurrence: Maintain current dose and schedule of umbralisib, 
acalabrutinib, and ublituximab (if applicable).
Begin supportive care (prednisone 0.5 – 1.0 mg/kg/day or equivalent 
per treating investigator’s discretion).4  
Monitor liver function laboratories at least weekly until Grade 1 or 
baseline. Once resolved to Grade 1 or baseline, taper prednisone by 
10 mg per week until off.
If liver toxicity recurs:

Re-initiate steroids.

Delay umbralisib and ublituximab dosing. 

Monitor liver function labs at least weekly until resolution to 
Grade 1 or baseline.  

Once resolved to Grade 1 or baseline, restart umbralisib at 
current dose and resume ublituximab at full dose and 
schedule.

Taper prednisone by 10 mg per week until off.

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Table 12: Non-Hematologic Toxicity Management
Event Terms
CTCAE 
Grade
Study Agent Management Guidelines1
Liver Toxicity 
Includes: ALT 
(SGPT), AST 
(SGOT), Bilirubin 
increased
Grade ≥ 3
Assess concomitant medications and risk factors.3  
Hold dosing of umbralisib, ublituximab, and acalabrutinib. 
Begin supportive care (prednisone 0.5 – 1.0 mg/kg/day or equivalent 
per treating investigator’s discretion).4  
Monitor liver function labs at least weekly until Grade 1 or resolution 
to baseline. Once resolved to Grade 1 or baseline, resume dosing with 
study agents, beginning with acalabrutinib and adding umbralisib and 
ublituximab (as applicable) one week later if the liver toxicity does not 
return upon re-introduction of acalabrutinib. Reduce dose of 
umbralisib by one dose level, resume full dose and schedule of 
acalabrutinib and ublituximab. Taper prednisone by 10 mg per week 
until off.
Any other non-
hematologic 
toxicity
≤ Grade 2
No change in study agent dosing or schedule.5 Implement supportive 
care as appropriate.
NOTE: If persistent grade 2 diarrhea despite supportive care, delay 
umbralisib until ≤ grade 1; thereafter, resume umbralisib at next lower 
dose level.  

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Table 12: Non-Hematologic Toxicity Management
Event Terms
CTCAE 
Grade
Study Agent Management Guidelines1
Any other non-
hematologic 
toxicity
≥ Grade 3
Implement supportive care as appropriate. 
First occurrence: hold dosing of study agents until resolution to ≤ 
Grade 2 or baseline. Upon resolution, may resume dosing with 
umbralisib and acalabrutinib at the same dose level, or at the treating 
investigator’s discretion, may reduce dose by one dose level. Resume 
ublituximab at the full dose and schedule.
Recurrence: hold dosing of study agents until resolution to ≤ Grade 2 
or baseline. Upon resolution, resume dosing with umbralisib and 
acalabrutinib with one dose level reduction. Resume ublituximab at 
the full dose and schedule.
Exceptions:

Asymptomatic laboratory abnormalities considered non-
clinically significant: participants may continue dosing at the 
treating investigator’s discretion.

Asymptomatic laboratory abnormalities that resolve to ≤ Grade 
2 or baseline within 48 hours of repletion or treatment: study 
medication should be held until resolution to Grade 2 and may 
be resumed at the same dose level or with one dose level 
reduction at the treating investigator’s discretion. Treatment 
and resumption of study medication dosing may occur on the 
same day.
1.
Management of acalabrutinib may be made in accordance with the FDA prescribing 
information.
2.
For sinopulmonary infections clearly not related to immune-mediated pneumonitis, 
umbralisib may be continued at the treating investigator’s discretion.  While pneumonitis has 
been minimal with umbralisib, it is a reported adverse event associated with other PI3K delta 
inhibitors.  Use of anti-pneumocystis and anti-herpetic viral prophylaxis is required prior to 
the start of therapy, refer to Section 5.4.
3.
Assess for disorders of lipids and glucose, thyroid disorders, alcohol use, viral infections, etc.
4.
Supportive Care may include aggressive management of lipid, glucose, other metabolic 
disorders, viral infections, etc. Important: Before initiating steroids, check for viral hepatitis or 
CMV infection.
5.
At the treating investigator’s discretion, dosing of the study agent(s) may be held and/or dose 
reduced for intolerable Grade 2 toxicity.

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5.4
Overdose
There are currently no specific treatments in the event of overdose with acalabrutinib, 
umbralisib or ublituximab and possible symptoms of overdose are not established. In the event 
of an overdose, the participant should be monitored as clinically appropriate (e.g. vital signs, 
hematologic parameters, etc.) and adverse reactions associated with the overdose should be 
treated symptomatically. Please refer to Section 7.4 for adverse event reporting requirements.
In the event of an overdose ingestion of acalabrutinib that is recent and substantial, and if there 
are no medical contraindications, use of gastric lavage or induction of emesis may be 
considered at the treating investigator’s discretion and in accordance with local institutional 
guidelines.
5.5
Withdrawal of Umbralisib and Ublituximab 
As of March 2023, TG therapeutics has decided to no longer provide umbralisib, ublituximab 
and funding for this study. Study participants still on treatment will still have the option to 
continue taking acalabrutinib.
6.
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
following list of reported and/or potential AEs (Section 7.1) and the characteristics of an 
observed AE (Sections 7.2, 7.3, 7.4 and 7.5) will determine whether the event requires 
expedited reporting in addition to routine reporting.
6.1
Expected Toxicities
6.1.1
Expected Toxicities for Acalabrutinib
For the purposes of suspected unexpected serious adverse reaction (SUSAR) reporting, the 
toxicities in the table below will be considered expected for acalabrutinib. Events that are fatal 
or life-threatening (i.e. posing an immediate risk of dying) must always be reported according to 
expedited timelines. Please also refer to the acalabrutinib IB.
Table 13: Acalabrutinib Expected Toxicities
System Organ Class
Event
Abdominal pain
Diarrhea
Gastrointestinal disorders
Vomiting
Nervous system disorders
Headache
Vascular disorders
Hematoma

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6.1.2
Expected Toxicities for Umbralisib
For the purposes of SUSAR reporting, the toxicities in the table below will be considered 
expected for umbralisib. Events that are fatal or life-threatening (i.e. posing an immediate risk 
of dying) must always be reported according to expedited timelines. Please also refer to the 
umbralisib IB.
Table 14: Umbralisib Expected Toxicities
System Organ Class
Event
Frequency 
(n=number of 
occurrences)
Serious
Febrile Neutropenia
8
Yes
Anemia
4
Yes
Neutropenia
2
Yes
Thrombocytopenia*
Leukopenia*
Blood and Lymphatic System 
Disorders
Leukocytosis*
Cardiac Failure 
Congestive
2
Yes
Heart Palpitations
1
Yes
Cardiac Disorders
Pulmonary Edema
1
Yes
Congenital, Familial and Genetic 
Disorders
Congestive Heart Failure
1
Yes
Diarrhea
9
Yes
Small Intestinal 
Obstruction
2
Yes
Nausea
2
Yes
Vomiting
2
Yes
Colitis
3
Yes
Anorectal Fistula
1
Yes
Acute Pancreatitis
1
Yes
Ileus
1
Yes
Abdominal Pain*
Gastrointestinal Disorders
Gastrointestinal 
Hemorrhage*
Pyrexia
6
Yes
Fatigue
3
Yes
General Disorders and 
Administrative Site Conditions
Pyrexia*
Uveitis
1
Yes
Immune System Disorders
Allergic Reaction
1
Yes
Pneumonia
18
Yes
Cellulitis
3*
Yes
Cytomegalovirus Colitis
2
Yes
Infections and Infestations
Lung Infection
2
Yes

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Table 14: Umbralisib Expected Toxicities
System Organ Class
Event
Frequency 
(n=number of 
occurrences)
Serious
Sepsis
12
Yes
Septic Shock
1
Yes
Upper Respiratory Tract 
Infection
2
Yes
Neutropenic Sepsis
2
Yes
Bacteremia
2
Yes
Pulmonary Infection
Transaminases 
Increased
2
Yes
Investigations
Elevated Liver Enzymes*
Dehydration
5
Yes
Hypophosphatemia
2
Yes
Metabolism & Nutrition Disorders
Tumor Lysis Syndrome*
2
Yes
Headache
3
Yes
Syncope
2
Yes
Nervous System Disorders
PML*
1
Yes
Neoplasms Benign, Malignant and 
Unspecified (incl cysts and polyps)
Malignant Melanoma*
1
Yes
Pneumonitis
4
Yes
Pleural Effusion
2
Yes
Hypoxia
2
Yes
Respiratory, Thoracic and 
Mediastinal Disorders
Shortness of Breath*
Rash
4
Yes
Eczema
2
Yes
Skin and Subcutaneous Tissue 
Disorders
Erythrodermic 
Eczematous Rash*
1
Yes
*: these events have not been seen as a serious adverse reaction ≥ 2 however are still 
considered to be of special interest for umbralisib
6.1.3
Expected Toxicities for Ublituximab
For the purposes of SUSAR reporting, the toxicities in the table below will be considered 
expected for ublituximab. Events that are fatal or life-threatening (i.e. posing an immediate risk 
of dying) must always be reported within expedited timelines. Please also refer to the 
ublituximab IB.

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Table 15: Ublituximab Expected Toxicities
System Organ 
Class
Event
Frequency
(n=number of 
occurrences)
Serious
Febrile Neutropenia
8
Yes
Anemia
2
Yes
Thrombocytopenia
2
Yes
Blood and 
Lymphatic System 
Disorders
Pancytopenia*
Gastrointestinal 
Disorders
Diarrhea
3
Yes
Pyrexia
5
Yes
General Disorders 
and 
Administrative 
Site Conditions
Fatigue
3
Yes
Serum Sickness-Like Reaction
1
Yes
Immune System 
Disorders
Hypersensitivity/Anaphylaxis*
Pneumonia
14
Yes
Sepsis
6
Yes
Neutropenic Sepsis
2
Yes
Cellulitis
2
Yes
Bacteremia
2
Yes
Infections and 
Infestations
Septic Shock
2
Yes
Injury, Poisoning 
and Procedural 
Complications
Infusion-Related Reactions
9
Yes
Hypercalcemia
1
Yes
Insulin Dependent Diabetes
1
Yes
Metabolism & 
Nutrition 
Disorders
Tumor Lysis Syndrome
4
Yes
Nervous System 
Disorders
PML
1
Yes
Neoplasms 
Benign, Malignant 
and Unspecified 
(incl cysts and 
polyps)
Malignant Melanoma
1
Yes
Rash
3
Yes
Skin and 
Subcutaneous 
Tissue Disorders
Erythrodermic Eczematous 
Rash
2
Yes
*: these events have not been seen as a serious adverse reaction ≥ 2 however are still 
considered to be of special interest for ublituximab

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6.2
Adverse Event Characteristics

Term (AE description) and grade:  The descriptions and grading scales found in the 
revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be 
utilized for AE reporting for non-hematologic toxicity.  All appropriate treatment areas 
should have access to a copy of the CTCAE version 5.0.  A copy of the CTCAE version 5.0 
can be downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. The 
iwCLL 2018 criteria will be used for grading and assessment of hematologic toxicity 
(Appendix E).1

For expedited reporting purposes only:  
-
AEs for the agent(s) that are listed above should be reported only if the adverse 
event varies in nature, intensity or frequency from the expected toxicity information 
which is provided.
-
Other AEs for the protocol that do not require expedited reporting are outlined in 
the next section (Expedited Adverse Event Reporting) under the sub-heading of 
Protocol-Specific Expedited Adverse Event Reporting Exclusions.

Attribution of the AE:
-
Definite – The AE is clearly related to the study treatment.
-
Probable – The AE is likely related to the study treatment.
-
Possible – The AE may be related to the study treatment.
-
Unlikely – The AE is doubtfully related to the study treatment.
-
Unrelated – The AE is clearly NOT related to the study treatment.
6.3
Serious Adverse Event Reporting
A serious adverse event (SAE) is any adverse event that occurs after the initial dose of study 
treatment, during treatment, or within 30 days of the last dose of treatment that results in one 
of the following outcomes or meets at least one of the following criteria:

Death

Hospitalization for greater than 24 hours

Prolonging an existing inpatient hospitalization

A life-threatening experience (that is, immediate risk of dying)

Persistent or significant disability/incapacity

Congenital anomaly/birth defect

Any suspected transmission of an infectious agent via a study agent (e.g. Prion Protein 
Transmitting Transmissible Spongiform Encephalopathy)

Any confirmed occurrence of Hy’s Law, defined as an ALT or AST ≥ 3 × institutional ULN 
AND concurrent total bilirubin ≥ 2 × institutional ULN without findings of cholestasis

Considered significant by the investigator for any other reason

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If an investigator becomes aware of an SAE that is considered related to acalabrutinib after 
completion of the 30-day period following the last dose of acalabrutinib, the event should also 
be reported as an SAE to Acerta Pharma at the contact information given below. 
Previously planned (prior to signing the informed consent form) surgeries, and non-disease 
related elective surgeries planned during the course of the study, should not be reported as 
SAEs unless the underlying medical condition has worsened or appeared during the course of 
the study. Events that occur prior to the first administration of study medication should not be 
reported as SAEs.
Preplanned hospitalizations or procedures for pre-existing conditions that are already recorded 
in the patient’s medical history at the time of study enrollment should not be considered SAEs. 
Hospitalization or prolongation of hospitalization without a precipitating clinical AE (e.g., for the 
administration of study therapy or other protocol-required procedure) should not be 
considered SAEs.
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered SAEs when, based on appropriate medical judgment, they 
may jeopardize the patient and may require medical or surgical intervention to prevent one of 
the outcomes listed in this definition.
Death due to disease progression should not be reported as an SAE unless the investigator 
deems it to be related to the use of study drug. Hospitalization due solely to the progression of 
underlying malignancy should NOT be reported as an SAE.  Clinical symptoms of progression 
may be reported as SAEs if the symptoms cannot be determined as exclusively due to the 
progression of the underlying malignancy, or if they do not fit the expected pattern of 
progression for the disease under study. If there is any uncertainty about an SAE being due only 
to the disease under study, it should be reported as an SAE.
Study site personnel must alert the sponsor-investigator of any SAE as soon as possible and no 
later than 1 business day of the treating investigator receiving notification of the SAE 
experienced by a patient participating in the study. Study site personnel must alert TG 
Therapeutics, Inc. of any SAE within 24 hours of the first knowledge of the event by the treating 
physician or research personnel. Study site personnel must alert Acerta Pharma within 15 
calendar days of awareness of any SAEs. The SAE reports should be on a standard reporting 
form (e.g. CIOMS, local institutional SAE form, MedWatch 3500a, or similar) and are to be sent 
via email to TG Therapeutics, Inc.: safety@tgtxinc.com and Acerta Pharma: 
AEMailboxClinicalTrialTCS@astrazeneca.com.

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6.4
Adverse Events of Special Interest (AESI)
6.4.1
Pregnancy
During the course of the study, all female participants of childbearing potential must contact 
the treating investigator immediately if they suspect that they may be pregnant (a missed or 
late menstrual period should be reported to the treating investigator). If an investigator 
suspects that a participant may be pregnant, the study drugs must be withheld until a 
pregnancy test has been administered and the result has been confirmed.  If a pregnancy is 
confirmed, the patient must be permanently discontinued from the study treatment. The 
investigator should counsel the subject, discussing any risks of continuing the pregnancy and 
any possible effects on the fetus.
Any pregnancy that occurs with the subject or with the partner of a treated subject during the 
study intervention period, or that occurs within 30 days following the last dose of study 
medication, will be reported, followed to conclusion, and the outcome reported. Abortions 
(spontaneous, accidental, or therapeutic) must also be reported.  
Study site personnel must alert the sponsor-investigator and submit an SAE form (CIOMS, local 
institutional SAE form, or similar) within 15 calendar days to Acerta Pharma at 
AEMailboxClinicalTrialTCS@astrazeneca.com.
Confirmed pregnancies, subject’s partner pregnancies, and abortions (spontaneous, accidental, 
or therapeutic) must be reported to TG Therapeutics, Inc. at safety@tgtxinc.com within 24 
hours of the first knowledge of the event by the treating physician or research personnel on a 
Pregnancy Report Form.  For subject’s partner pregnancies, the partner will be requested to 
consent to access to medical records.  After the subject’s partner provides consent, the 
pregnant partner and baby will be followed to see what effect the drug(s) under study may 
have on the outcome of the pregnancy or the health of the newborn.  
Congenital anomalies/birth defects always meet SAE criteria and should therefore be 
expeditiously reported as an SAE to TG Therapeutics, Inc. at safety@tgtxinc.com within 24 
hours of the first knowledge of the event by the treating physician or research personnel.
6.4.2
Study Drug Overdose
Study drug overdose is the accidental or intentional use of the drug in an amount higher than 
the dose being studied. Any study drug overdose or incorrect administration of study drug 
should be noted on the appropriate CRF. Any accidental or intentional overdose with the study 
treatment, even if not fulfilling a seriousness criterion, is to be reported to the sponsor-
investigator within 1 business day, to TG Therapeutics, Inc. at safety@tgtxinc.com within 24 
hours, and to Acerta Pharma at AEMailboxClinicalTrialTCS@astrazeneca.com within 15 calendar 
days on an SAE form (CIOMS, local institutional SAE form, or similar). 

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6.4.3
Secondary and Second Primary Malignancy
Secondary and second primary malignancies are considered AESIs for acalabrutinib. Any 
malignancy possibly related to cancer treatment, and any secondary (occurring as a direct 
result as study drug administered, including but not limited to MDS) or second primary 
(unrelated, new cancer, including but not limited to MDS and MPD) malignancy event must be 
reported to the sponsor-investigator and to Acerta Pharma at: 
AEMailboxClinicalTrialTCS@astrazeneca.com via the SAE form (CIOMS, local institutional SAE 
form, or similar) within 1 business day of awareness.
AEs for malignant tumors reported during a study should generally be assessed as serious AEs 
(refer to Section 7.3). If no other seriousness criteria apply, the “considered significant by the 
investigator for any other reason” criterion should be used. In certain situations, however, 
medical judgement on an individual event basis should be applied to clarify that the malignant 
tumor event should be assessed and reported as a Non-Serious AE. For example, if the tumor is 
included as medical history and progression occurs during the study, but the progression does 
not change treatment and/or prognosis of the malignant tumor, the AE may not fulfill the 
attributes for being assessed as serious, although reporting of the progression of the malignant 
tumor as an AE is valid and should occur. Also, some types of malignant tumors, which do not 
spread remotely after a routine treatment that does not require hospitalization, may be 
assessed as Non-Serious; examples include Stage 1 basal cell carcinoma and Stage 1A1 cervical 
cancer removed via cone biopsy.
6.4.4
Ventricular Arrhythmias
Ventricular arrhythmias (e.g. ventricular extrasystoles, ventricular tachycardia, ventricular 
arrhythmia, ventricular fibrillation, etc.) are considered AESIs for acalabrutinib. Any occurrence 
of a ventricular arrhythmia must be reported to the sponsor-investigator and Acerta Pharma 
irrespective of regulatory seriousness criteria or event causality. Report on an SAE form 
(CIOMS, local institutional SAE form, or similar) within 15 calendar days of awareness, email 
form to Acerta Pharma at: AEMailboxClinicalTrialTCS@astrazeneca.com 
6.5
Adverse Event Reporting 
6.5.1
In the event of an unanticipated problem or life-threatening complications treating 
investigators must immediately notify the PI.
6.5.2
Investigators must report to the PI any serious adverse event (SAE) or adverse event of 
special interest (AESI) 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. 

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6.5.3
DF/HCC Adverse Event Reporting Guidelines
Investigative sites within DF/HCC will report AEs directly to the DFCI Office for Human 
Research Studies (OHRS) per the DFCI IRB reporting policy. 
Other investigative sites will report AEs to their respective IRB according to the local 
IRB’s policies and procedures in reporting adverse events. A copy of the submitted 
institutional AE form should be forwarded to the Sponsor-Investigator within the 
timeframes detailed below:

Grade 2 and Grade 3 Events: Report events that are unexpected and there is a 
reasonable possibility the event is related to the study intervention (i.e. possible, 
probable, or definite attribution). Report to the sponsor-investigator within 5 
calendar days of the treating investigator or research site personnel learning of 
the event.

Grade 4 Events: Report all events that are unexpected. Report to the sponsor-
investigator within 5 calendar days of the treating investigator or research site 
personnel learning of the event.

Grade 5 Events: Report ALL grade 5 events. Report to the sponsor-investigator 
within 1 business day of the treating investigator or research site personnel 
learning of the event.
The Sponsor-Investigator will submit AE reports from outside institutions to the DFCI 
OHRS according to DFCI IRB policies and procedures in reporting adverse events. 
6.6
Reporting to the Food and Drug Administration (FDA)
The Sponsor-Investigator will be responsible for all communications with the FDA. The Sponsor-
Investigator 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.
Any adverse events meeting criteria for FDA reporting must also be reported to Acerta Pharma 
in parallel with FDA submission: AEMailboxClinicalTrialTCS@astrazeneca.com.
6.7
Reporting to Hospital Risk Management
Participating investigators will report to their local Risk Management office any participant 
safety reports, sentinel events or unanticipated problems that require reporting per 
institutional policy. 
6.8
Routine Adverse Event Reporting
All Adverse Events must be reported in routine study data submissions to the PI on the toxicity 
case report forms.  AEs reported through expedited processes (e.g., reported to the IRB, FDA, 

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etc.) must also be reported in routine study data submissions.
7.
PHARMACEUTICAL INFORMATION
A list of the adverse events and potential risks associated with the investigational agents 
administered in this study can be found in Section 7.1.
7.1
Acalabrutinib maleate
7.1.1
Description
Other Names: CALQUENCE®, ACP-196 Maleate
Molecular Formula: C26H23N7O2.C4H4O4
Molecular Weight: 581.58
Appearance: Orange film-coated tablet
7.1.2
Form
The investigational product, acalabrutinib maleate tablet, is presented as an orange 
film-coated tablet containing 129 mg of acalabrutinib maleate (equivalent to 100 mg of 
acalabrutinib) drug substance. 
Each tablet also contains the following compendial inactive ingredients: mannitol,
microcrystalline cellulose, low-substituted hydroxypropyl cellulose and sodium stearyl
fumarate. The tablet coating contains: hypromellose, copovidone, titanium dioxide, 
polyethylene glycol, caprylic/capric triglyceride, yellow iron oxide and red iron oxide.
7.1.3
Storage
Acalabrutinib maleate tablets are packed in white, high-density polyethylene (HDPE) 
bottles containing a silica gel desiccant and should be stored according to the storage 
conditions as indicated on the label. The recommended storage condition for 
acalabrutinib maleate tablets is below 30°C (86°F)
7.1.4
Handling
Qualified personnel, familiar with procedures that minimize undue exposure to 
themselves and the environment, should undertake the preparation, handling, and safe 
disposal of the chemotherapeutic agent in a self-contained and protective environment. 
7.1.5
Availability
Acalabrutinib is a commercially available agent that will be supplied by Acerta Pharma.

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7.1.6
Administration
See Section 5.3.
7.1.7
Ordering
Acalabrutinib should be ordered from Acerta Pharma by site pharmacy personnel.
7.1.8
Accountability
The investigator, or a responsible party designated by the investigator, should maintain 
a careful record of the inventory and disposition of the agent using the NCI Drug 
Accountability Record Form (DARF) or another comparable drug accountability form.  
(See the NCI Investigator’s Handbook for Procedures for Drug Accountability and 
Storage.)
7.1.9
Destruction and Return
Expired, returned, or unused supplies of acalabrutinib should be destroyed according to 
local institutional policies. Destruction will be documented in the Drug Accountability 
Record Form. 
7.2
Umbralisib
7.2.1
Description
Classification: Phosphatidylinositol-3-Kinase (PI3K) Delta Inhibitor
Other Names: TGR-1202
Appearance: off-white to brown colored powder
Solubility: Freely soluble in dimethyl sulfoxide and soluble in methanol
7.2.2
Form
Umbralisib is supplied as 200 mg light green, oval tablets with “L474” debossed on one 
side. It is supplied in HDPE bottles, each containing 30 tablets and a silica gel canister as 
a desiccant.
Table 16: Composition of Umbralisib Drug Product
Ingredients
%w/w
Umbralisib Tosylate
36.09
Microcrystalline Cellulose (Avicel PH 101)
9.96
Hydroxy Propyl Betadex (Kleptose HPB)
37.45
Croscarmellose Sodium (Ac-Di-Sol)
2.77
Hydroxypropyl Cellulose (Klucel LF)
0.83
Croscarmellose Sodium (Ac-Di-Sol)
9.71

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Table 16: Composition of Umbralisib Drug Product
Ingredients
%w/w
Magnesium Stearate (Vegetable Source)
0.28
Opadry II Green 40L510005
2.91
Total Weight
100.00
7.2.3
Storage 
Store umbralisib at 20˚C to 25˚C. Excursions permitted to 15˚C to 30˚C.    Do not freeze.  
For questions about product expiry email productquality@tgtxinc.com.
7.2.4
Handling
Qualified personnel, familiar with procedures that minimize undue exposure to 
themselves and the environment, should undertake the preparation, handling, and safe 
disposal of the chemotherapeutic agent in a self-contained and protective environment. 
7.2.5
Availability
Umbralisib is an investigational agent that will be supplied by TG Therapeutics, Inc.
7.2.6
Administration
Refer to Section 5.3.
7.2.7
Ordering
Umbralisib is available from TG Therapeutics, Inc. and will be ordered by site pharmacy 
personnel.  Ensure staff will be available to unpack shipment immediately upon arrival.  
Allow 5 to 7 business days between drug ordering and drug arrival.  Direct drug orders 
to ISTdrugorder@tgtxinc.com. The email should include the following:

Requested quantity of TG Therapeutics, Inc. study drug(s)

Date needed

Sponsor-investigator name

Study title  

TG Therapeutics, Inc. Tracking Number (U2-NTG-013)

Investigational drug pharmacy shipping address 
Upon receipt of the shipment, the pharmacist or appropriate person at the site should 
update the accountability forms for umbralisib.  If there is any abnormality in the 
supplied bottles, the pharmacist or the appropriate person must document it during the 
acknowledgement of receipt and contact TG Therapeutics, Inc. at 
productquality@tgtxinc.com.

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7.2.8
Accountability
The investigator, or a responsible party designated by the investigator, should maintain 
a careful record of the inventory and disposition of the agent using the NCI Drug 
Accountability Record Form (DARF) or another comparable drug accountability form.  
(See the NCI Investigator’s Handbook for Procedures for Drug Accountability and 
Storage.)
7.2.9
Destruction and Return
Expired, returned, or unused supplies of umbralisib should be destroyed according to 
local institutional policies. Destruction will be documented in the Drug Accountability 
Record Form. 
7.3
Ublituximab
7.3.1
Description
Chemical Name: Ublituximab
Other Names: TG-1101
Classification: Recombinant chimeric anti-CD20 monoclonal antibody
Ublituximab is a genetically engineered chimeric murine/human mAb directed against 
the CD20 antigen found on the surface of B lymphocytes.  Ublituximab displays the 
typical structure of immunoglobulins, consisting of two gamma (γ) heavy chains and two 
kappa (κ) light chains linked by disulfide bridges. It is composed of a murine variable 
region (37.2% of total amino acids) fused onto human constant regions.
7.3.2
Form
Concentration of 25 mg/mL in:

6 mL (150 mg) single-use glass vials
Or

36 mL (900mg) single-use glass vials
7.3.3
Storage and Stability
Ublituximab vials must be stored in a secured limited-access refrigerated area at a 
temperature ranging from 2-8°C (36-46°F). Once a vial of ublituximab has been diluted, 
it should be used immediately. If not used immediately, diluted solutions must be stored 
refrigerated. The storage duration of ublituximab diluted in poly vinyl chloride (PVC) or 
non-PVC polyolefin (PO) material is up to 24 hours when refrigerated at 2-8°C (36-46°F). 
After allowing the diluted bag to come to room temperature, use immediately.

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Ublituximab has a shelf-life of 36 months if stored between +2°C to +8°C, based on 
stability data.  For questions about product expiry email productquality@tgtxinc.com.
7.3.4
Compatibility
Ublituximab should not be mixed with other medicinal products.  Ublituximab should 
only be diluted in 0.9% NaCl before use. The compatibility of ublituximab with medical 
devices was investigated using a standard PVC bag containing 0.9% NaCl and standard 
PVC tubing, however dilution into non-PVC bags and use of non-PVC tubing is 
acceptable.
7.3.5
Handling
Qualified personnel, familiar with procedures that minimize undue exposure to 
themselves and the environment, should undertake the preparation, handling, and safe 
disposal of the chemotherapeutic agent in a self-contained and protective environment. 
7.3.6
Availability
Ublituximab is an investigational agent that will be supplied by TG Therapeutics, Inc.
7.3.7
Preparation
Ublituximab should not be mixed with other medicinal products.  Ublituximab should 
only be diluted in 0.9% NaCl before use.  No data are available for other solutions such 
as 5% dextrose and 5% mannitol.
Ublituximab is available in 150 mg (6 mL quantity vial) or 900mg (36 mL quantity vial) 
single use vials as a 25 mg/mL concentrate for dilution. Dilutions for ublituximab are as 
indicated in the tables below.
Ublituximab preparation instructions for 900mg Single use vial C7D1 & C7D2

Withdraw appropriate volume of ublituximab from the vial as per table 

For day 1 infusion, dilute 6 mL ublituximab into a 250 mL 0.9% sodium chloride infusion 
bag for administration on day 1.  If not used immediately, diluted solutions must be 
refrigerated.  After allowing the diluted bag to come to room temperature, use 
immediately. 

For day 2 infusion, dilute the remaining 30 mL into a 500 mL 0.9% sodium chloride 
infusion bag at the same time, and store at 2-8°C (36-46°F) for up to 24 hours for use on 
Day 2.  After allowing the diluted bag to come to room temperature, use immediately. 

Label each infusion bag clearly. 
o
Day 1 = 150 mg bag 

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o
Day 2 = 750 mg bag 

Mix diluted solution by gentle inversion prior to use.  Do not shake or freeze. 
Table 17: Ublituximab Dilutions for Cycle 7 Day 1 & Day 2
Dose of 
ublituximab
for infusion
Volume of 
ublituximab
(25 mg/mL)
Volume of NaCl 0.9% to be 
removed
Final volume in 
perfusion bag
Day 1: 150 mg
6 mL
6 mL
250 mL
Day 2: 750 mg
30 mL
30 mL
500 mL
Table 18: Ublituximab Dilutions for Cycle 7 Day 8 & Beyond
Dose of 
ublituximab
for infusion
Volume of 
ublituximab
(25 mg/mL)
Volume of NaCl 0.9% to be 
removed
Final volume in 
perfusion bag
900 mg
36 mL
36 mL
500 mL
Diluted ublituximab should be checked before administration for cloudiness, color, or 
deposits.  Ublituximab should not be administered if does not conform to the 
specifications. Immediately inform TG Therapeutics, Inc. at productquality@tgtxinc.com 
with any product quality concerns or questions.
7.3.8
Administration
Refer to Section 5.3.
7.3.9
Ordering
Ublituximab is available from TG Therapeutics, Inc. and will be ordered by site pharmacy 
personnel.  Order ublituximab Monday through Wednesday to ensure shipment arrives 
Monday through Friday.  Ensure staff will be available to unpack shipment immediately 
upon arrival.  Allow 5 to 7 business days between drug ordering and drug arrival.  Direct 
drug orders to ISTdrugorder@tgtxinc.com. The email should include the following:

Requested quantity of TG Therapeutics, Inc. study drug(s)

Data needed

Sponsor- investigator name

Study title  

TG Therapeutics, Inc. Tracking Number (U2-NTG-013) 

Investigational drug pharmacy shipping address 
Upon receipt of this shipment, the pharmacist or the appropriate person at the site 
should update the accountability forms for ublituximab.  If there is any abnormality in 

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the supplied boxes, the pharmacist or the appropriate person must document it during 
the acknowledgement of receipt and contact TG Therapeutics, Inc. at 
productquality@tgtxinc.com.
7.3.10 Accountability
The investigator, or a responsible party designated by the investigator, should maintain 
a careful record of the inventory and disposition of the agent using the NCI Drug 
Accountability Record Form (DARF) or another comparable drug accountability form.  
(See the NCI Investigator’s Handbook for Procedures for Drug Accountability and 
Storage.)
7.3.11 Destruction and Return
Expired or unused supplies of ublituximab should be destroyed according to local 
institutional policies. Destruction will be documented in the Drug Accountability Record 
Form. 
8.
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES
8.1
BH3 Profiling
BH3 profiling is a functional assay we previously developed that detects the proximity of CLL 
cells to the threshold of apoptosis (what we call ‘priming’) through interrogation of BCL-2 family 
members.  To perform a BH3 profile, we add individual BH3-only peptides to gently 
permeabilized malignant cells and use FACS to measure the amount of mitochondrial 
depolarization induced by each peptide, as measured by cytochrome c release. 
Assessments will be made on circulating CLL cells from the peripheral blood drawn from 
patients at baseline. We will attempt to identify potential resistance mechanisms by looking at 
whether patients who do not achieve CR have different upfront BH3 profiles from those who 
do. Additionally, another sample of peripheral blood will be collected from subjects at the time 
of relapse or disease progression, and the BH3 profile of these samples will be compared to 
subjects’ baseline samples to help identify whether a change in anti-apoptotic protein 
dependence is observed as a possible mechanism of resistance.
If we have bone marrow aspirates and fresh lymph node tissue available, we may also perform 
BH3 profiling to see whether the level of priming in CLL cells from these tissues is a better 
predictor of response than peripheral blood CLL cells.
Dynamic BH3 profiling, a technique that allows us to measure “delta priming,” defined as the 
difference in mitochondrial response to a BH3 peptide in a drug-treated sample versus an 
untreated control may also be performed. We will compare the dynamic BH3 profile of serially 
collected samples to a baseline sample, which will allow us to assess in vivo the short-term 

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change in apoptotic priming induced by the study agents. We will correlate this with clinical 
response.
All peripheral blood samples will promptly be delivered to the laboratory of Dr. Jennifer Brown 
at Dana-Farber Cancer Institute (DFCI), where they will undergo Ficoll purification and then be 
viably frozen in FBS with 10% DMSO.  The viably-frozen samples will be batched and stored, and 
the BH3 profiling assays will be performed in Dr. Matthew Davids’ lab at DFCI.
8.2
Genomic Analyses
We plan to perform whole exome sequencing (WES) on CLL cells and normal tissue from 
patients at baseline to evaluate for somatic mutations such as TP53, NOTCH1 and SF3B1 that 
may confer drug sensitivity and resistance. If the patient does not have significant circulating 
CLL cells, we will pursue sequencing of bone marrow aspirate samples in patients who require a 
new bone marrow biopsy for screening.  In addition, saliva as a source of germline will be 
collected prior to study drug initiation and may be collected more than once if inadequate 
specimen is obtained. 
All samples will promptly be delivered to the laboratory of Dr. Jennifer Brown at DFCI, where 
DNA will be extracted and then sent to the Broad Institute (Cambridge, MA) for WES.  In an 
exploratory analysis, we will assess novel mutations as potential predictors of response and 
PFS.  We will also collect a sample from each patient at time of relapse or progression for 
repeat analysis by WES to assess for acquired resistance mutations.
8.3
Adaptive ClonoSEQ Assay
To assess whether the presence of minimal residual CLL cells in the peripheral blood as 
measured by a novel sequencing platform is predictive of OS and PFS, peripheral blood and/or 
bone marrow samples will be serially collected for analysis. Samples will be sent to the Brown 
Lab at DFCI where they will be stored initially prior to batch shipping to Adaptive for analysis. 
Using Adaptive’s ClonoSEQ platform, rearranged immunoreceptor loci from genomic DNA will 
be extracted, amplified, and sequenced using V and J segment primers for each 
immunoreceptor gene.  Tumor-specific clonotypes will be identified for each patient based on 
their high prevalence in peripheral blood or bone marrow.  Sequences will be analyzed using 
standardized algorithms for clonotype determination.  Adaptive MRD levels will be quantified 
using spiked-in reference sequences.
8.4
T Cell Profiling
Cells will be banked serially for the determination of T cell subsets by flow cytometry and/or 
CyTOF, in order to determine the effects of umbralisib and acalabrutinib on T cell populations, 
particularly CD8s, Tregs and Th17s. Samples will be banked in the laboratory of Dr. Jennifer 

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Brown at DFCI. T cell functional studies, including proliferation and T reg suppression studies 
among others, will be performed on ex vivo PBMC samples when possible given cell numbers. 
8.5
Additional Prognostic Tests
Patients who have not had ZAP-70, IGHV, TP53 and NOTCH1 testing done locally will have 
baseline samples sent for testing to Genzyme/LabCorp. These samples will be shipped 
alongside the Integrated Oncology/LabCorp requisition form ambient priority overnight to:  
Genzyme/LabCorp Specialty Testing Group
521 West 57th Street 
New York, NY 10000
8.6
Correlative Study Sample Collection Summary
Correlative samples will be collected as indicated in the table below. 
Table 19: Correlative Sample Collection Schedule
Sample Time 
Point*
Container1
Sample Type2
Shipping Method
Recipient
6 × 6 mL Green Top
1 × 6 mL Red Top
Peripheral blood
2 × 6 mL Green Top
Bone Marrow 
Aspirate
Fridge pack overnight 
1 × Oragene Kit
Saliva3
Ambient overnight
Brown Laboratory, DFCI 
(BH3 profiling, WES, T cell 
profiling, Adaptive 
Clonoseq)
Screening or      
Pre-dose Day 1
2 × 6mL Green Top4
Peripheral blood
Fridge pack overnight
Genzyme/LabCorp4,5
Cycle 1, Day 8
6 × 6 mL Green Top
1 × 6 mL Red Top
Peripheral blood
Fridge pack overnight
Brown Laboratory, DFCI (T 
cell profiling, BH3 profile)
Cycle 2, Day 1
6 × 6 mL Green Top
1 × 6 mL Red Top
Peripheral blood
Fridge pack overnight
Brown Laboratory, DFCI 
(BH3 profile)
Cycle 4, Day 1
6 × 6 mL Green Top
1 × 6 mL Red Top
Peripheral blood
Fridge pack overnight
Brown Laboratory, DFCI (T 
cell profiling, BH3 profile)
6 × 6 mL Green Top
1 × 6 mL Red Top
Peripheral blood
Fridge pack overnight
Brown Laboratory, DFCI 
(BH3 profile, T cell 
profiling, Adaptive 
Clonoseq)
2 × 6 mL Green Top
Bone Marrow 
Aspirate
Fridge pack overnight
Brown Laboratory, DFCI 
(Adaptive Clonoseq)
Cycle 7, Day 1 
(prior to initiation 
of ublituximab)
1 × 6 mL Green Top
Bone Marrow 
Aspirate
Fridge pack overnight
Mayo Clinic (MRD 
Assessment)
Cycle 13, Day 1
6 × 6 mL Green Top
1 × 6 mL Red Top
Peripheral blood
Fridge pack overnight
Brown Laboratory, DFCI 
(BH3 profile, T cell 
profiling, Adaptive 
Clonoseq)

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Table 19: Correlative Sample Collection Schedule
Sample Time 
Point*
Container1
Sample Type2
Shipping Method
Recipient
2 × 6mL Green Top
Bone Marrow 
Aspirate
Fridge pack overnight
Brown Laboratory, DFCI 
(Adaptive Clonoseq)
1 × 6mL Green Top
Bone Marrow 
Aspirate
Fridge pack overnight
Mayo Clinic (MRD 
Assessment)
Every 6 Months 
after Cycle 13
6 × 6 mL Green Top
1 × 6 mL Red Top
Peripheral blood
Fridge pack overnight
Brown Laboratory, DFCI (T 
cell profiling, BH3 profile)
6 × 6 mL Green Top
1 × 6 mL Red Top
Peripheral Blood
Fridge pack overnight
Brown Laboratory, DFCI 
(BH3 profile, Adaptive 
Clonoseq)
2 × 6 mL Green Top
Bone Marrow 
Aspirate
Fridge pack overnight
Brown Laboratory, DFCI 
(Adaptive Clonoseq)
Cycle 25 Day 1
AND
Re-Treatment 
Cycle 13 Day 1 (as 
applicable)
1 × 6 mL Green Top
Bone Marrow 
Aspirate
Fridge pack overnight
Mayo Clinic (MRD 
Assessment)
6 × 6 mL Green Top
1 × 6 mL Red Top
Peripheral Blood
Fridge pack overnight
Treatment 
Discontinuation
2 × 6mL Green Top
Bone Marrow 
Aspirate
Fridge pack overnight
Brown Laboratory, DFCI 
(BH3 profile, T cell 
profiling, Adaptive 
Clonoseq)
1 × 6 mL Red Top
Peripheral Blood
Fridge pack overnight
6 × 6 mL Green Top
Peripheral Blood
Relapse/Disease 
Progression
2 × 6 mL Green Top
Bone Marrow 
Aspirate
Fridge pack overnight
Brown Laboratory, DFCI 
(BH3 profiling, whole 
exome sequencing, T cell 
profiling, Adaptive 
Clonoseq)
1.
Green top = sodium heparin tube; Red top = no additive 
2.
For time points that mention blood and/or aspirate: If patient has few circulating CLL cells in peripheral blood, 
send additional aspirate (1 × 6 mL green top tube) in addition to blood. 
3.
Oragene kits require approximately 2 mLs of saliva.
4.
Samples required for all patients at baseline unless previously tested for ZAP-70, IGHV, TP53, and NOTCH1.
5.
Genzyme/LabCorp only provides requisition form.
*: All sample time points have a ± 7 day scheduling window. Cycle 7 Day 1 samples must be collected prior to 
initiation of ublituximab.
Correlative studies note:  While the goal of the correlative studies is to provide supportive data 
for the clinical study, there may be circumstances when a decision is made to stop a collection, 
not perform, or discontinue an analysis due to either practical reasons (e.g., inadequate sample 
number, issues related to the quality of the sample or issues related to the assay that preclude 
analysis, impossibility to perform correlative analyses, etc.). Therefore, depending on the 
results
obtained during the study, sample collection/analysis may be omitted at the discretion of the 
PI. Additional correlative samples may be collected after the 24-cycle time point at the 
discretion of the investigators.
9.
STUDY CALENDAR
Screening evaluations are to be conducted within 14 days prior to start of protocol therapy, 
with the exception of screening radiologic scans which may be conducted within 30 days prior 

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to the start of protocol therapy and the bone marrow biopsy / aspirate which may be obtained 
up to 90 days prior to the start of protocol therapy as long as no intervening therapy has 
occurred. Assessments must be performed prior to administration of any study agent.

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Table 20: Study Calendar for All Participants, Cycles 1 - 12
Screening
Cycle 1 
Day 1
Cycle 
1 Day 
8a
Cycle 1 
Day 15a
Cycle 2 - 
6 Day 1b
Cycle 7 
Day 1a
Cycle 7 
Day 2
Cycle 7 
Day 8c
Cycle 7 
Day 
15c
Cycles 8 – 12 
Day 1a
Off Treatmentd
Long-term 
Follow-upe
EDC Timepoints∞
Demographics
X
Screening
Medical history
X
Screening
Physical exam
X
X
X
X
X
X
X
X
X
X
N/A
Vital signs
X
X
X
X
X
X
X
X
X
X
X
N/A
Height
X
N/A
Weight
X
X
X
X
X
X
X
X
X
X
N/A
ECOG performance status
X
X
X
X
X
X
Screening, Cycles 1 – 12 
Day 1, Off Treatment 
CBC w/diff, plts
X
X
X
X
X
X
X
X
X
X
X
All Visits
Serum chemistryf
X
X
X
X
X
X
X
X
X
X
X
N/A
PT-INR, aPTT
X
N/A
Serum β-HCGg
X
N/A
HCV, HBV, and CMV IgG or 
IgM serologiesh
X
N/A
CMV surveillance by PCRn
X
X
X
X
X
Echocardiogramo
X
Screening
EKGi
X
As clinically indicated
N/A
Adverse event evaluation
X--------------------------------------------------------------------------------------------------------X
X
All Visits
Radiologic evaluationj
X
CT or MRI scans to be repeated as described in Section 11.1
Screening, Day 28 of 
Cycles 2, 6, and 12, Off 
Treatment, and to confirm 
CR
Bone marrow biopsy / 
aspirate / MRD assessmentk
X
To be performed as described in Sections 9.6 and 11.2
Screening, Day 1 of Cycle 
7, Off Treatment, and to 
confirm CR
Peripheral Blood MRD 
Analysis
To be performed on Day 1 of Cycles 3, 7, and 10 (±7 day scheduling window)
X
Day 1 of Cycles 3,7, and 
10, Off Treatment

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Table 20: Study Calendar for All Participants, Cycles 1 - 12
Screening
Cycle 1 
Day 1
Cycle 
1 Day 
8a
Cycle 1 
Day 15a
Cycle 2 - 
6 Day 1b
Cycle 7 
Day 1a
Cycle 7 
Day 2
Cycle 7 
Day 8c
Cycle 7 
Day 
15c
Cycles 8 – 12 
Day 1a
Off Treatmentd
Long-term 
Follow-upe
EDC Timepoints∞
Correlative Analyses
As described in Section 9
N/A
Ublituximabl
X
X
X
X
X
Day 1 of Cycles 7 – 12
Acalabrutinibm
As described in Section 5.3
Day 1 of Cycles 1 - 12
Umbralisibm
As described in Section 5.3
Day 1 of Cycles 1 - 12
Medical Record Review / 
Care Provider Contact / 
Telephone Contact
X
Every 3 months following 
treatment discontinuation 
for a maximum of 5 years
∞: Column only relevant for CRF builders.
a.
A ± 3 day scheduling window is allowable to account for holidays, adverse weather, vacations, or any other scheduling issues.
b.
A ± 7 day scheduling window is allowable to account for holidays, adverse weather, vacations, or any other scheduling issues.
c.
A ± 2 day scheduling window is allowable to account for holidays, adverse weather, vacations, or any other scheduling issues.
d.
Off treatment evaluation. Note: for IND trials, follow up visits or other contact are required in order to identify SAEs during the 30 days following the end of study treatment. 
e.
Long-term follow-up will involve medical record review, telephone and/or care provider contact to confirm survival status and ongoing disease response following treatment discontinuation. 
To be completed every 3 months following the final dose of study drug (±1 month window) for a maximum of 5 years after treatment discontinuation or until death, whichever occurs first.
f.
Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, potassium, total protein, SGOT [AST], SGPT [ALT], sodium, phosphorus, uric acid, LDH.
g.
Serum pregnancy test within 3 days prior to Cycle 1 Day 1 only required for women of childbearing potential, as defined in Section 5.4.
h.
Hepatitis B surface antigen (HBsAg) and antibody (HBsAb), hepatitis B core antibody (HBcAb), HBV DNA, hepatitis C antibody, hep C viral load and CMV IgG or IgM testing is required for all 
participants during the screening period. Refer to Section 3.2.20 and Section 5.4. 
i.
Single EKG to be collected during the screening period. QTc to be calculated per institutional standards. 
j.
Screening chest/abdomen/pelvis CT or MRI required for all participants within 30 days prior to the start of protocol therapy. Refer to Section 11.1.
k.
Screening bone marrow biopsy / aspirate may be performed up to 90 days prior to the start of protocol therapy as long as no intervening therapy has occurred. Refer to Section 11.2. 
Correlative analyses on collected aspirate specimens will be performed as described in Section 9. Marrow sample requested for correlative studies if bone marrow biopsy is done as standard 
of care. Flow cytometry (lymphoma panel), karyotype, and FISH (CLL) should be performed on marrow at all bone marrow biopsies (FISH may be performed on either marrow or blood and is 
not required on both).  MRD should be performed on the marrows to evaluate response at years 1 and 2. 
l.
Refer to Section 5.3 for ublituximab administration and hypersensitivity reaction guidelines.
m.
Adequate supply of the study agent should be dispensed to account for any pre-planned scheduling delays.
n.
CMV surveillance by PCR approximately every 3 cycles during treatment with umbralisib and approximately 30 days after the last dose of umbralisib, aligned with scheduled visits.
o.
Baseline 2D echocardiogram required prior to start of protocol therapy.

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Table 21: Study Calendar for Participants in CR Cycles 13 - 37
Cycles 13 Day 
1a
Cycles 15, 18 
Day 1b
Cycles 21, 25, 28, 31, 34, 
37 Day 1a
Long-term Follow-
upc
EDC Timepoints∞
Physical exam
X
X
X
N/A
Vital signsd
X
X
X
N/A
Weight
X
X
X
N/A
ECOG performance status
X
X
X
Day 1 of Cycles 13, 15, 18, 21, 25, 28, 31, 34, 37
CBC w/diff, plts
X
X
X
Day 1 of Cycles 13, 15, 18, 21, 25, 28, 31, 34, 37
Serum chemistrye
X
X
X
N/A
CMV surveillance by PCRh
X
EKG
As Clinically Indicated
N/A
Adverse Event Evaluation
X------------------------------------------------------X
All Visits
Radiologic evaluation
CT or MRI scans to be repeated as described in Section 11.1
Day 28 of Cycle 17 and 24, Off Treatment, and to confirm 
CR or Relapse
Bone marrow biopsy / aspirate / MRD assessmentf
To be repeated as described in Sections 9.6 and 11.2
Day 1 of Cycle 25, and to confirm CR or Relapse
Peripheral Blood MRD Analysis
X
X
X
Day 1 of Cycles 13, 15, 18, 21, 25, 28, 31, 34, 37
Correlative Analyses
As described in Section 9.
N/A
Medical Record Review / Care Provider Contact / 
Telephone Contact
X
Every 3 months following the completion of Cycle 36 for a 
maximum of 2 years
∞: Column only relevant for CRF builders.
a.
A ± 7 day scheduling window is allowable to account for holidays, adverse weather, vacations, or any other scheduling issues.
b.
A ± 3 day scheduling window is allowable to account for holidays, adverse weather, vacations, or any other scheduling issues.
c.
Long-term follow-up will involve medical record review, telephone and/or care provider contact to confirm survival status and ongoing disease response. To be completed every 3 
months (±1 month window) following the completion of Cycle 36 for a maximum of 2 years or until death, whichever occurs first.
d.
Heart rate, respiratory rate, temperature, blood pressure, and oxygen saturation.
e.
Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, potassium, total protein, SGOT [AST], SGPT [ALT], sodium, phosphorus, uric acid, 
LDH.
f.
Marrow sample requested for correlative studies if bone marrow biopsy is done as standard of care. Flow cytometry (lymphoma panel), karyotype, and FISH (CLL) should be performed 
on marrow at all bone marrow biopsies (FISH may be performed on either marrow or blood and is not required on both). MRD should be performed on the marrows to evaluate 
response at years 1 and 2.
g.
CMV surveillance by PCR approximately every 3 cycles during treatment with umbralisib and approximately 30 days after the last dose of umbralisib, aligned with scheduled visits.

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Table 22: Study Calendar for Participants with Recurrence/Relapse after Discontinuation of Therapy
Retreatment Cycle 1 
Day 1a
Retreatment Cycle 2 
Day 1b
Retreatment Cycles 3, 7, 
10, and 13 Day 1b
Off 
Treatmentc
Long-term 
Follow-upd
EDC Timepoints∞
Physical exam
X
X
X
X
N/A
Vital signs
X
X
X
X
N/A
Weight
X
X
X
X
N/A
ECOG performance status
X
X
X
X
Day 1 of retreatment cycles 1 – 3, 7, 10, and 
13, Off Treatment
CBC w/diff, plts
X
X
X
X
Day 1 of retreatment cycles 1 – 3, 7, 10, and 
13, Off Treatment
Serum chemistrye
X
X
X
X
N/A
CMV surveillance by PCRh
X
X
X
EKG
As Clinically Indicated
N/A
Adverse Event Evaluation
X------------------------------------------------------X
X
All Visits
Radiologic evaluation
CT or MRI scans to be repeated as described in Section 11.1
Day 28 of retreatment cycles 2, 6, and 12, Off 
Treatment
Bone marrow biopsy / aspirate / MRD 
assessmentf
To be repeated as described in Sections 9.6 and 11.2.
Day 1 of Cycle 13
Peripheral Blood MRD Analysis
X
X
Day 1 of retreatment cycles 3, 7, 10, and 13, 
Off Treatment
Correlative Analyses
As described in Section 9.
N/A
Acalabrutinibg
As described in Section 5.3
Day 1 of Retreatment Cycles 1 - 12
Umbralisibg
As described in Section 5.3
Day 1 of Retreatment Cycles 1 - 12
Medical Record Review / Care Provider 
Contact / Telephone Contact
X
Every 3 months following treatment 
discontinuation for a maximum of 5 years

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Table 22: Study Calendar for Participants with Recurrence/Relapse after Discontinuation of Therapy
Retreatment Cycle 1 
Day 1a
Retreatment Cycle 2 
Day 1b
Retreatment Cycles 3, 7, 
10, and 13 Day 1b
Off 
Treatmentc
Long-term 
Follow-upd
EDC Timepoints∞
∞: Column only relevant for CRF builders.
a.
Participants who relapse following confirmed CR will be required to undergo repeat radiologic scans (if not performed within the prior 3 months) and bone marrow biopsy / aspirate (if 
not performed within the prior 6 months) prior to re-treatment as described in Section 11.1 and Section 11.2.
b.
A ± 7 day scheduling window is allowable to account for holidays, adverse weather, vacations, or any other scheduling issues.
c.
Off treatment evaluation. Note: for IND trials, follow up visits or other contact are required in order to identify SAEs during the 30 days following the end of study treatment. Participants 
coming off treatment at the completion of retreatment cycle 13 will undergo a single visit/set of assessments to meet both the off treatment and C13D1 trial requirements (not two 
separate visits).
d.
Long-term follow-up will involve medical record review, telephone and/or care provider contact to confirm survival status and ongoing disease response following treatment 
discontinuation. To be completed every 3 months following the final dose of study drug (±1 month window) for a maximum of 5 years after treatment discontinuation or until death, 
whichever occurs first.
e.
Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, potassium, total protein, SGOT [AST], SGPT [ALT], sodium, phosphorus, uric acid, 
LDH.
f.
Marrow sample requested for correlative studies if bone marrow biopsy is done as standard of care. Flow cytometry (lymphoma panel), karyotype, and FISH (CLL) should be performed 
on marrow at all bone marrow biopsies (FISH may be performed on either marrow or blood and is not required on both). MRD should be performed on the marrows to evaluate 
response at years 1 and 2.
g.
Adequate supply of the study agent should be dispensed to account for any pre-planned scheduling delays.
h.
CMV surveillance by PCR approximately every 3 cycles during treatment with umbralisib and approximately 30 days after the last dose of umbralisib, aligned with scheduled visits.

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Table 23: Study Calendar for Participants NOT in CR Cycles 13 - 24
Cycle 13 Day 
1a
Cycles 15, 18 
Day 1b
Cycles 21, 25 
Day 1a
Off Treatmentc
Long-term 
Follow-upd
EDC Timepoints∞
Physical exam
X
X
X
X
N/A
Vital signse
X
X
X
X
N/A
Weight
X
X
X
X
N/A
ECOG performance status
X
X
X
X
Day 1 of cycle 13, 15, 18, 21, and 25, Off Treatment
CBC w/diff, plts
X
X
X
X
Day 1 of cycle 13, 15, 18, 21, and 25, Off Treatment
Serum chemistrye
X
X
X
X
N/A
CMV surveillance by PCRi
X
X
X
X
EKG
As Clinically Indicated
N/A
Adverse Event Evaluation
X------------------------------------------------------X
X
All Visits
Radiologic evaluation
CT or MRI scans to be repeated as described in Section 11.1
Day 28 of cycle 17 and 24, Off Treatment, and to 
confirm CR
Bone marrow biopsy / aspirate / MRD 
assessmentf
To be repeated as described in Sections 9.6 and 11.2.
Day 1 of cycle 13 and 25 and to confirm CR
Peripheral Blood MRD Analysis
X
X
X
X
Day 1 of cycle 13, 15, 18, 21, and 25, Off Treatment
Correlative Analyses
As described in Section 9.
N/A
Acalabrutinibh
As described in Section 5.3
Day 1 of Cycles 13 - 24
Umbralisibh
As described in Section 5.3
Day 1 of Cycles 13 - 24
Medical Record Review / Care Provider Contact / 
Telephone Contact
X
Every 3 months following treatment discontinuation for 
a maximum of 5 years

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Table 23: Study Calendar for Participants NOT in CR Cycles 13 - 24
Cycle 13 Day 
1a
Cycles 15, 18 
Day 1b
Cycles 21, 25 
Day 1a
Off Treatmentc
Long-term 
Follow-upd
EDC Timepoints∞
∞: Column only relevant for CRF builders.
a.
A ± 7 day scheduling window is allowable to account for holidays, adverse weather, vacations, or any other scheduling issues.
b.
A ± 3 day scheduling window is allowable to account for holidays, adverse weather, vacations, or any other scheduling issues.
c.
Off treatment evaluation. Note: for IND trials, follow up visits or other contact are required in order to identify SAEs during the 30 days following the end of study treatment. Participants 
coming off treatment at the completion of cycle 24 will undergo a single visit/set of assessments to meet both the off treatment and C25D1 trial requirements (not two separate visits).
d.
Long-term follow-up will involve medical record review, telephone and/or care provider contact to confirm survival status and ongoing disease response following treatment 
discontinuation. To be completed every 3 months following the final dose of study drug (±1 month window) for a maximum of 5 years after treatment discontinuation or until death, 
whichever occurs first.
e.
Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, potassium, total protein, SGOT [AST], SGPT [ALT], sodium, phosphorus, uric acid, 
LDH.
f.
Marrow sample requested for correlative studies if bone marrow biopsy is done as standard of care. Flow cytometry (lymphoma panel), karyotype, and FISH (CLL) should be performed 
on marrow at all bone marrow biopsies (FISH may be performed on either marrow or blood and is not required on both). MRD should be performed on the marrows to evaluate 
response at years 1 and 2.
g.
Adequate supply of the study agent should be dispensed to account for any pre-planned scheduling delays.
h.
CMV surveillance by PCR approximately every 3 cycles during treatment with umbralisib and approximately 30 days after the last dose of umbralisib, aligned with scheduled visits.

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10. MEASUREMENT OF EFFECT
Response and progression of CLL participants will be evaluated using the 2018 iwCLL criteria for 
CLL.1
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination when both methods have been used to assess 
the anti-tumor effect of a treatment.
Clinical lesions will only be considered measurable when they are superficial (e.g., skin nodules 
and palpable lymph nodes). For the case of skin lesions, documentation by color photography, 
including a ruler to estimate the size of the lesion, is recommended. All lymph node 
measurements should be taken and recorded in metric notation, using a ruler, calipers, or 
digital measurement tool.
 
10.1 Imaging Evaluations
All participants will have screening CT or MRI scans of the chest, abdomen, and pelvis within 30 
days prior to the start of protocol therapy. Scans will be repeated on day 28 (± 7 day scheduling 
window) of cycles 2, 6, 12, 17, and 24, as well as at the off-treatment visit. Cycle 17 scan may be 
omitted for participants in confirmed CR at the treating investigator’s discretion. 
In addition, scans will be repeated at any point to confirm a CR and in any participant with 
suspected relapse following achievement of CR (if not done within the prior three months). 
Participants who undergo re-treatment will have scans on day 28 of re-treatment cycles 2, 6, 
and 12 as well as at the off-treatment visit (± 7 day scheduling window). Scans may also be 
repeated at any other time at the discretion of the treating investigator.
Conventional CT and MRI should be performed. These techniques should be performed with 
cuts of 10 mm or less in slice thickness contiguously. Spiral CT should be performed using a 5 
mm contiguous reconstruction algorithm.
10.2 Bone Marrow Biopsy / Aspirate
Screening bone marrow biopsy / aspirate is required for all participants and may be obtained 
up to 90 days prior to the start of protocol therapy as long as no intervening therapy has 
occurred. Repeat bone marrow biopsy / aspirate is required on day 1 of cycles 7, 13, and 25 (i.e. 
at the completion of 24 cycles of therapy), with an allowable ± 7 day window (cycle 7 day 1 
bone marrow must be performed prior to the initiation of ublituximab therapy). Bone marrow 
biopsy / aspirate is also required at any point to confirm a CR, at the time of suspected relapse 
following achievement of CR (if not done within the prior 6 months), and on re-treatment cycle 
13 day 1 for participants who undergo re-treatment (± 7 day window). Bone marrow biopsy / 
aspirate may also be done at any time at the treating investigator’s discretion.

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10.3 Response Criteria
Table 24: Response Definition Following Treatment of CLL Participants
Group
Parameter
Complete 
Remission 
(CR)1
Partial 
Remission 
(PR)2
Stable 
Disease 
(SD)3
Progressive 
Disease (PD)4
Lymph nodes
None ≥ 1.5 cm
Decrease ≥ 50% 
(from baseline)5
Change of -49% 
to +49%
Increase ≥ 50% 
from
baseline or from
response
Liver and/or 
spleen size6
Spleen size < 13 
cm;
liver size normal
Decrease ≥ 50% 
(from
baseline)
Change of -49% 
to +49%
Increase ≥ 50% 
from
baseline or from
response
Constitutional 
symptoms
None
Any
Any
Any
A
Circulating
lymphocyte 
count
Normal
Decrease ≥ 50% 
from
baseline
Change of -49% 
to +49%
Increase ≥ 50% 
from
Baseline
Platelet count
≥ 100 × 109/L
≥ 100 × 109/L or 
increase
≥ 50% over 
baseline
Change of -49% 
to +49%
Decrease of ≥ 
50% from
baseline 
secondary
to CLL
Hemoglobin
≥ 11.0 g/dL 
(untransfused
and without
erythropoietin)
≥ 11 g/dL or 
increase
≥ 50% over 
baseline
Increase < 11.0 
g/dL
or < 50% over 
baseline,
or decrease < 2 
g/dL
Decrease of ≥2 
g/dL from
baseline 
secondary
to CLL
B
Marrow
Normocellular, 
no CLL
cells, no B-
lymphoid
nodules
Presence of CLL 
cells, or
of B-lymphoid 
nodules,
or not done
No change in 
marrow
infiltrate
Increase of CLL 
cells by
≥ 50% on 
successive
biopsies
1.
For CR, all criteria have to be met from groups A and B.
2.
For PR, at least 2 of the parameters of group A and 1 parameter of group B need to improve if previously 
abnormal; if only 1 parameter of both groups A and B is abnormal before therapy, only 1 needs to 
improve.
3.
For SD, all of the criteria have to be met.
4.
For PD, at least 1 of the criteria of group A or group B has to be met.
5.
Sum of the products of 6 or fewer lymph nodes (as evaluated by CT scans and physical examination in 
clinical trials or by physical examination in general practice).
6.
Spleen size is considered normal if < 13 cm. There is no firmly established international consensus on 
the size of a normal liver; therefore, liver size should be evaluated by imaging and manual palpation in 
accordance with local standard of care guidelines.

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10.4 Definitions
Treatment Failure: Responses that should be considered clinically beneficial include CR 
and PR; all others (e.g., stable disease, non-response, PD, death from any cause) should 
be rated as a treatment failure.
Overall Survival (OS): Defined as the time from first treatment day to death due to any 
cause, or censored at date last known alive.
Progression-Free Survival (PFS): Defined as the time from first treatment day to the 
earlier of progression or death due to any cause. Participants alive without disease 
progression are censored at date of last disease evaluation.
Event-Free Survival (EFS): Defined as the interval between the first treatment day to the 
first sign of disease progression or start of a new treatment or withdrawal from the trial 
because of toxicity or death (whichever occurs first).
Time to Next Treatment (TTNT): Defined as the interval between the first treatment day 
until the patient starts an alternative therapy for progressive CLL.
Relapse: Defined as evidence of disease progression in a patient who has previously 
achieved the above criteria of a CR or PR for ≥ 6 months.
Refractory Disease: Defined as treatment failure or as progression within 6 months from 
the last dose of therapy.
Minimal Residual Disease (MRD)-Negative: Blood or marrow with < 1 CLL cell per 10,000 
leukocytes assessed by at least four color flow cytometry (MRD flow), allele-specific 
oligonucleotide PCR, or high-throughput sequencing using the ClonoSEQ assay.
Complete Remission with incomplete marrow recovery (CRi): Some patients fulfill all the 
criteria for a CR, but have a persistent anemia, thrombocytopenia or neutropenia 
apparently unrelated to CLL, but related to drug toxicity. These patients should be 
considered as a different category of remission, CR with incomplete marrow recovery 
(CRi). The marrow evaluation should be performed with scrutiny and not show any 
clonal disease infiltrate.
10.5 Response Review
Confirmation of scan results will be reviewed centrally by the Tumor Imaging Metrics Core 
(TIMC) at DF/HCC, however treatment decisions may be made based on local scan 
interpretation. 

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11. 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).
11.1 Data Reporting
11.1.1 Method
The Office of Data Quality (ODQ) will collect, manage, and perform quality checks on the 
data for this study.
11.1.2 Responsibility for Data Submission
Investigative sites within DF/HCC or DF/PCC are responsible for submitting data and/or 
data forms to the Office of Data Quality (ODQ) in accordance with DF/HCC policies. 
11.2 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 medical oncologists, research 
nurses, pharmacists and biostatisticians with direct experience in cancer clinical research.  
Information that raises any questions about participant safety will be addressed with the 
Sponsor-Investigator and study team.
The DSMC will review each protocol up to four times a year with the frequency determined by 
the outcome of previous reviews. 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 
within 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. 
11.3 Multi-Center Guidelines
This protocol will adhere to DF/HCC Policy MULTI-100 and the requirements of the DF/HCC 
Multi-Center Data and Safety Monitoring Plan. The specific responsibilities of the Sponsor-
Investigator, Coordinating Center, and Participating Institutions and the procedures for auditing 
are presented in Appendix C.

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12. STATISTICAL CONSIDERATIONS
12.1 Study Design
An open label, non-randomized phase 2 trial assessing the combination of acalabrutinib, 
umbralisib, and ublituximab in adult participants with chronic lymphocytic leukemia (CLL). 
Participants will be enrolled to one of two treatment cohorts:

Cohort 1: Participants with relapsed disease

Cohort 2: Participants who are treatment naïve
Each cohort will follow a one-stage enrollment design, accruing a maximum of 30 participants. 
12.2 Sample Size, Accrual Rate and Study Duration
A total of 30 participants will be accrued to each cohort, for a maximum total of 60 participants. 
The anticipated overall accrual rate is approximately 4 patients per month, for a planned 
accrual duration of about 15 months. Participants will receive treatment for 24 cycles (2 years) 
and will continue to be followed for a maximum of 5 years following treatment discontinuation 
for survival, for a total study length of approximately 8 years.
Table 25: Accrual Targets
Sex/Gender
Ethnic Category
Females
Males
Total
Hispanic or Latino
1
+
3
=
4
Not Hispanic or Latino
20
+
36
=
56
Ethnic Category: Total of all subjects
21                   (A1)
+     39                  (B1)
=
60
(C1)
Racial Category
American Indian or Alaskan Native
0
+
0
=
0
Asian
1
+
1
=
2
Black or African American
1
+
3
=
4
Native Hawaiian or other Pacific 
Islander
0
+
0
=
0
White
19
+
35
=
54
Racial Category: Total of all subjects
21
(A2)
+
39
(B2) =
60
(C2)
(A1 = A2)
(B1 = B2)
(C1 = C2)
12.3 Interim Monitoring Plan
The triplet combination of umbralisib, ublituximab, and the BTK inhibitor ibrutinib has been 
previously tested in this patient population with an acceptable safety profile.16 Acalabrutinib is 
a second-generation FDA approved BTK inhibitor that is typically better tolerated by patients 
and has fewer off-target side effects than ibrutinib (note that a direct head-to-head study has 

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not been performed).22 This trial will substitute acalabrutinib for ibrutinib to test efficacy of the 
combination. 
If in the first 10 participants who receive at least one cycle of triple therapy with acalabrutinib, 
umbralisib, and ublituximab, 3 or more develop serious toxicity, this will trigger a consultation 
with the DSMC about stopping accrual (see Section 12.2). Toxicities would include the following 
events that occur during the first cycle of triple therapy, unless they are clearly due to 
underlying disease or extraneous causes: grade 4 or higher infusion-related reaction, grade 4 or 
higher infection, or any other grade 3 or higher, clinically significant, non-hematologic toxicity, 
except asymptomatic laboratory abnormalities or nausea/vomiting/diarrhea that improves with 
supportive care. With this design, the probability of triggering a consultation is 0.07 if the true 
but unknown rate of serious toxicity is 10%, 0.18 if the rate is 15%, 0.74 if the rate is 35%, and 
0.83 if the rate is 40%.
12.4 Analysis of Primary Endpoints
The primary endpoint is the rate of CR after 24 cycles of treatment with acalabrutinib, 
umbralisib, and ublituximab in previously untreated and relapsed CLL patients, assessed per 
2018 IW-CLL criteria.1
Nastoupil et al. reported a CR rate of 44% in previously treated CLL participants who received 
ibrutinib, umbralisib, and ublituximab.16 We hypothesize the CR rate will be 44% in Cohort 1; 
given that the depth of response for treatment naïve disease will likely be greater, we 
hypothesize a CR rate of 50% in Cohort 2. 
For Cohort 1, if  10 or more patients achieve CR by the completion of 24 cycles, we will regard 
the treatment as efficacious. This sample size provides an α=0.06 (false positive type I error) 
and power β = 91% (one minus false negative type II error) using a one-sided one sample 
binomial test comparing to a null hypothesis of 20% complete response rate with one BCR 
inhibitor plus an antibody.
For Cohort 2, if 13 or more patients achieve CR by the completion of 24 cycles, we will regard 
the treatment as efficacious. This sample size provides an α=0.08 (false positive type I error) 
and power β = 82% (one minus false negative type II error) using a one-sided one sample 
binomial test comparing to a null hypothesis of 30% response rate for one BCR inhibitor plus an 
antibody.
12.5 Analysis of Secondary and Exploratory Endpoints
The analysis of secondary endpoints will be primarily descriptive, including rate of PR and CRi 
after 24 cycles of therapy, as well as best achieved rate of PR, CR, and CRi; PFS, time to new 
therapy (TTNT), and OS (including 2-year, 3-year, and 5-year landmark rates), rate of 
undetectable MRD in the bone marrow after 6, 12 and 24 cycles, rate of peripheral blood 
undetectable MRD after 6, 12, and 24 cycles, correlation between undetectable MRD in the 

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peripheral blood and bone marrow, time to MRD-positive disease recurrence in the peripheral 
blood, time to clinical disease progression, and safety/tolerability.
A descriptive analysis of rates of therapy discontinuation by cycle 12 will be performed, with 
subjects grouped by reasons for discontinuation (e.g. achievement of CR, progressive disease, 
or intolerability). Rates of discontinuation of individual components of the regimen will also be 
included in this analysis. 
The Kaplan Meier method will be used to estimate the median PFS time, PFS, median OS time, 
TTNT, and OS.
Association between clinical response and established CLL prognostic factors (ZAP70, FISH 
cytogenetics, IGHV mutation status, TP53 mutation status) will be tested using Fisher’s exact 
test.  A similar descriptive analysis will be performed for laboratory correlative studies of BH3 
profiling and genomic markers such as SF3B1, NOTCH1, and BCR/NFKB pathway somatic 
mutations.  If feasible, association between clinical response and correlative endpoints will be 
explored.
12.6 Reporting and Exclusions
Participants who never initiate protocol therapy will be excluded from all analyses.
12.6.1 Evaluation of Toxicity
All participants will be evaluable for toxicity from the time of their first dose of study 
medication.
12.6.2 Evaluation of the Primary Efficacy Endpoint
All participants who receive at least one dose of at least one of the study agents will be 
considered evaluable for the primary efficacy endpoint in an intent-to-treat analysis.
13. PUBLICATION PLAN
The results should be made public within 24 months of reaching the end of the study. The end 
of the study is the time point at which the last data items are to be reported, or after the 
outcome data are sufficiently mature for analysis, as defined in the section on Sample Size, 
Accrual Rate and Study Duration. If a report is planned to be published in a peer-reviewed 
journal, then that initial release may be an abstract that meets the requirements of the 
International Committee of Medical Journal Editors. A full report of the outcomes should be 
made public no later than three (3) years after the end of the study. 

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15. PROTOCOL AMENDMENTS 
Proposed amendments to the protocol require review and approval by TG Therapeutics, Inc. 
prior to implementation.  

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treatment, response assessment, and supportive management of CLL. Blood. 
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Eichhorst B, Hallek M, Goede V. New treatment approaches in CLL: Challenges and 
opportunities in the elderly. J Geriatr Oncol. 2016;7(5):375-382.
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CLL-IPIwg I. An international prognostic index for patients with chronic lymphocytic 
leukaemia (CLL-IPI): a meta-analysis of individual patient data. Lancet Oncol. 
2016;17(6):779-790.
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Byrd JC, Furman RR, Coutre SE, et al. Three-year follow-up of treatment-naïve and 
previously treated patients with CLL and SLL receiving single-agent ibrutinib. Blood. 
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Brown JR, Byrd JC, Coutre SE, et al. Idelalisib, an inhibitor of phosphatidylinositol 3-
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Kwok M, Rawstron AC, Varghese A, et al. Minimal residual disease is an independent 
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Honigberg LA, Smith AM, Sirisawad M, et al. The Bruton tyrosine kinase inhibitor PCI-
32765 blocks B-cell activation and is efficacious in models of autoimmune disease and B-
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Brown JR, Moslehi J, S OB, et al. Characterization of atrial fibrillation adverse events 
reported in ibrutinib randomized controlled registration trials. Haematologica. 2017.
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Lampson BL, Kasar SN, Matos TR, et al. Idelalisib Given Front-line for Treatment of 
Chronic Lymphocytic Leukemia Causes Frequent Immune-Mediated Hepatotoxicity. 
Blood. 2016;In press.
10.
de Rooij MF, Kuil A, Kater AP, Kersten MJ, Pals ST, Spaargaren M. Ibrutinib and idelalisib 
synergistically target BCR-controlled adhesion in MCL and CLL: a rationale for 
combination therapy. Blood. 2015;125(14):2306-2309.
11.
Niemann CU, Mora-Jensen HI, Dadashian EL, et al. Combined BTK and PI3Kdelta 
Inhibition with Acalabrutinib and ACP-319 Improves Survival and Tumor Control in CLL 
Mouse Model. Clinical cancer research : an official journal of the American Association 
for Cancer Research. 2017;23(19):5814-5823.
12.
Davids MS, Kim HT, Nicotra A, et al. Umbralisib in combination with ibrutinib in patients 
with relapsed or refractory chronic lymphocytic leukaemia or mantle cell lymphoma: a 
multicentre phase 1–1b study. The Lancet Haematology. 2019;6(1):e38-e47.
13.
Sawas A, Farber CM, Schreeder MT, et al. A phase 1/2 trial of ublituximab, a novel anti-
CD20 monoclonal antibody, in patients with B-cell non-Hodgkin lymphoma or chronic 
lymphocytic leukaemia previously exposed to rituximab. Br J Haematol. 
2017;177(2):243-253.
14.
Sharman JP, Brander DM, Mato A, et al. UBLITUXIMAB AND IBRUTINIB FOR PREVIOUSLY 

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TREATED GENETICALLY HIGH-RISK CHRONIC LYMPHOCYTIC LEUKEMIA: RESULTS OF THE 
GENUINE PHASE 3 STUDY. Hematological Oncology. 2017;35:111-112.
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Lunning MA, Vose J, Fowler N, et al. Ublituximab + TGR-1202 Demonstrates Activity and 
a Favorable Safety Profile in Relapsed/Refractory B-Cell NHL and High-Risk CLL: Phase I 
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16.
Nastoupil LJ, Lunning MA, Vose JM, et al. Tolerability and activity of ublituximab, 
umbralisib, and ibrutinib in patients with chronic lymphocytic leukaemia and non-
Hodgkin lymphoma: a phase 1 dose escalation and expansion trial. The Lancet 
Haematology. 2019;6(2):e100-e109.
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Kohrt HE, Sagiv-Barfi I, Rafiq S, et al. Ibrutinib antagonizes rituximab-dependent NK cell-
mediated cytotoxicity. Blood. 2014;123(12):1957-1960.
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Skarzynski M, Niemann CU, Lee YS, et al. Interactions between Ibrutinib and Anti-CD20 
Antibodies: Competing Effects on the Outcome of Combination Therapy. Clinical cancer 
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Pavlasova G, Borsky M, Seda V, et al. Ibrutinib inhibits CD20 upregulation on CLL B cells 
mediated by the CXCR4/SDF-1 axis. Blood. 2016;128(12):1609-1613.
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Burger JA, Keating MJ, Wierda WG, et al. Safety and activity of ibrutinib plus rituximab 
for patients with high-risk chronic lymphocytic leukaemia: a single-arm, phase 2 study. 
Lancet Oncol. 2014;15(10):1090-1099.
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Woyach JA, Ruppert AS, Heerema NA, et al. Ibrutinib Regimens versus 
Chemoimmunotherapy in Older Patients with Untreated CLL. New England Journal of 
Medicine. 2018;379(26):2517-2528.
22.
Byrd JC, Wierda WG, Schuh A, et al. Acalabrutinib Monotherapy in Patients with 
Relapsed/Refractory Chronic Lymphocytic Leukemia: Updated Results from the Phase 
1/2 ACE-CL-001 Study. Blood. 2017;130(Suppl 1):498-498.
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Golay J, Ubiali G, Introna M. The specific Bruton tyrosine kinase inhibitor acalabrutinib 
(ACP-196) shows favorable in vitro activity against chronic lymphocytic leukemia B cells 
with CD20 antibodies. Haematologica. 2017;102(10):e400-e403.
24.
Rawstron A, Munir T, Brock K, et al. Ibrutinib and Obinutuzumab in CLL: Improved MRD 
Response Rates with Substantially Enhanced MRD Depletion for Patients with &gt;1 Year 
Prior Ibrutinib Exposure. Blood. 2018;132(Suppl 1):181.
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Prasanna R VS. PI3Kgamma enzyme assay. Shameerpet, India: Incozen 
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Seeta N VS. AKT phosphorylation in THP-1 cells. Study Report IVT-5264-ATP-08. 
Shameerpet, India: Incozen Therapeuticis PVT Ltd;2011.
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Seeta N VS. AKT phosphorylation in MOLT-4 cells. June Study Report IVT-5264-APM-10. 
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28.
Esteves IT DC, Herveau S, Reslan L, Brune F, Van Overtvelt L, Salcedo M, Fournes B. LFB-
R603 (ublituximab), a third-generation monoclonal anti-CD20 antibody, displays additive 
antitumor activity with antileukemic chemotherpeutic agents in mouse xenograft 

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models. American Society of Hematology. 2011:abstract 1660.
29.
de Romeuf C DC, Le Garff-Tavernier M, Fournier N, Gaucher C, Glacet A, Jorieux S, 
Bihoreau N, Behrens CK, Beliard R, Vieillard V, Cazin B, Bourel D, Prost JF, Teillaud JC, 
Merle-Beral H. Chronic lymphocytic leukaemia cells are effeciently killed by an anti-CD20 
monoclonal antibody selected for improved engagement of FcgammaRIIIA/CD16. British 
Journal of Haematology. 2008;6(140):635-643.
30.
Cazin B LS, Coiffier B, Aurran T, Cartron G, Feugier P, Brehar O, Sadoun A, Sportelli P, 
Miskin H, ribrag V. Final results of a multicenter phase Ib single agent study with the 
novel anti-CD20 monoclonal antibody ublituximab (TG-1101) in patients with relapsed 
chronic lymphocytic leukemia (CLL). Paper presented at: European Hematology 
Assocation2013; Stockholm.
31.
Lunning MA, Vose JM, Schreeder MT, et al. Ublituximab, a novel glycoengineered anti-
CD20 mAb, in combination with TGR-1202, a next generation once daily PI3Kdelta 
inhibitor, demonstrates activity in heavily pre-treated and high-risk chronic lymphocytic 
leukemia and B-cell lymphoma. Paper presented at: American Society of 
Hematology2014; San Francisco, CA.
32.
Ryan JA, Brunelle JK, Letai A. Heightened mitochondrial priming is the basis for 
apoptotic hypersensitivity of CD4+ CD8+ thymocytes. Proc Natl Acad Sci U S A. 
2010;107(29):12895-12900.
33.
Davids MS, Deng J, Wiestner A, et al. Decreased mitochondrial apoptotic priming 
underlies stroma-mediated treatment resistance in chronic lymphocytic leukemia. 
Blood. 2012;120(17):3501-3509.
34.
Wang L, Lawrence MS, Wan Y, et al. SF3B1 and Other Novel Cancer Genes in Chronic 
Lymphocytic Leukemia. New England Journal of Medicine. 2011;365(26):2497-2506.
35.
Landau DA, Carter SL, Stojanov P, et al. Evolution and impact of subclonal mutations in 
chronic lymphocytic leukemia. Cell. 2013;152(4):714-726.

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

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APPENDIX B: HEPATITIS B SEROLOGIC TEST RESULTS
 

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APPENDIX C: DANA-FARBER/HARVARD CANCER CENTER MULTI-CENTER DATA SAFETY 
MONITORING PLAN
INTRODUCTION
The Dana-Farber/Harvard Cancer Center Multi-Center Data and Safety Monitoring Plan (DF/HCC 
DSMP) outlines the procedures for conducting a DF/HCC Multi-Center research protocol. The 
DF/HCC DSMP serves as a reference for any sites external to DF/HCC that are participating in a 
DF/HCC clinical trial. 
1.1 Purpose
To establish standards that will ensure that a Dana-Farber/Harvard Cancer Center Multi-Center 
protocol will comply with Federal Regulations, Health Insurance Portability and Accountability 
Act (HIPAA) requirements and applicable DF/HCC Standard Operating Procedures.
2
GENERAL ROLES AND RESPONSIBILITIES
For DF/HCC Multi-Center Protocols, the following general responsibilities apply, in addition to 
those outlined in DF/HCC Policies for Sponsor-Investigators: 
2.1 External Site
An External Site is an institution that is outside the DF/HCC and DF/PCC consortium that is 
collaborating with DF/HCC on a protocol where the sponsor is a DF/HCC investigator.  The 
External Site acknowledges the DF/HCC Sponsor as having the ultimate authority and 
responsibility for the overall conduct of the study. 
Each External Site is expected to comply with all applicable DF/HCC requirements stated within 
this Data and Safety Monitoring Plan and/or the protocol document.
The general responsibilities for each External Site may include but are not limited to:

Document the delegation of research specific activities to study personnel.

Commit to the accrual of participants to the protocol.

Submit protocol and/or amendments to their local IRB. For studies under a single IRB, 
the Coordinating Center with regulatory documents or source documents as requested.

Maintain regulatory files as per ICH GCP and federal requirements.

Provide the Coordinating Center with regulatory documents or source documents as 
requested.

Participate in protocol training prior to enrolling participants and throughout the trial as 
required.

Update Coordinating Center with research staff changes on a timely basis.

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
Register participants through the Coordinating Center prior to beginning research 
related activities when required by the sponsor.

Submit Serious Adverse Event (SAE) reports to the Sponsor, Coordinating Center, and 
IRB of Record as applicable. 

Submit protocol deviations and violations to sponsor, Coordinating Center, and IRB of 
record as applicable, in accordance with DF/HCC requirements.

Order, store and dispense investigational agents and/or other protocol mandated drugs 
per federal guidelines and protocol requirements.

Participate in any quality assurance activities and meet with monitors or auditors at the 
conclusion of a visit to review findings.

Promptly provide follow-up and/or corrective action plans for any monitoring queries or 
audit findings.

Notify the sponsor immediately of any regulatory authority inspection of this protocol at 
the External Site.
3
DF/HCC REQUIREMENTS FOR MULTI-CENTER PROTOCOLS
Certain DF/HCC Policy requirements apply to External Sites participating in DF/HCC research. 
The following section will clarify DF/HCC requirements and further detail the expectations for 
participating in a DF/HCC Multi-Center protocol. 
3.1 Protocol Revisions and Closures
The External Sites will receive notification of protocol revisions and closures from the 
Coordinating Center.  When under a separate IRB, it is the individual External Site’s 
responsibility to notify its IRB of these revisions.

Protocol revisions: External Sites will receive written notification of protocol revisions 
from the Coordinating Center. All protocol revisions must be IRB approved and 
implemented within a timely manner from receipt of the notification.

Protocol closures and temporary holds: External Sites will receive notification of 
protocol closures and temporary holds from the Coordinating Center. Closures and 
holds will be effective immediately.  In addition, the Coordinating Center, will update 
the Participating Institutions on an ongoing basis about protocol accrual data so that 
they will be aware of imminent protocol closures.
3.2 Informed Consent Requirements
The DF/HCC approved informed consent document will serve as a template for the informed 
consent for External Sites. The External Site consent form must follow the consent template as 
closely as possible and should adhere to specifications outlined in the DF/HCC Guidance 

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Document on Model Consent Language for Investigator-Sponsored Multi-Center Trials.  This 
document will be provided separately to each External Site upon request.
External Sites are to send their version of the informed consent document to the Coordinating 
Center for review and approval prior to submission to their local IRB. The approved consent 
form must also be submitted to the Coordinating Center after approval by the local IRB for all 
consent versions.
The Principal Investigator (PI) at each External Site will identify the physician members of the 
study team who will be obtaining consent and signing the consent form for therapeutic 
protocols. External Sites must follow the DF/HCC requirement that for all interventional drug, 
biologic, or device research, only attending physicians may obtain initial informed consent and 
any re-consent that requires a full revised consent form.  
3.3 IRB Re-Approval
Verification of IRB re-approval from the External Sites is required in order to continue research 
activities.  There is no grace period for continuing approvals.
The Coordinating Center will not register participants if a re-approval letter is not received from 
the Participating Institution on or before the anniversary of the previous approval date.  
3.4 DF/HCC Multi-Center Protocol Confidentiality
All documents, investigative reports, or information relating to the participant are strictly 
confidential. Whenever reasonably feasible, any participant specific reports (i.e. Pathology 
Reports, MRI Reports, Operative Reports, etc.) submitted to the Coordinating Center should be 
de-identified. It is recommended that the assigned protocol case number (as described below) 
be used for all participant specific documents. Participant initials may be included or retained 
for cross verification of identification. 
3.5 Participant Registration
3.5.1
Participant Registration 
To register a participant, the following documents should be completed by the External Site 
and e-mailed to the Coordinating Center: 
Kim E. Pena del Aguila
Dana-Farber Cancer Institute
450 Brookline Ave
Boston, MA 02215
Email: kime_penadelaguila@dfci.harvard.edu 
Phone: 857-215-1707

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
Signed participant consent form

HIPAA authorization form

DFCI eligibility checklist

Screening provider note including the medical/surgical history, ECOG performance 
status, vital signs, and physical exam findings

Copies of laboratory reports and clinical information confirming satisfaction of 
eligibility criteria.
The Coordinating Center will review the submitted documents in order to verify eligibility 
and consent. To complete the registration process, the Coordinating Center will:

Register the participant on the study with the DF/HCC Clinical Trial Management System 
(CTMS).

Upon receiving confirmation of registration, the Coordinating Center will inform the 
External Site and provide the study specific participant case number, and if applicable, 
assigned treatment and/or dose level. 
At the time of registration, the following identifiers are required for all subjects: initials, date of 
birth, gender, race and ethnicity. Once eligibility has been established and the participant 
successfully registered, the participant is assigned a unique protocol case number. External 
Sites should submit all de-identified subsequent communication and documents to the 
Coordinating Center, using this case number to identify the subject.  
3.5.2
Initiation of Therapy
Participants must be registered with the DF/HCC CTMS before the initiation of treatment or 
other protocol-specific interventions.  Treatment and other protocol-specific interventions may 
not be initiated until the External Site receives confirmation of the participant’s registration 
from the Coordinating Center. The DF/HCC Sponsor and DFCI IRB must be notified of any 
violations to this policy.
3.5.3
Eligibility Exceptions
No exceptions to the eligibility requirements for a protocol without DFCI IRB approval will be 
permitted. All External Sites are required to fully comply with this requirement. The process for 
requesting an eligibility exception is defined below.

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3.6 Data Management
DF/HCC develops case report forms (CRF/eCRFs), for use with the protocol.  These forms are 
designed to collect data for each study. DF/HCC provides a web-based training for all eCRF 
users.
  
3.6.1
Data Forms Review
Data submissions are monitored for timeliness and completeness of submission. If study forms 
are received with missing or questionable data, the submitting institution will receive a written 
or electronic query from the DF/HCC Office of Data Quality, Coordinating Center, or designee.  
Responses to all queries should be completed and submitted within 14 calendar days.  
If study forms are not submitted on schedule, the External Site will periodically receive a 
Missing Form Report from the Coordinating Center noting the missing forms. 
3.7 Protocol Reporting Requirements
3.7.1
Protocol Deviations, Exceptions and Violations
Federal Regulations require an IRB to review proposed changes in a research activity to ensure 
that researchers do not initiate changes in approved research without IRB review and approval, 
except when necessary to eliminate apparent immediate hazards to the participant. DF/HCC 
requires all departures from the defined procedures set forth in the IRB approved protocol to 
be reported to the DF/HCC Sponsor and to the IRB of record.
3.7.2
Reporting Procedures
Requests to deviate from the protocol require approval from the IRB of record and the sponsor.
All protocol violations must be sent to the Coordinating Center in a timely manner.  The 
Coordinating Center will provide training for the requirements for the reporting of violations. 
3.7.3
Guidelines for Processing IND Safety Reports 
The DF/HCC Sponsor will review all IND Safety Reports per DF/HCC requirements and ensure 
that all IND Safety Reports are distributed to the External Sites as required by DF/HCC Policy. 
External Sites will review/submit to the IRB according to their institutional policies and 
procedures.

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4
MONITORING: QUALITY CONTROL
The Coordinating Center, with the aid of the DF/HCC Office of Data Quality, provides quality 
control oversight for the protocol.
4.1 Ongoing Monitoring of Protocol Compliance
The External Sites may be required to submit participant source documents to the Coordinating 
Center for monitoring. External Sites may also be subject to on-site monitoring conducted by 
the Coordinating Center. 
The Coordinating Center will implement ongoing monitoring activities to ensure that External 
Sites are complying with regulatory and protocol requirements, data quality, and participant 
safety. Monitoring practices may include but are not limited to; source data verification, and 
review and analysis of eligibility requirements, informed consent procedures, adverse events 
and all associated documentation, review of study drug administration/treatment, regulatory 
files, protocol departures reporting, pharmacy records, response assessments, and data 
management. 
External Sites will be required to participate in regular Coordinating Center initiated 
teleconferences. 
Remote Monitoring: External Sites will be required to forward de-identified copies of 
participants’ medical record and source documents to the Coordinating Center to aid in source 
data verification.
and/or
On-Site Monitoring:  Source documentation verification (SDV) will be conducted yearly by 
having access to participants’ complete medical record and source documents.
4.2 Monitoring Reports
The DF/HCC Sponsor will review all monitoring reports to ensure protocol compliance. The 
DF/HCC Sponsor may increase the monitoring activities at External Sites that are unable to 
comply with the protocol, DF/HCC Sponsor requirements or federal and local regulations. 
4.3 Accrual Monitoring
Prior to extending a protocol to an external site, the DF/HCC Sponsor will establish accrual 
requirements for each External Site. Accrual will be monitored for each External Site by the 
DF/HCC Sponsor or designee. Sites that are not meeting their accrual expectations may be 
subject to termination. Minimum site accrual expectations have been set to 3 subjects per year.

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5
AUDITING: QUALITY ASSURANCE
5.1 DF/HCC Internal Audits
 
All External Sites are subject to audit by the DF/HCC Office of Data Quality (ODQ). Typically, 
approximately 3-4 participants would be audited at the site over a 2-day period.  If violations 
which impact participant safety or the integrity of the study are found, more participant records 
may be audited. 
5.2 Audit Notifications
It is the External Site’s responsibility to notify the Coordinating Center of all external audits or 
inspections (e.g., FDA, EMA, NCI) that involve this protocol. All institutions will forward a copy 
of final audit and/or re-audit reports and corrective action plans (if applicable) to the 
Coordinating Center, within 12 weeks after the audit date. 
5.3 Audit Reports 
The DF/HCC Sponsor will review all final audit reports and corrective action plans, if applicable. 
The Coordinating Center must forward any reports to the DF/HCC ODQ per DF/HCC policy for 
review by the DF/HCC Audit Committee. For unacceptable audits, the DF/HCC Audit Committee 
would forward the final audit report and corrective action plan to the DFCI IRB as applicable.
5.4 External Site Performance
The DF/HCC Sponsor and the IRB of record are charged with considering the totality of an 
institution’s performance in considering institutional participation in the protocol.
External Sites that fail to meet the performance goals of accrual, submission of timely and 
accurate data, adherence to protocol requirements, and compliance with state and federal 
regulations, may be put on hold or closed. 

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APPENDIX D: NEW YORK HEART ASSOCIATION CLASSIFICATION
Class
Functional Capacity
Objective Assessment
I
Patients with cardiac disease but without resulting 
limitations of physical activity. Ordinary physical 
activity does not cause undue fatigue, palpitation, 
dyspnea, or anginal pain.
No objective evidence of 
cardiovascular disease.
II
Patients with cardiac disease resulting in slight 
limitation of physical activity. They are comfortable at 
rest. Ordinary physical activity results in fatigue, 
palpitation, dyspnea, or anginal pain.
Objective evidence of 
minimal cardiovascular 
disease.
III
Patients with cardiac disease resulting in marked 
limitation of physical activity. They are comfortable at 
rest. Less than ordinary activity causes fatigue, 
palpitation, dyspnea, or anginal pain.
Objective evidence of 
moderately severe 
cardiovascular disease.
IV
Patients with cardiac disease resulting in inability to 
carry on any physical activity without discomfort. 
Symptoms of heart failure or the anginal syndrome may 
be present even at rest. If any physical activity is 
undertaken, discomfort is increased.
Objective evidence of 
severe cardiovascular 
disease.
Source: The Criteria Committee of New York Heart Association. Nomenclature and Criteria for 
Diagnosis of Diseases of the Heart and Great Vessels. 9th Ed. Boston, MA: Little, Brown & Co; 
1994:253-256.

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APPENDIX E: IWCLL 2018 HEMATOLOGIC TOXICITY GUIDELINES
Table 26: Grading Scale For Hematological Toxicity in CLL Studies1
Grade2
Decrease in platelets3 or hemoglobin4 (nadir) 
from baseline value, %
Absolute neutrophil count 
(nadir)5 × 109/L
0
No change to 10
≥ 2
1
11 – 24
≥ 1 and < 2
2
25 – 49
≥ 1 and < 1
3
50 – 74
≥ 0.5 and < 1
4
≥ 75
< 0.5
1. Refer to iwCLL 2018 Criteria1
2. Grades: 1, mild; 2, moderate; 3, severe; 4, life-threatening; 5, fatal. Death occurring as 
a result of toxicity at any level of decrease from baseline will be recorded as grade 5.
3. Platelet counts must be below normal levels for grades 1-4. If, at any level of decrease 
the platelet count is <20 × 109/L, this will be considered grade 4 toxicity unless a 
severe or life-threatening decrease in the initial platelet count (e.g., 20 × 109/L) was 
present at baseline, in which case the patient is not evaluable for toxicity referable to 
platelet counts.
4. Hb levels must be below normal levels for grades 1-4. Baseline and subsequent Hb 
determinations must be performed before any given transfusions. The use of 
erythropoietin is irrelevant for the grading of toxicity but should be documented.
5. If the absolute neutrophil count (ANC) reaches <1 × 109/L, it should be judged to be 
grade 3 toxicity. Other decreases in the white blood cell count or in circulating 
granulocytes are not to be considered because a decrease in the white blood cell 
count is a desired therapeutic end point. A gradual decrease in granulocytes is not a 
reliable index in CLL for stepwise grading of toxicity. If the ANC was <1 × 109/L before 
therapy, the patient is not evaluable for toxicity referable to the ANC. The use of G-
CSF is irrelevant for the grading of toxicity but should be documented.

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APPENDIX F: ACALABRUTINIB DRUG DIARY
Study Participant Self-Administration Instructions
The study staff will explain how to take acalabrutinib, but these are points to remember:
1. Take the drug twice daily approximately 12 hours apart. 
2. Take the drug with about 8 ounces of water.  Acalabrutinib can be taken with or without 
meals.
3. You may NOT consume:  Grapefruit or grapefruit products, Seville oranges (including 
marmalade containing Seville oranges) or starfruit within the 3-day period prior to the first 
study drug administration and until the last day of treatment is completed due to possible 
CYP3A mediated metabolic interaction.
4. If you miss taking your dose at the scheduled time, it can be taken as soon as possible up to 
3 hours after the scheduled time. If a dose is missed by more than 3 hours, it should be 
skipped, and the next dose should be taken at its regularly scheduled time. Please make 
sure to record the reason for missing the dose. If you vomit a dose, do not take it again 
unless you can see the capsule. 
5. Please remember to bring your study drug supply, including empty bottles and remaining 
pills, and drug diary with you to your clinic appointment.  Please do not throw away any 
empty bottles.  On clinic days please take your study medication on your regular schedule.
6. If you are taking a H2 receptor antagonist, then it should be taken approximately 2 hours 
after an acalabrutinib dose.
7. The drug can be stored at room temperature. 
8. Keep this drug out of the reach of children.
Please call your doctor or research nurse before taking any new prescription or over-the-
counter medications/supplements other than the study drugs or if any other questions arise.

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Study Participant Self-Administration Diary for Acalabrutinib
Please record how many tablets you take and the time you take them and bring the completed diary as well as 
your study drug supply, including empty bottles, to every study visit. This will help us keep track of your study drug 
and how well you are tolerating it.
FOR STUDY TEAM USE ONLY
Staff initials: 
Date dispensed:
Date returned:
# pills/caps/tabs dispensed:
# pills/caps/tabs returned:
# pills/caps/tabs that should have been taken:
Discrepancy Notes:
Participant Identifier: _____________                          Cycle Number: ____________
Protocol #: _____________________                           
Study Doctor: ___________________
Study Nurse: ____________________
Contact Number: ________________
You will take the following number of tablets each time (per dose) as listed in the table below:
Study Drug 
Name
# of tablets to take 
per dose 
# of times 
each day 
Acalabrutinib

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Day
Date
Number of 
Acalabrutinib 
tablets
Time of First Dose each day
Number of 
Acalabrutinib 
tablets
Time of Second Dose each day
1
______:______  □ AM / □ PM 
□ Dose Not Taken  
Why:____________________
______:______  □ AM / □ PM
 □ Dose Not Taken  
Why:_______________
2
______:______  □ AM / □ PM 
□ Dose Not Taken  
Why:____________________
______:______  □ AM / □ PM
 □ Dose Not Taken  
Why:_______________
3
______:______  □ AM / □ PM 
□ Dose Not Taken  
Why:____________________
______:______  □ AM / □ PM
 □ Dose Not Taken  
Why:_______________
4
______:______  □ AM / □ PM 
□ Dose Not Taken  
Why:____________________
______:______  □ AM / □ PM
 □ Dose Not Taken  
Why:_______________
5
______:______  □ AM / □ PM 
□ Dose Not Taken  
Why:____________________
______:______  □ AM / □ PM
 □ Dose Not Taken  
Why:_______________
6
______:______  □ AM / □ PM 
□ Dose Not Taken  
Why:____________________
______:______  □ AM / □ PM
 □ Dose Not Taken  
Why:_______________
7
______:______  □ AM / □ PM 
□ Dose Not Taken  
Why:____________________
______:______  □ AM / □ PM
 □ Dose Not Taken  
Why:_______________
8
______:______  □ AM / □ PM 
□ Dose Not Taken  
Why:____________________
______:______  □ AM / □ PM
 □ Dose Not Taken  
Why:_______________
9
______:______  □ AM / □ PM 
□ Dose Not Taken  
Why:____________________
______:______  □ AM / □ PM
 □ Dose Not Taken  
Why:_______________
10
______:______  □ AM / □ PM 
□ Dose Not Taken  
Why:____________________
______:______  □ AM / □ PM
 □ Dose Not Taken  
Why:_______________
11
______:______  □ AM / □ PM 
□ Dose Not Taken  
Why:____________________
______:______  □ AM / □ PM
 □ Dose Not Taken  
Why:_______________
12
______:______  □ AM / □ PM 
□ Dose Not Taken  
Why:____________________
______:______  □ AM / □ PM
 □ Dose Not Taken  
Why:_______________
13
______:______  □ AM / □ PM 
□ Dose Not Taken  
Why:____________________
______:______  □ AM / □ PM
 □ Dose Not Taken  
Why:_______________
14
______:______  □ AM / □ PM 
□ Dose Not Taken  
Why:____________________
______:______  □ AM / □ PM
 □ Dose Not Taken  
Why:_______________
15
______:______  □ AM / □ PM 
□ Dose Not Taken  
Why:____________________
______:______  □ AM / □ PM
 □ Dose Not Taken  
Why:_______________
16
______:______  □ AM / □ PM 
□ Dose Not Taken  
Why:____________________
______:______  □ AM / □ PM
 □ Dose Not Taken  
Why:_______________

DF/HCC Protocol #: 20-394
Version Date: 04 November 2022
Page 100 of 104
Day
Date
Number of 
Acalabrutinib 
tablets
Time of First Dose each day
Number of 
Acalabrutinib 
tablets
Time of Second Dose each day
17
______:______  □ AM / □ PM 
□ Dose Not Taken  
Why:____________________
______:______  □ AM / □ PM
 □ Dose Not Taken  
Why:_______________
18
______:______  □ AM / □ PM 
□ Dose Not Taken  
Why:____________________
______:______  □ AM / □ PM
 □ Dose Not Taken  
Why:_______________
19
______:______  □ AM / □ PM 
□ Dose Not Taken  
Why:____________________
______:______  □ AM / □ PM
 □ Dose Not Taken  
Why:_______________
20
______:______  □ AM / □ PM 
□ Dose Not Taken  
Why:____________________
______:______  □ AM / □ PM
 □ Dose Not Taken  
Why:_______________
21
______:______  □ AM / □ PM 
□ Dose Not Taken  
Why:____________________
______:______  □ AM / □ PM
 □ Dose Not Taken  
Why:_______________
22
______:______  □ AM / □ PM 
□ Dose Not Taken  
Why:____________________
______:______  □ AM / □ PM
 □ Dose Not Taken  
Why:_______________
23
______:______  □ AM / □ PM 
□ Dose Not Taken  
Why:____________________
______:______  □ AM / □ PM
 □ Dose Not Taken  
Why:_______________
24
______:______  □ AM / □ PM 
□ Dose Not Taken  
Why:____________________
______:______  □ AM / □ PM
 □ Dose Not Taken  
Why:_______________
25
______:______  □ AM / □ PM 
□ Dose Not Taken  
Why:____________________
______:______  □ AM / □ PM
 □ Dose Not Taken  
Why:_______________
26
______:______  □ AM / □ PM 
□ Dose Not Taken  
Why:____________________
______:______  □ AM / □ PM
 □ Dose Not Taken  
Why:_______________
27
______:______  □ AM / □ PM 
□ Dose Not Taken  
Why:____________________
______:______  □ AM / □ PM
 □ Dose Not Taken  
Why:_______________
28
______:______  □ AM / □ PM 
□ Dose Not Taken  
Why:____________________
______:______  □ AM / □ PM
 □ Dose Not Taken  
Why:_______________
Participant/Caregiver Signature: __________________________ Date: _______________________

DF/HCC Protocol #: 20-394
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APPENDIX G: UMBRALISIB DRUG DIARY
Study Participant Self-Administration Instructions
The study staff will explain how to take Umbralisib, but these are points to remember:
1.       Take the drug once daily, approximately every 24 hours. 
2.    Take within 30 minutes of a meal.
3. The tablets should be swallowed whole. Do not attempt to crush, chew, or dissolve the 
tablets.  
4. If you miss taking your dose at the scheduled time, it can be taken as soon as possible up to 
12 hours after the scheduled time. If a dose is missed by more than 12 hours, it should be 
skipped and the next dose should be taken at its regularly scheduled time. Please make sure 
to record the reason for missing the dose. If you vomit a dose, the dose should not be re-
taken. Instead wait until the next regularly scheduled dose.
5. Please remember to bring your study drug supply, including empty bottles and remaining 
pills, and drug diary with you to your clinic appointment.  Please do not throw away any 
empty bottles.  On clinic days please take your study medication on your regular schedule.
6. The drug can be stored at room temperature. 
7. Keep this drug out of the reach of children.
Please call your doctor or research nurse before taking any new prescription or over-the-
counter medications/supplements other than the study drugs or if any other questions arise.

DF/HCC Protocol #: 20-394
Version Date: 04 November 2022
Page 102 of 104
Study Participant Self-Administration Diary for Umbralisib
Please record how many capsules you take and the time you take them and bring the completed diary as well as 
your study drug supply, including empty bottles, to every study visit. This will help us keep track of your study drug 
and how well you are tolerating it.
FOR STUDY TEAM USE ONLY
Staff initials: 
Date dispensed:
Date returned:
# pills/caps/tabs dispensed:
# pills/caps/tabs returned:
# pills/caps/tabs that should have been taken:
Discrepancy Notes:
Participant Identifier: _____________                          Cycle Number: ____________
Protocol #: _____________________                           
Study Doctor: ___________________
Study Nurse: ____________________
Contact Number: ________________
You will take the following number of capsules each time (per dose) as listed in the table below:
Study Drug 
Name
# of capsules (tablets) 
to take per dose 
# of times 
each day 
Umbralisib

DF/HCC Protocol #: 20-394
Version Date: 04 November 2022
Page 103 of 104
Day
Date
Number of Umbralisib 
Capsules
Time of First Dose each day
1
______:______  □ AM / □ PM 
□ Dose Not Taken  Why:____________________
2
______:______  □ AM / □ PM 
□ Dose Not Taken  Why:____________________
3
______:______  □ AM / □ PM 
□ Dose Not Taken  Why:____________________
4
______:______  □ AM / □ PM 
□ Dose Not Taken  Why:____________________
5
______:______  □ AM / □ PM 
□ Dose Not Taken  Why:____________________
6
______:______  □ AM / □ PM 
□ Dose Not Taken  Why:____________________
7
______:______  □ AM / □ PM 
□ Dose Not Taken  Why:____________________
8
______:______  □ AM / □ PM 
□ Dose Not Taken  Why:____________________
9
______:______  □ AM / □ PM 
□ Dose Not Taken  Why:____________________
10
______:______  □ AM / □ PM 
□ Dose Not Taken  Why:____________________
11
______:______  □ AM / □ PM 
□ Dose Not Taken  Why:____________________
12
______:______  □ AM / □ PM 
□ Dose Not Taken  Why:____________________
13
______:______  □ AM / □ PM 
□ Dose Not Taken  Why:____________________
14
______:______  □ AM / □ PM 
□ Dose Not Taken  Why:____________________
15
______:______  □ AM / □ PM 
□ Dose Not Taken  Why:____________________
16
______:______  □ AM / □ PM 
□ Dose Not Taken  Why:____________________
17
______:______  □ AM / □ PM 
□ Dose Not Taken  Why:____________________

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Day
Date
Number of Umbralisib 
Capsules
Time of First Dose each day
18
______:______  □ AM / □ PM 
□ Dose Not Taken  Why:____________________
19
______:______  □ AM / □ PM 
□ Dose Not Taken  Why:____________________
20
______:______  □ AM / □ PM 
□ Dose Not Taken  Why:____________________
21
______:______  □ AM / □ PM 
□ Dose Not Taken  Why:____________________
22
______:______  □ AM / □ PM 
□ Dose Not Taken  Why:____________________
23
______:______  □ AM / □ PM 
□ Dose Not Taken  Why:____________________
24
______:______  □ AM / □ PM 
□ Dose Not Taken  Why:____________________
25
______:______  □ AM / □ PM 
□ Dose Not Taken  Why:____________________
26
______:______  □ AM / □ PM 
□ Dose Not Taken  Why:____________________
27
______:______  □ AM / □ PM 
□ Dose Not Taken  Why:____________________
28
______:______  □ AM / □ PM 
□ Dose Not Taken  Why:____________________
Participant/Caregiver Signature: _________________________ Date:_______________________