A Phase II Study of BTK Inhibitor Acalabrutinib and PI3Kδ Inhibitor Umbralisib in Combination With Ublituximab (AU2) in Patients With Previously Untreated Mantle Cell Lymphoma (MCL)
Phase: PHASE2
Conditions: Mantle Cell Lymphoma
Sponsor: City of Hope Medical Center

 
IRB #20459 
 
03/06/2023 
Packet: 05 
CITY OF HOPE MEDICAL CENTER 
1500 E. DUARTE ROAD 
DUARTE, CA 91010 
 
DEPARTMENT OF HEMATOLOGY AND HEMATOPOIETIC CELL TRANSPLANTATION 
 
TITLE: A Phase II study of BTK inhibitor acalabrutinib and PI3Kδ inhibitor umbralisib in combination 
with ublituximab (AU2) in patients with previously untreated mantle cell lymphoma (MCL) 
 
CITY OF HOPE PROTOCOL VERSION: 
 
IRB #20459 
 
       Protocol Date: 03/06/2023 
 
DATE(S)/ OF AMENDMENT(S)/REVISION(S): 
 
Initial Submission  
 
Protocol dated 12/30/2020 
 
 
 
 
Version: 00 
COH Amendment 01  
Protocol dated 05/27/2021 
 
 
 
 
Packet: 01 
COH Amendment 02  
Protocol dated 08/03/2021 
 
 
 
 
Packet: 02 
COH Amendment 03  
Protocol dated 08/03/2021(TP) 
 
 
 
Packet: 03 
COH Amendment 04             Protocol dated 08/03/2021 (TP)                                             Packet: 04 
COH Amendment 05             Protocol dated 03/06/2023                                                     Packet: 05 
 
 
 
 
DISEASE SITE: 
 
 
 
 
  
 
STAGE: 
 
 
 
 
 
 
 
MODALITY(IES): 
 
 
 
 
  
 
TYPE:  
 
 
 
 
 
  
 
PRINCIPAL INVESTIGATOR: 
 
 
Alexey Danilov, M.D., Ph.D.  
 
PARTICIPATING CLINICIANS: 
 
 
Elizabeth Budde, M.D., Ph.D. 
Alex Herrera, M.D. 
Matthew Mei, M.D. 
Leslie Popplewell, M.D. 
Steven Rosen, M.D. 
Geoffrey Shouse, D.O. 
Tanya Siddiqi, M.D. 
Jasmine Zain, M.D. 
Swetha Kambhampati, M.D. 
John Baird, M.D. 
Tycel Phillips, M.D. 
 
  
 
 
 
 

This document is confidential and for research purposes only. Do not copy, redistribute, disclose or use except as 
authorized.  
 
 
 
 
 
City of Hope National Medical Center 
1500 E. Duarte Road 
Duarte, CA 91010 
Clinical Trial Protocol 
A Phase 2 Study of Acalabrutinib and PI3Kδ inhibitor Umbralisib in Combination with 
Ublituximab (AU2) in Patients with Previously Untreated Mantle Cell Lymphoma 
Version Date: 
03/06/2023 
Protocol Version: 
05  
 
City of Hope #: 
20459 
Agents: 
Acalabrutinib, Umbralisib, Ublituximab 
IND Number: 
153853 
Sponsor/ IND Holder: 
City of Hope 
Funding Support/ Industry partners: 
AstraZeneca, TG Therapeutics 
Industry Partner Protocol ID: 
TG Therapeutics, Inc. tracking number U2-NTG-017  
NCT Number: 
NCT04783415 
Participating Sites: 
City of Hope (Duarte), Arizona Cancer Center, Roswell Park, 
Yale University School of Medicine 
Short Title 
Acalabrutinib, Umbralisib, and Ublituximab (AU2) for 
previously untreated MCL 
 
 
Principal Investigator 
Alexey Danilov, MD, PhD 
City of Hope National Medical Center 
Dept. of Hematology 
T: 626-256-4673 ext. 82405 
Email: adanilov@coh.org 
Coordinating Center 
Data Coordinating Center 
City of Hope National Medical Center 
Email: DCC@coh.org 
 
 

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PROTOCOL TEAM 
Biostatistician 
Lu Chen, PhD 
City of Hope National Medical Center 
Dept. of Computational and 
Quantitative Medicine 
T: 626-256-4673 x 86626 
Email: lchen@coh.org 
Protocol Development Scientist 
Sandrine Puverel, PhD 
City of Hope National Medical Center 
Dept. of Hematology 
T: 626-256-4673 x 84220 
Email: spuverel@coh.org  
  
 
 
Participating non-COH sites 
Site Lead Investigator 
Daniel Persky, MD 
Arizona Cancer Center 
T: 888-366-5491 
Email: DPersky@uacc.arizona.edu 
 
Site Lead Investigator 
Pallawi Torka, MD 
Roswell Park Cancer Institute 
T: 716-845-4485 
Email: Pallawi.Torka@roswellpark.org 
 
 
Site Lead Investigator 
Shalin Kothari, MD 
Yale University School of Medicine 
T: 203-737-3509 
Email: shalin.kothari@yale.edu 
 
 
 
 
 
 
 

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STUDY SCHEMA 
 
Each cycle = 28 days 
 
* Participants with stable disease (SD) or better response (PR, CR) at the end of Induction will be eligible to proceed to 
Maintenance. 
** And every 6 months thereafter until end of protocol therapy. 
1 Disease staging will be by PET/CT (preferred) or CT (with Study PI’s approval). Refer to Study Calendar and Section 11.1 for 
details. 
2 Peripheral blood for correlative studies. Blood will also be collected at time of relapse. Refer to Section 9.1.3 for additional 
details and a list of time points. 
3 EOM = End of maintenance. Visit to occur at the end of Cycle 25. 
4 Participants may continue therapy with acalabrutinib beyond 25 cycles of protocol therapy at the treating physician’s 
discretion. 
5 Safety visit (within 30 days from last dose of protocol therapy).  
6 Active Follow-up will include staging after 6, 12, 18, and 24 months from last on-treatment scan, and will occur until disease 
progression or initiation of a new anti-lymphoma therapy. Refer to Section 5.8 and Study Calendar. 
Each participant will be on study for a maximum of 6 years. Participants who continue therapy beyond 25 cycles with 
acalabrutinib for a total of 6 years of protocol therapy will only proceed with the safety follow-up visit; there will be no 
response/survival follow-up for these patients. Refer to Section 5.7. 
 

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PROTOCOL SYNOPSIS 
Protocol Title 
A Phase 2 Study of Acalabrutinib and PI3Kδ inhibitor Umbralisib in Combination with Ublituximab (AU2) in 
Patients with Previously Untreated Mantle Cell Lymphoma 
Study Detail 
Population/Indication(s): 
Previously untreated Mantle Cell Lymphoma 
Phase: 
2 
Sample Size: 
Expected: 24; Maximum: 27 
Estimated Accrual Duration: 
2 years 
Estimated Study Duration 
7 years 
Participant Duration: 
5.5 years 
Participating Sites: 
 City of Hope Duarte, CA 
 Arizona Cancer Center 
 Roswell Park Cancer Institute 
 Yale University School of Medicine 
Study Agents: 
Acalabrutinib, Umbralisib, Ublituximab 
Sponsor: 
City of Hope 
Industry Partners:  AstraZeneca, TG Therapeutics  
 
 
 
 
Rationale for this Study 
A combination of bendamustine and rituximab (BR) has become an accepted standard in frontline therapy of newly 
diagnosed MCL among patients who are poor candidates for intensive chemotherapy regimens and autologous stem cell 
transplantation. However, BR regimen is not curative, and the majority of patients ultimately relapse within 5 years. In 
addition, chemo-immunotherapy combinations have limited efficacy in MCL with aberrant TP53 and/or complex karyotype 
(CK). Thus, achievement of a durable remission following upfront therapy of MCL remains an important goal in lymphoma 
therapeutics, and MCL with TP53 aberrations and CK is a particular area of unmet need. 
Emerging data indicate that upfront therapy with ibrutinib-rituximab combination is associated with 100% ORR in MCL. 
Therefore, BTK inhibitors combined with CD20-targeting agents are poised to be effective in upfront setting in MCL. 
However, patients who develop resistance to ibrutinib have dismal outcomes. Activation of the phosphoinotiside-3 kinase 
(PI3K) pathway has been implicated in resistance to chemotherapy and ibrutinib in MCL, and thus represents an actionable 
target in this disease. Idelalisib, a selective PI3Kδ inhibitor, has demonstrated single agent efficacy in relapsed/refractory 
MCL, albeit responses were short-lived. Moreover, additive or synergistic effects of the combination of ibrutinib and 
idelalisib have been reported in pre-clinical studies in lymphoid malignanices. Thus, combined targeting of BTK and PI3K 
may result in improved efficacy in MCL and prevent disease relapse, particularly when employed in the frontline setting. 
Acalabrutinib is a next-generation BTK inhibitor that shows higher selectivity for BTK, while simultaneously lacking 
irreversible inhibition of other kinases. This higher target selectivity is expected to contribute to the improved safety profile 
over that of ibrutinib. Acalabrutinib is at least as efficacious as ibrutinib in MCL and it is expected to have fewer toxicities 
than ibrutinib. 
Umbralisib is a highly-specific orally available dual inhibitor of PI3K-δ and casein kinase 1 epsilon (CK1ε) with nanomolar 
inhibitory potency. Umbralisib is currently being investigated in clinical trials in lymphoma. The first report suggested high 
tolerability of umbralisib, with decreased rates of colitis, pneumonitis and hepatic abnormalities compared to other PI-3Kδ 
inhibitors. The extended integrated safety follow-up results from 5 clinical trials using umbralisib that we presented at ASH 
2017 confirmed a favorable tolerability. In addition, a triplet combination of umbralisib, ibrutinib and CD20-targeting 
antibody ublituximab was well tolerated, with umbralisib 800 mg daily becoming the RP2D in patients with relapsed B-cell 
malignancies. 
Ublituximab is a glycolengineered chimeric monoclonal antibody engineered to optimally target the human CD20 antigen. 
A review of the adverse events observed to date for ublituximab indicates that several risks are associated with ublituximab 
infusions and treatment. Nevertheless, the risks associated with ublituximab therapy appear to be consistent with those 

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associated with existing CD20-directed therapy, and the proof of clinical activity of single agent ublituximab has been 
demonstrated in relapsed/refractory subjects with CLL and NHL, and subjects with MS. The potential benefits of 
ublituximab in subjects with CD20-positive B-cell lymphoproliferative disorders have been suggested from several 
nonclinical studies demonstrating a better in vitro ADCC activity compared with rituximab. 
Based on the favorable safety profile reported with single agent ublituximab, subsequent combination studies were 
undertaken. Ublituximab has been evaluated in combination with lenalidomide, with ibrutinib, with bendamustine, with 
pembrolizumab, with venetoclax, and/or with umbralisib. To date, ublituximab in combination with these agents has been 
well tolerated. The combinations of ublituximab with ibrutinib, and of ublituximab with umbralisib have particularly 
displayed robust clinical activity in subjects with CLL, for which registration directed studies are ongoing. 
We hypothesize that acalabrutinib in combination with the second-generation CD20-targeting antibody ublituximab and 
selective PI3Kδ inhibitor umbralisib (AU2) will demonstrate high efficacy and tolerability as frontline therapy in older/unfit 
MCL patients, and in patients with TP53 aberrations or complex karyotype. 
Objectives 
Primary Objective(s) 
 Evaluate the anti-tumor activity of acalabrutinib, umbralisib and ublituximab (AU2) regimen as induction therapy in 
patients with treatment-naïve mantle cell lymphoma (MCL), as assessed by the complete response (CR) rate. 
Secondary Objective(s) 
 Evaluate the overall response rate (ORR) to AU2 in treatment-naïve MCL. 
 Evaluate the progression-free survival (PFS), overall survival (OS) and duration of response (DOR) in patients with 
treatment-naïve MCL who received AU2. 
 Evaluate the safety and tolerability of AU2 in patients with treatment-naïve MCL. 
Exploratory Objective(s) 
 Examine the T-cell populations and functionality in patients treated with AU2. 
 Explore the predictive value of minimal residual disease (MRD) in MCL. 
 Explore the mechanisms of resistance to AU2 therapy. 
Study Design 
This is a phase 2 study of BTK inhibitor acalabrutinib and PI3Kδ umbralisib in combination with ublituximab (AU2) in 
treatment-naïve MCL patients. Patients with previously untreated MCL ≥ 65 years; or ≥ 50 years and deemed ineligible for 
aggressive induction therapy or autologous stem cell transplant by the investigator, or unwilling to undergo such therapy; 
or ≥ 18 years with documented del(17p), or TP53 mutation, or complex karyotype (CK) will be enrolled.  As noted above, 
older patients with MCL do not have curative options, and current standard chemo-immunotherapy regimens (i.e., BR) are 
associated with a PFS of <4 years and significant toxicities. Furthermore, chemo-immunotherapy regimens are ineffective 
in patients high-risk MCL (TP53 aberration and/or CK). 
Participants will receive 6 cycles of Induction therapy (1 Cycle = 28 days) using the approved standard dose of acalabrutinib 
(100 mg PO, twice daily), and a previously demonstrated safe dose of umbralisib (800 mg PO, once daily, see schedule 
below) and ublituximab (900 mg IV, on Day 1, Day 8 and Day 15 of the first cycle, and Day 1 of each Cycle afterward). 
Umbralisib will be administered daily for 14 days during cycle 1, followed by daily on days 1-7 with subsequent cycles. 
Maintenance therapy with anti-CD20 targeting antibodies has become standard approach post-induction in MCL, leading 
to improved OS [49, 50]. Participants with stable disease or better response at the end of Induction therapy will then receive 
19 cycles of Maintenance therapy with the 3 agents, during which ublituximab (900 mg IV) will only be administered every 
2 cycles. Participants may continue therapy with acalabrutinib beyond 25 cycles of protocol therapy at the treating 
physician’s discretion.  
The study will use a Simon’s optimal two-stage design to evaluate the CR rate of the AU2 induction therapy. The first stage 
will accrue 9 patients. If there are 2 or fewer CR among 9 patients, the accrual will be terminated; if there are 3+ CR, the 
accrual will continue to second stage for a total of 24 patients. The study will require 10 or more CR in 24 patients to 
consider AU2 promising. The incidence of certain adverse events at least possibly related to study treatment will be 
monitored (see Section 12.4.2). 
 

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Evaluation Criteria and Endpoints 
Primary Endpoint:  
 Complete response (CR) rate at the end of induction therapy with AU2. 
Secondary Endpoints:  
 Overall response rate (ORR). 
 Progression-free survival (PFS), overall survival (OS), and duration of response (DOR). 
 Toxicity of AU2 regimen. 
Exploratory Endpoints:  
 T-cell populations, minimal residual disease, gene expression/mutation profiles. 
Statistical Considerations 
The primary endpoint is complete response (CR) rate after AU2 induction therapy. Secondary endpoints include toxicities, 
ORR to protocol treatment, PFS, OS, and DOR. The study sample size is based on the desire to discriminate a promising CR 
rate of 50% (alternative hypothesis) from a disappointing CR rate of 25% (null hypothesis). These  response rates were 
chosen because 1) BR, a current standard, has been associated with an ORR of 80-90% and a CR rate of 40% [5, 7]; 2) In the 
phase 2 ACE-LY-004 trial in R/R MCL, treatment with acalabrutinib was associated with an ORR of 81% and a CR rate of 40% 
[39].  However, it is anticipated that this study will enroll a higher proportion of patients with high-risk MCL (TP53 
aberrations, CK) where BR is ineffective.  
Simon's optimal two-stage design will be used. In the first stage, 9 evaluable patients will be accrued. If there are 2 or fewer 
CRs in these 9 patients, the study will be stopped. Otherwise, 15 additional evaluable patients will be accrued for a total of 
24. The null hypothesis will be rejected and AU2 induction therapy will be considered promising if 10 or more CRs are 
observed in 24 evaluable patients. This design yields a 1-sided type I error rate of 0.05 and power of 0.8. When the CR rate 
is disappointing (25%), there is an 60% chance that the study will be terminated after the first stage.  
Abbreviated Eligibility Criteria 
Main Inclusion Criteria 
 Histologically confirmed mantle cell lymphoma with documentation of monoclonal CD20+ B cells that have a 
chromosome translocation t(11;14)(q13;q32) and/or overexpress cyclin D1. 
 Age ≥ 65 years; or ≥ 50 years and deemed ineligible for aggressive induction therapy or autologous stem cell 
transplant by the investigator, or unwilling to undergo aggressive induction; or ≥ 18 years with documented del(17p), 
or TP53 mutation, or complex karyotype (CK) by cytogenetics and/or FISH studies. 
 Requiring treatment for MCL, and for which no prior systemic anticancer therapies have been received (local 
radiotherapy not exceeding a total dose of 20 Gy at least 2 weeks prior the first dose of study therapy is allowed). 
 Measurable disease by CT or PET/CT scan with one or more sites of disease ≥ 1.5 cm in longest dimension (including 
splenomegaly), or bone marrow involvement with or without malignant lymphocytosis. 
 ECOG ≤ 2. 
 Adequate hematological, renal, and hepatic function. 
 Adequate coagulation. 
 LVEF≥ 40%. 
 Women of childbearing potential: negative serum pregnancy test. 
 Agreement by females and males of childbearing potential to use a highly effective method of birth control or abstain 
from heterosexual activity for the course of the study through at least 2 days after the last dose of acalabrutinib for 
females, and at least 4 months after the last dose of ublituximab or umbralisib for both men and women. 
Main Exclusion Criteria 
 Subjects for whom the goal of therapy is tumor debulking before stem cell transplant. 
 Chronic use of corticosteroids ≥20 mg/day (short-term use of steroids <14 days is allowed). 
 Major surgical procedure within 28 days of start of protocol therapy.  Note:  If a subject had major surgery, they must 
have recovered adequately from any toxicity and/or complications from the intervention before the first dose of study 
drug. 
 Known history of hypersensitivity or anaphylaxis to study drug(s) including active product or excipient components. 

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 Concurrent participation in another therapeutic clinical trial. 
 History of prior malignancy. Exceptions include malignancy treated with curative intent and no known active disease 
present for ≥ 2 years prior to initiation of protocol therapy; adequately treated non-melanoma skin cancer or lentigo 
maligna (melanoma in situ) without evidence of disease; adequately treated in situ carcinomas (e.g., cervical, 
esophageal, etc.) without evidence of disease; asymptomatic prostate cancer managed with “watch and wait” 
strategy. 
 Uncontrolled AIHA (autoimmune hemolytic anemia) or ITP (idiopathic thrombocytopenic purpura). 
 Requires treatment with proton pump inhibitors (e.g., omeprazole, esomeprazole, lansoprazole, dexlansoprazole, 
rabeprazole, or pantoprazole).  Subjects receiving proton pump inhibitors who switch to H2-receptor antagonists or 
antacids are eligible for enrollment to this study. 
 Requires treatment with a strong cytochrome P450 3A4 (CYP3A4) inhibitor/inducer. 
 Requires or receiving anticoagulation with warfarin or equivalent vitamin K antagonists. 
 Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small 
bowel that is likely to affect absorption, symptomatic inflammatory bowel disease, partial or complete bowel 
obstruction, or gastric restrictions and bariatric surgery, such as gastric bypass. 
 Presence of a gastrointestinal ulcer diagnosed by endoscopy within 3 months before screening. 
 Known bleeding disorders (e.g., von Willebrand's disease or hemophilia). 
 History of significant cerebrovascular disease/event, including stroke, myocardial infarction, or intracranial 
hemorrhage, within 6 months prior to start of protocol therapy. 
 Known active central nervous system (CNS) involvement by lymphoma, including leptomeningeal involvement. 
 Clinically significant cardiovascular disease such as symptomatic arrhythmias, congestive heart failure, or myocardial 
infarction within 6 months of screening, or any Class III or IV cardiac disease as defined by the New York Heart 
Association Functional Classification. Note: Subjects with controlled, asymptomatic atrial fibrillation can enroll on 
study. 
 Unstable angina (angina symptoms at rest), new-onset angina (begun within the last 6 months). 
 History of or current progressive multifocal leukoencephalopathy (PML). 
 Inability to swallow and retain an oral medication. 
 Clinically significant uncontrolled illness, including active infection requiring antibiotics or antiviral agents. 
 Live virus vaccines within 4 weeks of start of protocol therapy or planned administration of live virus vaccines during 
ublituximab therapy. 
 Evidence of chronic active hepatitis B virus (HBV) or hepatitis C virus (HCV), or active cytomegalovirus (CMV) infection 
(See Section 3.2). 
 Known history of human immunodeficiency virus (HIV) infection 
 Females only: Pregnant or breastfeeding 

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Investigational Product Dosage and Administration 
The treatment plan is as follows. 
Induction phase: 
Agent 
Dose 
Route 
Schedule 
Ublituximab 
900 mg 
IV 
Cycle 1: Day 1, Day 8, and Day 15 
Cycles 2-6: Day 1 
Acalabrutinib 
100 mg - Twice daily 
Orally 
Every day of each cycle 
Umbralisib 
800 mg - Once daily 
Orally 
Cycle 1: Days 1-14 
Cycle 2-6: Days 1-7 
Maintenance phase: 
Agent 
Dose 
Route 
Schedule 
Ublituximab 
900 mg 
IV 
Every 2 cycles (Cycles 8, 10, 12, 14, 16, 18, 20, 22, 
24), on Day 1, starting on Day 1 of Cycle 8 
Acalabrutinib 
100 mg - Twice daily 
Orally 
Every day of each cycle 
Umbralisib 
800 mg - Once daily 
Orally 
Days 1-7 of each cycle 
 
 
 
 
Treatment will be administered on an out-patient basis (in-patient administration is allowed if deemed necessary by the 
Investigator). 
Clinical Observations and Tests to be Performed 
 Safety assessments (CBCs with differential, comprehensive chemistry panel, coagulation, ECHO/MUGA) 
 Response assessments 
 CT/PET/MRI scans  
 Correlative tumor tissue, bone marrow and blood samples. 
 
 

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TABLE OF CONTENTS 
SECTION .................................................................................................................................................................... PAGE 
Protocol Team ................................................................................................................................................................. 2 
Study Schema .................................................................................................................................................................. 3 
Protocol Synopsis ............................................................................................................................................................ 4 
Table of Contents ............................................................................................................................................................ 9 
Abbreviations ................................................................................................................................................................ 12 
1.0 
Objectives ........................................................................................................................................................ 13 
1.1 
Primary Objective 
13 
1.2 
Secondary Objectives 
13 
1.3 
Exploratory Objectives 
13 
2.0 
Background ...................................................................................................................................................... 13 
2.1 
Introduction/Rationale for Development 
13 
2.2 
Rationale for correlative studies 
17 
2.3 
Overview and Rationale of Study Design 
17 
3.0 
Eligibility Criteria .............................................................................................................................................. 19 
3.1 
Inclusion Criteria 
19 
3.2 
Exclusion Criteria 
20 
4.0 
Participant Enrollment ..................................................................................................................................... 23 
4.1 
Pre-Enrollment Informed Consent and Screening Procedures 
23 
4.2 
Participant Enrollment 
23 
4.3 
Screen Failures and Registered Participants Who Do Not begin Study Treatment 
24 
5.0 
Treatment Program .......................................................................................................................................... 24 
5.1 
Treatment Program Overview 
24 
5.2 
Cycle Definition 
24 
5.3 
Treatment Plan 
24 
5.4 
Agent Administration 
25 
5.5 
Assessments and Special Monitoring 
26 
5.6 
Duration of Therapy and Criteria for Removal from Protocol Therapy 
27 
5.7 
Follow-Up 
27 
5.8 
Duration of Study Participation 
28 
5.9 
Prohibited and Concomitant Therapies/Medications 
28 
5.10 
Supportive care 
29 
6.0 
Anticipated Adverse Events .............................................................................................................................. 31 
6.1 
Ublituximab 
31 
6.2 
Acalabrutinib 
32 
6.3 
Umbralisib 
36 
6.4 
Ublituximab plus umbralisib 
37 
7.0 
Dose Delay / Modification Guidelines ............................................................................................................... 38 
7.1 
Dose Delays/ Modification 
38 
8.0 
Agent Information ............................................................................................................................................ 46 
8.1 
Ublituximab 
46 
8.2 
Acalabrutinib 
48 
8.3 
Umbralisib 
51 
9.0 
Correlative/ Special Studies .............................................................................................................................. 52 
9.1 
Research Sample Collection and Dispensation 
52 
9.2 
Laboratory Studies Performed 
55 
9.3 
Collection of data from standard of care tests at screening 
56 
10.0 
Study Calendar ................................................................................................................................................. 57 
11.0 
Endpoint Definitions/Measurement of Effect .................................................................................................... 61 
11.1 
Assessment of Response 
61 

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11.2 
Primary Endpoint(s) 
61 
11.3 
Secondary Endpoint(s) 
61 
11.4 
Exploratory Endpoint(s) 
62 
12.0 
Statistical Considerations ................................................................................................................................. 62 
12.1 
Study Design 
62 
12.2 
Evaluable Participants and Participant Replacement 
62 
12.3 
Sample Size and Accrual Rate 
63 
12.4 
Interim Analyses/Stopping Rules 
63 
12.5 
Statistical Analysis Plan 
63 
13.0 
Data Handling, Data Management, Record Keeping .......................................................................................... 64 
13.1 
Source Documents 
64 
13.2 
Data Capture Methods and Management 
64 
13.3 
Case Report Forms/Data Submission Schedule 
64 
13.4 
Regulatory Records 
65 
14.0 
Reporting of Adverse Events, Unanticipated Problems & Other Events of Interest............................................. 65 
14.1 
Assessment of Adverse Events 
65 
14.2 
Adverse Events of Special Interest (AESI) 
66 
14.3 
Overdose and Pregnancies 
66 
14.4 
Routine AE Collection and Reporting Guidelines 
67 
14.5 
Expedited Reporting 
67 
14.6 
Reporting to the FDA 
69 
14.7 
Reporting to Industry Partners 
70 
15.0 
Adherence to the Protocol & Reporting of Protocol Deviations ......................................................................... 71 
16.0 
Study Oversight, Quality Assurance, & Data and Safety Monitoring .................................................................. 72 
16.1 
All Investigator Responsibilities 
72 
16.2 
Study Principal Investigator Responsibilities 
72 
16.3 
Protocol Management Team (PMT) 
72 
16.4 
Quality Assurance 
72 
16.5 
Risk Determination 
72 
16.6 
City of Hope Data and Safety Monitoring Committee 
73 
16.7 
Protocol Amendments 
73 
17.0 
Ethical and Regulatory Considerations .............................................................................................................. 73 
17.1 
Ethical Standard 
73 
17.2 
Regulatory Compliance 
73 
17.3 
Institutional Review Board 
73 
17.4 
Informed Consent 
74 
17.5 
Participant Withdrawal 
75 
17.6 
Special and Vulnerable Populations 
75 
17.7 
Participant Confidentiality 
76 
17.8 
Use of Unused (Leftover) Specimens Collected for this Trial 
76 
17.9 
Conflict of Interest 
77 
17.10 
Financial Obligations, Compensation, and Reimbursement of Participants 
77 
17.11 
Publication/ Data Sharing 
77 
18.0 
References ....................................................................................................................................................... 78 
Appendix A: ECOG Performance Status Scale ................................................................................................................. 81 
Appendix B: NYHA Cardiac Grading Criteria .................................................................................................................... 82 
Appendix C: Lymphoma Response Criteria [54] .............................................................................................................. 83 
Appendix D: Registration Coversheet ............................................................................................................................. 87 
Appendix E: Proton Pump Inhibitors and CYP3A Inhibitors and Inducers ......................................................................... 88 
Appendix F: Correlative Tissue Form (for all sites) .......................................................................................................... 89 
Appendix G: Tissue Shipping Guidelines to Dr. Danilov’s Laboratory ............................................................................... 90 
Appendix H: Correlative Blood/ Bone Marrow Collection Form for Non-COH Sites Only .................................................. 91 

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Appendix I: Blood & Bone Marrow Shipping Guidelines to Dr. Danilov’s Laboratory ....................................................... 92 
Appendix J: Hepatitis B Serologic Test Results ................................................................................................................ 93 
Appendix K: Highly Effective Contraception Methods ..................................................................................................... 94 
Appendix l-1: Patient Drug Diary instructions ................................................................................................................. 95 
Appendix l-2: Patient Drug Diary *** for cycle 1 only *** ............................................................................................... 96 
Appendix l-3: Patient Drug Diary *** for all other cycles *** .......................................................................................... 98 
 
 
 

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ABBREVIATIONS  
Abbreviation 
Meaning 
AE 
ALT 
ANC 
AST 
AU2 
BCR 
BTK 
CFR 
CK 
COH 
CR 
CRA 
CRF 
CTCAE 
DCC 
DLT 
DOR 
DSMC 
ECOG 
EOT 
FDA 
GCP 
HIV 
IB 
IDS 
IND 
IRB 
IV 
MCL 
MRD 
NCI 
NGS 
OIDRA 
ORR 
PD 
PI 
PI3K 
PMT 
PR 
RNAseq 
SAE 
SD 
Adverse Event 
Alanine Aminotransferase 
Absolute Neutrophil Count 
Aspartate Aminotransferase 
Acalabrutinib, umbralisib, ublituximab regimen 
B-cell receptor 
Bruton tyrosine kinase 
Code of Federal Regulations 
Complex Karyotype 
City of Hope 
Complete Response 
Clinical Research Coordinator 
Case Report Form 
Common Terminology Criteria for Adverse Events 
Data Coordinating Center 
Dose Limiting Toxicity 
Duration of response 
Data & Safety Monitoring Committee 
Eastern Cooperative Oncology Group 
End of Treatment 
Food and Drug Administration 
Good Clinical Practice 
Human Immunodeficiency Virus 
Investigator’s Brochure 
Investigational Drug Services 
Investigational New Drug 
Institutional Review Board 
Intravenous 
Mantle cell lymphoma 
Minimal residual disease 
National Cancer Institute 
Next generation sequencing 
Office of IND Development and Regulatory Affairs 
Overall response rate 
Progressive Disease 
Principal Investigator 
Phosphoinositide 3-kinase 
Protocol Management Team 
Partial Response 
RNA sequencing 
Serious Adverse Event 
Stable disease 

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1.0 OBJECTIVES 
1.1 Primary Objective  
o Evaluate the anti-tumor activity of acalabrutinib, umbralisib and ublituximab (AU2) regimen as 
induction therapy in patients with treatment-naïve mantle cell lymphoma (MCL), as assessed by the 
complete response (CR) rate. 
1.2 Secondary Objectives 
o Evaluate the overall response rate (ORR) to AU2 in treatment-naïve MCL. 
o Evaluate the progression-free survival (PFS), overall survival (OS) and duration of response (DOR) in 
patients with treatment-naïve MCL who received AU2. 
o Evaluate the safety and tolerability of AU2 in patients with treatment-naïve MCL. 
1.3 Exploratory Objectives 
o Examine the T-cell populations and functionality in patients treated with AU2. 
o Explore the predictive value of minimal residual disease (MRD) in MCL. 
o Explore the mechanisms of resistance to AU2 therapy. 
2.0 BACKGROUND 
2.1 Introduction/Rationale for Development 
2.1.1 
Mantle cell lymphoma (MCL) 
MCL is a rare subtype of non-Hodgkin lymphoma (NHL) typically characterized by atypical small lymphoid cells 
with wide mantles around benign germinal centers [1]. The vast majority of patients present with stage IV disease 
that often includes lymphadenopathy, splenomegaly, bone marrow involvement, and gastrointestinal infiltration 
at the time of diagnosis [2]. The disease is twice as common in men as in women. Additionally, the risk of MCL is 
nearly 12-times greater for those aged 50–59 years compared to those <50 years. MCL is often characterized by a 
hallmark translocation t(11;14)(q13;q32), in which CCND1 is juxtaposed to the immunoglobulin heavy chain 
enhancer. This rearrangement manifests as an overexpression of cyclin D1 and is an important oncogenic driver 
promoting cell cycle deregulation [3]. MCL typically follows an aggressive clinical course with an overall poor 
prognosis. Intensive chemo-immunotherapy regimens remain the mainstay of treatment of newly diagnosed MCL. 
However, with an average age at diagnosis of 68 years, many patients are poor candidates for such therapy due 
to the presence of comorbidities. Despite high initial response rates, most patients eventually relapse and 
succumb to their disease [4]. 
2.1.2 
Frontline immunotherapy for MCL 
2.1.2.1 In older patients 
A combination of bendamustine and rituximab (BR) has become an accepted standard in frontline therapy of 
newly diagnosed MCL among patients who are poor candidates for intensive chemotherapy regimens and 
autologous stem cell transplantation. In a prospective, multicenter, randomized trial which compared BR with R-
CHOP as first-line treatment for patients with non-Hodgkin lymphoma (NHL), of a total of 549 patients, 94 (17%) 
carried a diagnosis of MCL [5]. Of these 94 patients, 46 received BR and 48 received R-CHOP. At a median follow 
up of 45 months, the median PFS was 35.4 months in the BR group versus 22.1 months in the R-CHOP group. 
Similar results were obtained in another large randomized study [6]. This improvement in PFS over R-CHOP, along 
with an acceptable side-effect profile, has made the BR regimen a popular first-line treatment option in treatment-
naïve older MCL patients. A recent SWOG S1106 study demonstrated that BR may achieve high rate of minimal 

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residual disease (MRD) among patients with MCL [7]. Despite these successes, BR regimen is not curative, and all 
patients ultimately relapse after a median of <3 years. 
2.1.2.2 In patients with TP53 and/or complex karyotype 
Chemo-immunotherapy combinations have limited efficacy in MCL with aberrant TP53 and/or complex karyotype 
(CK). In the Nordic trials, patients who had mutations in TP53 did not benefit from intensive induction 
chemotherapy [8]. 50% of such patients relapsed by 1 year, and overall survival was 1.8 years. In a multicenter 
retrospective study, we have found that patients with CK similarly did not benefit from intensive induction 
chemotherapy, and had an OS of 3.5 years following low-intensity therapy such as BR [9]. Thus, achievement of a 
durable remission following upfront therapy of MCL remains an important goal in lymphoma therapeutics, and 
MCL with TP53 aberrations and CK is a particular area of unmet need. 
2.1.3 
Bruton tyrosine kinase (BTK) inhibition in B-cell malignancies  
Chronic active B-cell receptor (BCR) signaling pathway has been implicated in the pathogenesis of B-cell neoplasia, 
including MCL [10]. Activation of Bruton tyrosine kinase (BTK) and its downstream targets plays a pivotal role in 
regulation of proliferation, survival and homing of malignant B-cells [11, 12]. Overexpression of BTK is commonly 
found in MCL and its pharmacologic targeting induces apoptosis in vitro [13]. Ibrutinib (Imbruvica) is a potent, 
orally bioavailable irreversible inhibitor of BTK that covalently binds the kinase active site at C481 residue. Ibrutinib 
received FDA approval in therapy of relapsed/refractory MCL based on the results of a phase II trial. 111 patients 
with MCL were treated with ibrutinib at 560 mg by mouth daily. 68% of patients achieved an objective response, 
and 21% entered complete response [14]. Among all patients, duration of response was limited to 13 months, and 
overall survival was less than 2 years [15]. However, patients who were exposed to fewer prior therapies derived 
increased benefit from BTK inhibition, with prolonged PFS and OS [16]. Furthermore, a combination of ibrutinib 
and rituximab resulted in further improvement of outcomes among patients with relapsed MCL, with median PFS 
of 43 months, thereby exceeding the expected efficacy of BR in this setting [17]. Emerging data indicate that 
upfront therapy with ibrutinib-rituximab combination is associated with 100% ORR in MCL.[18] Therefore, BTK 
inhibitors combined with CD20-targeting agents are poised to achieve durable remissions in upfront setting in MCL. 
2.1.4 
Resistance to ibrutinib 
Patients with MCL who develop resistance to ibrutinib have dismal outcomes [19, 20]. A large retrospective cohort 
study of 114 patients who progressed on ibrutinib documented an overall survival of <3 months following 
cessation of the drug [20]. Mutations in BTK (C481S) and its downstream target PLCγ2 have been implicated in 
resistance to ibrutinib in CLL where they may account for the majority of resistant cases [21, 22]. In fact, 
emergence of BTK/PLCγ mutations typically pre-dates ibrutinib resistance in CLL [22]. By contrast, while such 
mutations are found in late ibrutinib failures in MCL, most patients relapse early in the course of therapy (within 
the first 6 months) and lack such mutations [20, 23]. Activation of the phosphoinotiside-3 kinase (PI3K) pathway 
has been implicated in resistance to chemotherapy and ibrutinib in MCL, and thus represents an actionable target 
in this disease [23, 24]. Idelalisib, a selective PI3Kδ inhibitor, has demonstrated single agent efficacy in 
relapsed/refractory MCL, albeit responses were short-lived [25].  
Additive or synergistic effects of the combination of ibrutinib and idelalisib have been reported in CLL, MCL, and 
diffuse large B-cell lymphoma (DLBCL) cell lines [26, 27]. Combined inhibition of PI3K and BTK induced apoptosis 
of the DLBCL cell line TMD8, which was resistant to inhibition of either kinase alone [28]. Furthermore, 
acalabrutinib demonstrated enhanced efficacy when combined with PI3K inhibitor ACP-319 (no longer in 
development) in a CLL mouse model [29]. Thus, combined targeting of BTK and PI3K may result in improved 
efficacy in MCL and prevent disease relapse, particularly when employed in the frontline setting.  
 

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2.1.5 
Umbralisib 
Umbralisib (TGR-1202) is a highly-specific and orally available dual inhibitor of PI3K-δ and casein kinase 1 epsilon 
(CK1ε) with nanomolar inhibitory potency, and high selectivity over the alpha, beta, and gamma Class I isoforms 
of PI3K. With a dissociation constant (Kd) of 6.2 nM, umbralisib is a more selective inhibitor of PI3Kδ than idelalisib 
(1.2 nM) or duvelisib (0.047 nM) [30].  Moreover, umbralisib, unlike other p110-δ inhibitors (e.g., duvelisib and 
idelalisib), has a different chemical structure in which carbon and oxygen atoms replace the nitrogen atoms of the 
heterocyclic quinazolinone backbone [31]. Compared to other p110-δ inhibitors, this altered chemical structure is 
thought to not only reduce hepatotoxicity, but is also associated with conferring umbralisib with CK-1ε inhibitory 
potential [31, 32]. 
Umbralisib is currently being investigated in clinical trials in lymphoma. The first report suggested high tolerability 
of umbralisib, with decreased rates of colitis, pneumonitis and hepatic abnormalities compared to other PI-3Kδ 
inhibitors [33]. The extended integrated safety follow-up results from 5 clinical trials using umbralisib that we 
presented at ASH 2017 confirmed a favorable tolerability [34]. Furthermore, combinations of ibrutinib and 
umbralisib have not resulted in significant toxicities. In a Phase I trial of umbralisib and ibrutinib in patients with 
CLL and MCL, ibrutinib was used in standard doses (420 and 560 mg, respectively), while umbralisib dose was 
escalated from 400 to 800 mg (NCT02268851) [34, 35]. There were no DLTs at the RP2D of umbralisib 800 mg daily 
in combination with ibrutinib. This combination was highly efficacious in both CLL and MCL, with complete 
responses documented in both conditions. This study thus demonstrated favorable safety profile and high 
response rate of ibrutinib in combination with umbralisib in patients with relapsed/refractory MCL [35]. Similarly, 
a triplet combination of umbralisib, ibrutinib and CD20-targeting antibody ublituximab was well tolerated, with 
umbralisib 800 mg daily becoming the RP2D in patients with relapsed B-cell malignancies [36]. There is by now 
substantial precedence of use of umbralisib in upfront therapy of CLL, with the phase 3 UNITY-CLL trial fully 
accrued.  
2.1.6 
Acalabrutinib 
Acalabrutinib (also known as ACP-196 and/or Calquence®) is a selective, irreversible small molecule inhibitor of 
BTK currently under clinical investigation. Acalabrutinib is an investigational product. Calquence® has been 
approved in the United States and other markets for the treatment of adult patients with mantle cell lymphoma 
(MCL) who have received at least one prior therapy, chronic lymphocytic leukemia (CLL), and small lymphocytic 
lymphoma (SLL). A detailed description of the chemistry, pharmacology, mechanism of action, efficacy, and safety 
of acalabrutinib is provided in the Investigator Brochure. Acalabrutinib is a next-generation BTK inhibitor that 
shows higher selectivity for BTK, while simultaneously lacking irreversible inhibition of activities of other kinases 
such as epidermal growth factor receptor (EGFR), interleukin-2-inducible T-cell kinase (ITK), and T cell X 
chromosome kinase (Txk), among others [37, 38]. This higher target selectivity is expected to contribute to the 
favorable safety profile [39]. In the phase 2 ACE-LY-004 trial consisting of 124 patients with MCL, administration 
of acalabrutinib (100 mg PO twice daily [bid]) was associated with an ORR of 81% (95% CI, 73%-87%), including a 
CR rate of 40% and a PR rate of 41%. The most common adverse events (AE) were primarily grade 1 or 2, with 
headache (38%), diarrhea (31%), fatigue (27%), and myalgia (21%). The most common grade 3 or worse AEs were 
neutropenia (10%), anemia (9%), and pneumonia (5%) [39]. Incidences of grade 3 and above atrial fibrillation and 
flutter, infection and bleeding complications were low in patients receiving acalabrutinib. Based on these findings, 
acalabrutinib received FDA approval in August 2017 for the treatment of adult patients with mantle cell lymphoma 
(MCL) who have received at least one prior therapy [40, 41]. Finally, emerging data suggest that the mechanisms 
of treatment resistance for acalabrutinib are similar to ibrutinib [42]. 
Thus, acalabrutinib is at least as efficacious as ibrutinib in MCL. However, given that acalabrutinib is a selective 
inhibitor of BTK, it is expected to have fewer toxicities than ibrutinib. 

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2.1.7 
Ublituximab 
Ublituximab (TG-1101) is a glycolengineered chimeric monoclonal antibody engineered to optimally target the 
human CD20 antigen. Ublituximab targeting of CD20 promotes antibody-dependent cell-mediated cytotoxicity 
(ADCC) of cells expressing this protein. Notably, ublituximab has a high affinity for FcγRIIIa (CD16) receptors, which 
is associated with eliciting greater ADCC than targeting by the other CD20 antibodies [43, 44].  Ublituximab 
targeting of CD20 is also associated with classical activation of the complement pathway (CDC), as well as 
induction of B-cell apoptosis. 
Excluding the three Phase III studies that are being conducted under SPA (UTX-TGR-304, TG1101-RMS301, and 
TG1101-RMS302) and the three Phase II extension studies (UTX-TGR-204, UTX-TGR-501, and TG1101-RMS201E), 
as of 10 May 2019, over 1020 subjects have been exposed to ublituximab through ten Phase I or II clinical trials 
and one Phase III clinical trial (three of which are still enrolling).  
Ublituximab exposure in oncology has ranged in dose from 450 mg to 1200 mg, both as induction (weekly infusions 
x 4 or 6 weeks) and maintenance (monthly through month 6 followed by quarterly). The maximum tolerated 
dose/exposure has not been established however the Phase II and III dose in oncology settings has been selected 
at 900 mg/infusion. 
In oncology, the following adverse reactions have been observed: Infusion-related reaction was the most frequent 
drug-related AE in all studies, typically occurring during the first ublituximab infusion. Grade 3-4 neutropenia, 
rarely associated with a febrile episode, has been reported and usually resolved either spontaneously or in a few 
days with G-CSF therapy for oncology. Drug-related Grade 3 thrombocytopenia and worsening from slight to 
Grade 3-4 pancytopenia has also been reported although minimal. Asymptomatic, isolated, and transient Grade 
2-3 drug-related elevated liver enzymes have been observed as well. Most subjects who experience ublituximab 
related adverse events may have a dose interruption or delay, and usually resume at the original dose. 
A review of the adverse events observed to date for ublituximab indicates that several risks are associated with 
ublituximab infusions and treatment. Nevertheless, the risks associated with ublituximab therapy appear to be 
consistent with those associated with existing CD20-directed therapy, and the proof of clinical activity of single 
agent ublituximab has been demonstrated in relapsed/refractory subjects with CLL and NHL, and subjects with 
MS. 
The potential benefits of ublituximab in subjects with CD20-positive B-cell lymphoproliferative disorders have 
been suggested from several nonclinical studies demonstrating a better in vitro ADCC activity compared with both 
rituximab [43] and ofatumumab. Moreover, the difference of activity was more pronounced when target cells 
expressed few CD20 molecules. Data from the completed Phase I study showed significant circulating lymphocyte 
depletion of up to 98% in subjects with relapsed/refractory CLL after at least one prior course of fludarabine. 
Moreover, 3 out of 18 (17%) evaluable subjects presented with a partial response after a 4-dose regimen of 
ublituximab and 5 out of 11 (45%) evaluable subjects after an 8-dose regimen.  
The second single agent ublituximab Phase I study TGTX-1101-101 in subjects with relapsed/refractory B-cell 
lymphoma was completed. Of the 31 out of 35 subjects evaluable for efficacy, 14 out of 31 (45%) subjects have 
achieved an objective response. Responses were observed in both rituximab relapsed and rituximab refractory 
subjects, including subjects who had been exposed to several lines of rituximab therapy. The median time to 
response was 1.8 (range 1–11) months, with a median duration of response of 9.2 (range 1–24) months. Median 
PFS for all evaluable subjects was 7.7 (95% CI:4.5–16.2) months with a median PFS for the rituximab-refractory 
subjects of 4.7 (95% CI:1.9–16.2) months. Rapid and profound lymphocyte depletion was observed in subjects 
with the median time to a >50% reduction of 1 day (O’Connor et al., ASCO and EHA, 2014).  
Based on the favorable safety profile reported with single agent ublituximab, subsequent combination studies 
were undertaken. Ublituximab has been evaluated in combination with lenalidomide, with ibrutinib, with 
bendamustine, with pembrolizumab, with venetoclax, and/or with umbralisib (TGR-1202). To date, ublituximab in 
combination with these agents has been well tolerated. 

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The combinations of ublituximab with ibrutinib, and of ublituximab with umbralisib have particularly displayed 
robust clinical activity in subjects with CLL, for which registration directed studies are ongoing. 
We hypothesize that acalabrutinib in combination with the second-generation CD20-targeting antibody 
ublituximab and selective PI3Kδ inhibitor umbralisib (AU2) will demonstrate high efficacy and tolerability as 
frontline therapy in older/unfit MCL patients, and in patients with TP53 aberrations or complex karyotype. 
2.2 Rationale for correlative studies 
2.2.1 
Minimal residual disease (MRD) 
MRD is defined as the minimal traceable persistence of lymphoma cells following treatment. The ability to detect 
MRD positivity can facilitate better stratification of patients at higher risk of recurrence, as well as further aid in 
predicting upcoming clinical relapse [45]. This allows for better tailoring of treatments and helps to prevent or 
delay overt disease progression. Although numerous methods to monitor MRD have been reported, the allele-
specific oligonucleotide (ASO) quantitative polymerase chain reaction (qPCR) method is currently the most 
sensitive and most commonly used approach. This approach is designed to detect immunoglobulin heavy chain 
(IGH) gene rearrangements, which are present in about 80-90% of MCLs [45]. While considered the gold standard 
for MRD assessment in MCL, ASO-qPCR requires design and testing of individual primers that are specific to the 
clonal rearrangement of the IGH gene, BCL-1/IGH rearrangement, or t(11;14) translocation. With the IGH-based 
marker present in approximately 70% of cases and a BCL-1/IGH marker observed in approximately 35–40% of 
cases (with some overlap between these two), an estimated 10–15% of MCL patients lack reliable markers for 
MRD [45, 46] To overcome these challenges, samples from participants may be evaluated using next-generation 
sequencing (NGS). This approach does not rely on specific primers and can also aid in identification of novel 
molecular markers associated with MCL [45]. 
2.2.2 
Mechanisms of resistance 
Increasing our understanding of the molecular mechanisms driving MCL is crucial to the development of new 
treatment strategies and identifying novel therapeutic targets.  In addition to primary oncogenic drivers such as 
overexpression of cyclin D1 via t(11;14)(q13;q32) translocations, several other aberrant gene expression 
signatures are also associated with driving MCL [47].  BCR signaling is notable among these as it elicits several 
other downstream kinases (e.g., SYK, LYN, BTK) that are associated with promoting cell survival and facilitating 
increased resistance to treatments [48].  Likewise, aberrant activation of the NF-κB pathway is also associated 
with promoting increased resistance to treatment [47].  In this study, NGS will be used to evaluate gene expression 
(and mutations) from participant samples derived prior to and at time of relapse. Examination of cancer samples 
at these crucial time points will allow for novel identification of gene profiles that can be correlated with overall 
treatment outcomes; particularly, in the development of predictive markers of shortened PFS and therapy 
resistance. 
2.3 Overview and Rationale of Study Design 
This is a phase 2 study of BTK inhibitor acalabrutinib and PI3Kδ umbralisib in combination with ublituximab (AU2) 
in treatment-naïve MCL patients. 
Patients with previously untreated MCL ≥ 65 years; or ≥ 50 years and deemed ineligible for aggressive induction 
therapy or autologous stem cell transplant by the investigator, or unwilling to undergo such therapy; or ≥ 18 years 
with documented del(17p), or TP53 mutation, or complex karyotype (CK) will be enrolled.  
As noted in the introduction, older patients with MCL do not have curative options, and current standard chemo-
immunotherapy regimens (i.e., BR) are associated with a PFS of <4 years and significant toxicities. Furthermore, 
chemo-immunotherapy regimens are ineffective in patients high-risk MCL (TP53 aberration and/or CK). 
Participants will receive 6 cycles of Induction therapy (1 Cycle = 28 days) using the approved standard dose of 
acalabrutinib (100 mg PO, twice daily), and a previously demonstrated safe dose of umbralisib (800 mg PO, once 

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daily, see schedule below) and ublituximab (900 mg IV, on Day 1, Day 8 and Day 15 of the first cycle, and Day 1 of 
each cycle afterward). 
Umbralisib will be administered daily on days 1-14 during cycle 1, followed by daily on days 1-7 with subsequent 
cycles. This intermitted dosing has been successfully employed with other PI3K inhibitors (ME-401; TIDAL study) 
and was associated with improved toxicity profile without a compromise in efficacy. This approach is particularly 
attractive in patients with previously untreated MCL who have an intact immune system and thus are at an 
increased risk of immune-mediated toxicities with PI3K inhibitors. 
Maintenance therapy with anti-CD20 targeting antibodies has become standard approach post-induction in MCL, 
leading to improved OS [49, 50]. 
Participants with stable disease or better response at the end of Induction therapy will then receive 19 cycles of 
Maintenance therapy with the 3 agents, during which ublituximab (900 mg IV) will only be administered every 2 
cycles. 
Participants may continue therapy with acalabrutinib beyond 25 cycles of protocol therapy at the treating 
physician’s discretion.  
The study will use a Simon’s optimal two-stage design to evaluate the CR rate of the AU2 induction therapy. The 
first stage will accrue 9 patients. If there are 2 or fewer CR among 9 patients, the accrual will be terminated; if 
there are 2+ CR, the accrual will continue to second stage for a total of 24 patients. The study will require 10 or 
more CR in 24 patients to consider AU2 promising.  
 

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3.0 ELIGIBILITY CRITERIA 
Patient MRN (COH Only) 
Patient Initials (F, M, L): 
Institution:     
Participants must meet all of the following criteria on screening examination to be eligible to participate in the 
study:  
3.1 Inclusion Criteria 
Informed Consent and Willingness to Participate 
__1. Documented informed consent of the participant and/or legally authorized representative. 
 
Assent, when appropriate, will be obtained per institutional guidelines 
Nature of Illness and Illness Related Criteria 
__2. Histologically confirmed mantle cell lymphoma with documentation of monoclonal CD20+ B cells that have a 
chromosome translocation t(11;14)(q13;q32) and/or overexpress cyclin D1. 
__3. Age ≥ 65 years; or ≥ 50 years and deemed ineligible for aggressive induction therapy or autologous stem cell 
transplant by the investigator, or unwilling to undergo aggressive induction; or ≥ 18 years with documented 
del(17p), or TP53 mutation, or complex karyotype (CK) by cytogenetics and/or FISH studies. 
__4. Requiring treatment for MCL, and for which no prior systemic anticancer therapies have been received (local 
radiotherapy not exceeding a total dose of 20 Gy at least 2 weeks prior the first dose of study therapy is allowed). 
__5. Measurable disease by CT or PET/CT scan with one or more sites of disease ≥ 1.5 cm in longest dimension 
(including splenomegaly), or bone marrow involvement with or without malignant lymphocytosis. 
__6. ECOG ≤ 2 (Appendix A). 
Clinical Laboratory and Organ Function Criteria 
__7. Without bone marrow involvement: ANC ≥ 1000/mm3  
With bone marrow involvement: ANC ≥ 500/mm3 
NOTE: Growth factor is not permitted within 7 days of ANC 
assessment unless cytopenia is secondary to disease 
involvement. 
ANC: 
Date: 
__8. Without bone marrow involvement: Platelets ≥ 75,000/mm3 
 With bone marrow involvement: Platelets ≥ 30,000/mm3 
NOTE: Platelet transfusions are not permitted within 7 days of 
platelet assessment unless cytopenia is secondary to disease 
involvement. 
Plts: 
 
Date: 
__9. Total bilirubin ≤ 1.5 X ULN or ≤ 3X ULN for Gilbert’s disease. 
ULN: 
Bil: 
Date: 
__10. AST ≤ 2.5 x ULN 
 
ULN: 
AST: 
Date: 
__11. ALT ≤ 2.5 x ULN 
 
ULN: 
ALT: 
Date: 
 
 
 

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Patient MRN (COH Only) 
Patient Initials (F, M, L): 
Institution:     
 
__12. Creatinine clearance of ≥ 30 mL/min per 24 hour urine test or the 
Cockcroft-Gault formula or  
 
Serum Cr: 
 
Cr Clearance: 
Date: 
__13. If not receiving anticoagulants: International Normalized Ratio 
(INR) OR Prothrombin (PT) ≤ 1.5 x ULN 
If on anticoagulant therapy: PT must be within therapeutic range 
of intended use of anticoagulants 
ULN: 
INR: 
PT: 
Date: 
__14. If not receiving anticoagulants: Activated Partial Thromboplastin 
Time (aPTT) ≤ 1.5 x ULN 
If on anticoagulant therapy: aPTT must be within therapeutic 
range of intended use of anticoagulants 
ULN: 
 
aPTT: 
Date: 
__15. Left ventricular ejection fraction (LVEF) ≥ 40%  
 
LVEF: 
Date: 
__16. Women of childbearing potential (WOCBP): negative serum 
pregnancy test  
Serum: 
Date: 
 
Contraception 
__17. Agreement by females and males of childbearing potential* to use a highly effective method of birth control 
or abstain from heterosexual activity for the course of the study through at least 2 days after the last dose of 
acalabrutinib for females, and at least 4 months after the last dose of ublituximab or umbralisib, whichever comes 
later, for both men and women. Highly effective methods of birth control are defined in Appendix K. 
* Childbearing potential defined as not being surgically sterilized (men and women) or have not been 
free from menses for > 1 year (women only).  
3.2 Exclusion Criteria 
Prior and concomitant therapies 
__1.  Chronic use of corticosteroids ≥20 mg/day (short-term use of steroids <14 days is allowed). 
__2.  Major surgical procedure within 28 days of start of protocol therapy.  Note:  If a subject had major surgery, 
they must have recovered adequately from any toxicity and/or complications from the intervention before the first 
dose of study drug. 
__3.  Known history of hypersensitivity or anaphylaxis to study drug(s) including active product or excipient 
components 
__4.  Concurrent participation in another therapeutic clinical trial.   
Other illnesses or conditions 
__5.  Subjects for whom the goal of therapy is tumor debulking before stem cell transplant. 
 
 

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Patient MRN (COH Only) 
Patient Initials (F, M, L): 
Institution:     
 
__6.  History of prior malignancy. Exceptions include malignancy treated with curative intent and no known active 
disease present for ≥ 2 years prior to initiation of protocol therapy; adequately treated non-melanoma skin cancer 
or lentigo maligna (melanoma in situ) without evidence of disease; adequately treated in situ carcinomas (e.g., 
cervical, esophageal, etc.) without evidence of disease; asymptomatic prostate cancer managed with “watch and 
wait” strategy. 
__7.  Uncontrolled AIHA (autoimmune hemolytic anemia) or ITP (idiopathic thrombocytopenic purpura). 
__8.  Requires treatment with proton pump inhibitors (e.g., omeprazole, esomeprazole, lansoprazole, 
dexlansoprazole, rabeprazole, or pantoprazole). Subjects receiving proton pump inhibitors who switch to H2-
receptor antagonists or antacids are eligible for enrollment to this study. 
__9.  Requires treatment with a strong cytochrome P450 3A4 (CYP3A4) inhibitor/inducer. 
__10.  Requires or receiving anticoagulation with warfarin or equivalent vitamin K antagonists. 
__11.  Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the 
stomach or small bowel that is likely to affect absorption, symptomatic inflammatory bowel disease, partial or 
complete bowel obstruction, or gastric restrictions and bariatric surgery, such as gastric bypass. 
__12.  Presence of a gastrointestinal ulcer diagnosed by endoscopy within 3 months before screening. 
__13.  Known bleeding disorders (e.g., von Willebrand's disease or hemophilia). 
__14.  History of significant cerebrovascular disease/event, including stroke, myocardial infarction or intracranial 
hemorrhage, within 6 months prior to start of protocol therapy. 
__15.  Known active central nervous system (CNS) involvement by lymphoma, including leptomeningeal 
involvement. 
__16.  Clinically significant cardiovascular disease such as symptomatic arrhythmias, congestive heart failure, or 
myocardial infarction within 6 months of screening, or any Class III or IV cardiac disease as defined by the New York 
Heart Association Functional Classification. Note: Subjects with controlled, asymptomatic atrial fibrillation can 
enroll on study. See Appendix B. 
__17.  Unstable angina (angina symptoms at rest), new-onset angina (begun within the last 6 months). 
__18.  History of or current progressive multifocal leukoencephalopathy (PML). 
__19.  Inability to swallow and retain an oral medication. 
__20.  Clinically significant uncontrolled illness, including active infection requiring antibiotics.  
__21.  Live virus vaccines within 4 weeks of start of protocol therapy or planned administration of live virus 
vaccines during ublituximab therapy.  
__22.  Evidence of chronic active Hepatitis B (HBV, not including patients with prior hepatitis B vaccination; or 
positive serum Hepatitis B antibody) or chronic active Hepatitis C infection (HCV), or active cytomegalovirus (CMV).  
If HBc antibody is positive, the subject must be evaluated for the presence of HBV DNA by PCR.  If HCV antibody is 
positive, the subject must be evaluated for the presence of HCV RNA by PCR. (See Appendix J:  Hepatitis B serologic 
test results). If the subject is CMV IgG or CMV IgM positive, the subject must be evaluated for the presence of CMV 
DNA by PCR.  Subjects with positive HBc antibody and negative HBV DNA by PCR are eligible.  Subjects with positive 
HCV antibody and negative HCV RNA by PCR are eligible. Subjects who are CMV IgG or CMV IgM positive but who 
are CMV DNA negative by PCR are eligible. Patients with a prior known history of hepatitis B and those with a 
positive anti-HBc with negative HBsAg at screening must be able to receive antiviral agents effective against 
hepatitis B.   
__23.  Known history of human immunodeficiency virus (HIV) infection. 

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__24.  Females only: Pregnant or breastfeeding 
__25.  Any other condition that would, in the Investigator’s judgment, contraindicate the patient’s participation 
in the clinical study due to safety concerns with clinical study procedures. 
Noncompliance 
__26.  Prospective participants who, in the opinion of the investigator, may not be able to comply with all study 
procedures (including compliance issues related to feasibility/logistics). 
Eligibility Confirmed* by 
(Choose as applicable): 
Print Name 
Signature 
Date 
 Site PI 
 
 
 
 Authorized study MD 
 
 
 
 Study Nurse 
 
 
 
 Study CRA/ CRC 
 
 
 
Other:______________ 
 
 
 
*Eligibility should be confirmed per institutional policies. 
 
 
Patient MRN (COH Only) 
Patient Initials (F, M, L): 
Institution:     

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4.0 PARTICIPANT ENROLLMENT 
NOTE: Sites must meet activation requirements prior to enrolling participants. 
4.1 Pre-Enrollment Informed Consent and Screening Procedures 
Diagnostic or laboratory studies performed exclusively to determine eligibility will be done only after obtaining 
written informed consent. Studies or procedures that are performed for clinical indications (not exclusively to 
determine study eligibility) may be used for baseline values and/or to determine pre-eligibility, even if the studies 
were done before informed consent was obtained. 
The informed consent process is to be fully documented (see Section 17.4), and the prospective participant must 
receive a copy of the signed informed consent document. Screening procedures are listed in Section 10.0 (Study 
Calendar). 
4.2 Participant Enrollment 
4.2.1 
COH DCC Availability and Contact Information 
Eligible participants will be registered on the study centrally by the Data Coordinating Center (DCC) at City of Hope.   
DCC staff are available between the hours of 8.00 am and 5.00 pm PST, Monday through Friday (except holidays).  
o E-mail: DCC@coh.org 
4.2.2 
Slot verification and reservation 
A designated study team member should email the DCC to verify current slot availability, and to reserve a slot for 
a specific prospective subject (provide DCC with subject initials), including a tentative treatment date. Slots can 
only be held for a limited time, at the discretion of the study PI. 
The DCC should be notified of cancellations of prospective participants holding slots as soon as possible.   
4.2.3 
Registration Process  
Allow up to 24 hours for the DCC to review eligibility. To register a participant the subsequent procedure is to be 
followed: 
1. The study team should contact the DCC via email to provide notification regarding the pending registration 
and communicate desired timeline of the registration, especially if it must be completed promptly to meet 
the registration window.  
2. The study team will email a Complete Registration Packet to the DCC, which consists of a copy of the 
following documents: 
o Registration Cover Sheet (Appendix D) 
o Completed eligibility checklist (printed from Section 3.0 of the protocol) with required 
signature(s) 
o Source documents that support all eligibility criteria listed in the eligibility checklist 
o Signed Informed Consent  
o Signed HIPAA authorization form (if separate from informed consent) 
o Signed subject’s bill of Rights (California only) 
3. In some cases, the DCC may request additional documentation prior to registration. Please refer to the 
Work Instruction – Reviewing Packets and Registering Subjects for more information. A copy of this work 
instruction can be provided by the DCC, upon request. 
4. When all source documents are received, the DCC will review to verify eligibility, working with the study 
team to resolve any missing required source elements. Any missing documents may delay review and 

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registration.  A participant failing to meet all protocol eligibility requirements will not be registered and 
the study team will be immediately notified. 
5. Once eligibility is confirmed, the DCC will send a Confirmation of Registration Form and signed Eligibility 
Checklist, including the Subject Study Number and cohort assignment to:  
o The study team: Site Lead Investigator, treating physician/ sub-investigator, protocol nurse, CRC 
and pharmacy (as needed). 
o The COH Study PI and COH study team designees (including but not limited to study monitor(s) 
and statistician(s)). 
6. Upon receipt of the Confirmation of Registration Form, COH study team will register the patient in OnCore. 
The DCC will register non-COH patients in OnCore. 
4.3 Screen Failures and Registered Participants Who Do Not begin Study Treatment 
Notify the DCC immediately if the participant screen fails after registration or if the participant does not start 
treatment. 
For non-COH sites, the reason for screen failure will be documented in the registration coversheet (Appendix D) 
and submitted to the DCC. 
Issues that would cause treatment delays should be discussed with the Study Principal Investigator. 
5.0 TREATMENT PROGRAM 
5.1 Treatment Program Overview 
This is a multicenter, open-label, single cohort, phase 2 study of BTK inhibitor acalabrutinib and PI3Kδ umbralisib 
in combination with ublituximab (AU2) for patients with previously untreated mantle cell lymphoma (MCL). 
The trial consists of an Induction phase (6 cycles), followed by a Maintenance phase (19 cycles) for a total of 25 
cycles of protocol therapy. Participants with stable disease (SD) or better response at the end of Induction will be 
eligible to proceed to Maintenance. At the end of Maintenance, participants may be allowed to continue therapy 
with acalabrutinib per treating physician’s decision. For both Induction and Maintenance, each cycle will be 28 
days. 
Please refer to the Study Schema for additional details. 
Participants who end protocol therapy will undergo follow-up (Section 5.7). Windows for all assessments and 
treatments are detailed in Section 10. 
5.2 Cycle Definition 
In the absence of a delay due to toxicity, each treatment cycle lasts 28 days with a ± 3 day window during Induction 
and 28 days with a ± 7 day window during Maintenance. 
During the Induction phase (Cycles 1-6), Day 1 of each cycle is defined as the first day of administration of 
ublituximab. 
During the Maintenance phase (Cycles 7-25), ublituximab is administered every 2 cycles (every 8 weeks) starting 
on Day 1 of Cycle 8, and each cycle is defined as 28 days.  
5.3 Treatment Plan 
The treatment regimen and schedule are as follows: 

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Induction phase: 
Agent 
Dose 
Route 
Schedule 
Ublituximab 
900 mg 
IV 
Cycle 1: Day 1, Day 8, and Day 15 
Cycles 2-6: Day 1 
Acalabrutinib 
100 mg - Twice daily 
Orally 
Every day of each cycle 
Umbralisib 
800 mg - Once daily 
Orally 
Cycle 1: Days 1-14 
Cycles 2-6: Days 1-7 
 
Maintenance phase: 
Agent 
Dose 
Route 
Schedule 
Ublituximab 
900 mg 
IV 
Every 2 cycles (Cycles 8, 10, 12, 14, 16, 18, 
20, 22, 24), on Day 1, starting on Day 1 of 
Cycle 8 
Acalabrutinib 
100 mg - Twice daily 
Orally 
Every day of each cycle 
Umbralisib 
800 mg - Once daily 
Orally 
Days 1-7 of each cycle 
Treatment will be administered on an out-patient basis (in-patient administration is allowed if deemed necessary 
by the Investigator). 
 
5.4 Agent Administration 
5.4.1 
Required Premedications 
▪ Patients should be premedicated prior to all ublituximab infusions. Pre-medications should include an 
antihistamine (diphenhydramine 50 mg or equivalent), and a corticosteroid (dexamethasone 10-20 mg or 
equivalent).  
o If pre-medications are administered IV:  start the ublituximab infusion 30 minutes after conclusion 
of the last pre-medication infusion 
o If pre-medications are administered orally:  start the ublituximab infusion 45-60 minutes after 
ingestion of the oral pre-medications 
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 Use of oral acetaminophen 650 mg (or equivalent) should be restricted to patients who 
experience fever or pyrexia during week 1 dosing, or as clinically warranted 
▪ After cycle 6, if use of a corticosteroid is of clinical concern, please contact the Principal Investigator. 
▪ Use of anti-pneumocystis and antiviral prophylaxis is required for subjects receiving umbralisib. Refer to 
Section 5.10 for guidelines. 
▪ Prophylaxis with an antiviral agent effective against hepatitis B is required in subjects with a prior known history 
of hepatitis B and for those with a positive anti-HBc with negative HBsAg at screening. 
Promptly consult clinicians with an expertise in managing subjects with a prior history of hepatitis B regarding 
monitoring and consideration of options for hepatitis B antiviral therapy for prophylaxis/ treatment. 

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5.4.2 
Ublituximab 
Ublituximab will be administered as an intravenous infusion through a dedicated line. Do not administer as an IV 
push or bolus. Do not mix ublituximab with, or administer as an infusion with, other medicinal products. 
The first infusion of ublituximab (Cycle 1, Day 1) will be administered over a target period of 4 hours. Ublituximab 
infusions on Cycle 1, Days 8 and 15 will be administered over a target period of 3 hours. For all subsequent 
ublituximab infusions, infusion time may be reduced to approximately 90 minutes. 
Since infusion-related hypotension may occur, consider holding antihypertensive medications 12 to 24 hours prior 
to and throughout infusion of ublituximab. Decision to withhold antihypertensive medication is at investigator 
discretion. 
Medication and resuscitation equipment must be available per institutional guidelines prior to ublituximab 
administration for the emergency management of potential anaphylactic reactions. 
5.4.3 
Acalabrutinib 
Acalabrutinib will be administered as a 100 mg tablet taken orally approximately every 12 hours. The tablets 
should be swallowed intact with water without being crushed, dissolved, broken, or chewed. Acalabrutinib can be 
taken with or without food. 
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 missed dose will not be made up and must be returned to the site at the next 
scheduled visit. 
As acalabrutinib is metabolized by CYP3A, participants should be strongly cautioned against using herbal remedies 
or dietary supplements (in particular, St John’s wort, which is a potent CYP3A inducer). Otherwise, subjects should 
maintain their regular diet unless modifications are required to manage an AE such as diarrhea, nausea, or 
vomiting. 
5.4.4 
Umbralisib 
Umbralisib should be taken at approximately the same time each day within 30 minutes of starting a meal. Subjects 
should be instructed to swallow the tablets whole and should not chew or crush them. 
If a dose of umbralisib is missed, it should be taken as soon as possible on the same day. If it is missed for a period 
of greater than 12 hours, it should not be replaced. If vomiting occurs, no attempt should be made to replace 
the vomited dose. 
5.5 Assessments and Special Monitoring 
For a detailed list of all study procedures including timing and windows, see Section 10.  
Note: Initiate a new cycle after all procedures/safety assessments have been completed. 
5.5.1 
Special Monitoring 
o Infusion reactions 
 
Infusion related reactions including severe reactions have been reported with ublituximab 
administration.  
 
If such a reaction were to occur, it might manifest with fever, chills, rigors, headache, rash, pruritus, 
arthralgias, hypotension, hypertension, bronchospasm, or other allergic-like reactions. 
 
Refer to Section 5.10 for management guidelines. 
o Infections 

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 
Participants receiving umbralisib are at risk for infection, including pneumocystis, herpes, aspergillus, 
cytomegalovirus (CMV), and respiratory syncytial virus (RSV), as well as various bacterial infections. 
Use of anti-pneumocystis and antiviral prophylaxis is required for subjects receiving umbralisib. 
 
Participants receiving acalabrutinib are at risk for infection (bacterial, viral, or fungal). 
 
Refer to Section 5.10 for guidelines. 
o Tumor lysis syndrome (TLS) 
 
A TLS laboratory assessment (serum chemistry) will be performed during cycle 1 (see Section 10.0). 
 
Refer to Section 5.10 for guidelines. 
o Hepatitis B reactivation 
 
In addition to mandatory prophylaxis with an antiviral agent effective against hepatitis B (Section 
5.4.1), monitor subjects with a prior history of hepatitis B and those with a positive anti-HBc with 
negative HBsAg at screening closely 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. 
 
Refer to Section 5.10 for guidelines when there is an increase in liver enzymes while on study. 
 
5.6 Duration of Therapy and Criteria for Removal from Protocol Therapy 
Participants will receive protocol therapy until one of the below criteria are met: 
o Confirmed Disease progression per 2014 Lugano classification 
o Completed protocol therapy  
o Participant is deemed intolerant to protocol therapy because of toxicity, despite dose modification/ 
delay  
 
Note: If one agent is discontinued due to toxicity, then the participant may continue to receive the 
other study agents  
o General or specific changes in the patient's condition which render the patient unacceptable for 
further treatment in the judgment of the investigator 
o Withdrawal of consent for further protocol therapy (See Section 17.5) 
Once participants meet criteria for removal from protocol therapy, the participant should then proceed to follow-
up assessments (Section 5.7). 
Documentation of the reason for discontinuing protocol therapy and the date effective should be made in the 
Electronic Health Record/medical record and appropriate eCRF. 
The COH DCC and the Study PI should be promptly notified of the change in participant status. 
5.7 Follow-Up 
Following completion of protocol therapy, participants will enter follow-up. 
Follow-up is comprised of: 
o Safety Follow-up- 30 days post-last dose of protocol therapy. 
 
Note the period for safety follow-up will be extended until stabilization or resolution for all reportable 
AEs (per the agreement of the Study PI) and accompanying follow-up safety report. 
o Response Follow-up- for those who have yet to have disease progression and have not initiated a 
new anti-lymphoma therapy. 

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o Survival Follow-up- for all participants who have progressed OR completed Active Response Follow-
Up OR initiated a new anti-lymphoma therapy. It will entail (a) Disease status (for those who have yet 
to progress) (b) Vital status (all participants). 
Assessment time points and windows are detailed in Section 10. 
Note: if a participant continues therapy beyond 25 cycles with acalabrutinib for a total of 6 years of protocol 
therapy, the participant will only proceed with the safety follow-up visit; there will be no response/survival follow-
up. 
5.8 Duration of Study Participation 
Study participation may conclude when any of the following occur:  
o Completion of study activities (treatment and follow-up) 
o Withdrawal of consent (See Section 17.5) 
o Patient decided to proceed with autologous transplantation 
o Participant is lost to follow-up. All attempts to contact the participant must be documented. 
o At the discretion of the investigator for safety, behavioral, study termination or administrative 
reasons 
Documentation of the reason for discontinuing study participation and the date effective should be made in the 
Electronic Health Record/medical record and appropriate eCRF. 
The COH DCC and the Study PI should be promptly notified of the change in participant status. 
5.9 Prohibited and Concomitant Therapies/Medications  
5.9.1 
Allowed concomitant medications 
If concomitant therapy must be added or changed, including over-the-counter medications or alternative 
therapies, the reason and name of the agent/therapy should be recorded in the eCRF and documented in the 
Electronic Health Record/medical record. 
Concurrent glucocorticoid therapy as long as started for at least 7 days prior to study entry (<20 mg per day of 
prednisone or equivalent) is allowed as clinically warranted. 
Vaccination Guidance: Based on nonclinical data, no changes are recommended to standard of care practices with 
regard to vaccinations in subjects treated with acalabrutinib. As appropriate, vaccines consistent with standard 
practices for specific subject populations should be used.  
5.9.2 
Precautionary and Prohibited medications/ therapies 
This is not intended to be an exhaustive list; the investigator should consider each concomitant medication and 
potential for drug-drug interactions. 
• Prohibited from Day 1 of protocol therapy until end of protocol therapy (last day of study agent or decision 
to end study agent(s) whichever occurs later). 
 Herbal and natural remedies 
 Other investigational therapy  
 Other concurrent systemic anti-cancer therapy: chemotherapy, biological response modifiers, hormone 
therapy, surgery, palliative radiation therapy, or immunotherapy. 
 Live vaccines. 
 Systemic corticosteroid therapy at a daily dose ≥20 mg prednisone or equivalent. Patients may be using 
topical or inhaled corticosteroids. 

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• 
Guidelines for co-administration with acalabrutinib: 
 
Warfarin or equivalent Vitamin K antagonists are prohibited in patients on acalabrutinib as they may 
increase the risk of hemorrhage. 
 
Co-administration of acalabrutinib and a proton pump inhibitor should be avoided.  
 
Co-administration of acalabrutinib with a strong or moderate CYP3A inhibitor may increase acalabrutinib 
plasma concentrations resulting in increased toxicity. Use of strong or moderate CYP3A inhibitors should 
be avoided. 
 
Conversely, co-administration of acalabrutinib with a strong CYP3A inducer should be avoided as this may 
decrease acalabrutinib concentrations. 
Refer to Appendix E for examples. 
Refer to Section 8.2.6 for appropriate acalabrutinib dose adjustments if co-administration with a CYP3A inhibitor 
or inducer is required. 
If treatment with a gastric reducing agent is required, consider using a H2-receptor antagonist (e.g. famotidine) 
or an antacid (e.g. calcium carbonate). 
- If receiving antacids, acalabrutinib dosing should be separated by at least 2 hours.  
- If receiving H2-Receptor Antagonists, acalabrutinib should be taken 2 hours before taking a H2-
receptor antagonist. 
5.10 Supportive care 
With the exception of prohibited therapies (Section 5.9.2), participants should receive prophylactic or supportive 
as clinically indicated per institutional policies. 
Blood products and growth factors 
 
Platelet and/or red blood cell supportive growth factors or transfusions 
− 
Permitted when applicable 
 
Colony stimulating factors (CSFs) 
− 
Per investigator’s discretion and institutional practice. 
Anti-emetic prophylaxis 
 
Routine anti-emetic prophylaxis regimen should be administered per institutional standards. 
Corticosteroids 
 
Topical, ocular, intra-articular, intranasal, and inhalational corticosteroids (with minimal systemic 
absorption) 
− 
Permitted 
 
Systemic corticosteroids 
− 
permitted if <20 mg/day prednisone or equivalent. 
 
Brief course of corticosteroids (< 14 days)  
− 
Permitted for prophylaxis (e.g. contrast dye allergy)  
− 
Permitted for treatment of non-autoimmune conditions (e.g, delayed-type hypersensitivity reaction 
caused by contact allergen)  
Management of infusion related reactions   
Symptomatic infusion reactions, despite premedication, may be treated at the discretion of the treating 
physician, including but not limited to: oral acetaminophen 650 mg (or equivalent), corticosteroids, 
antihistamines, oxygen, and bronchodilators.   
If an infusion related reaction (IRR) is observed at any time during the ublituximab treatment, the treating 
investigator may reduce the infusion rate at their discretion. 

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The following are recommended infusion rate reduction/delay guidelines for patients who experience severe 
infusion related reactions that result in treatment interruption. Final decision for infusion rate reduction/delay 
or discontinuation resides with the treating investigator. 
 
 
1st or 2nd Infusion Interruption: 
Hold infusion and closely monitor subject.  Institute symptomatic medical management until resolution of IRR 
symptoms. 
Following the judgment of the 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 (see Infusion Rate Recommendations 
for Ublituximab Administration below). 
 
 
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 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. 
 
Infusion Rate Recommendations for Ublituximab Administration: 
Cycle 1 Day 1 infusion over 4 hours  
Cycle 1 
Ublituximab 
Dose 
Total volume to 
be infused 
Infusion rate 
T0 to T30’ 
T30' to T1H 
T1H to T2H 
T2H to T4H 
Day 1 
900 mg 
500 mL 
10 mL/H 
20 mL/H 
85 mL/H 
200 mL/H 
 
Cycle 1 Day 8 & 15 infusions over 3 hours 
Ublituximab Dose 
Total volume to be 
infused 
Infusion rate 
T0 to T1H 
T1H to T2H 
T2H to T3H 
900 mg 
500 mL 
50 mL/H 
150 mL/H 
300 mL/H 
 
Cycle 2 and remaining infusions over 90 minutes 
 
Moderate CYP3A4/5 inhibitors or inducers, and proton pump inhibitors 
 
Closely monitor for AEs when administered concomitantly with acalabrutinib. Refer to Appendix E for 
examples. 
Prophylaxis and management of infections 
 
Subjects receiving umbralisib are required to start prophylactic treatment with pneumocystis jiroveci 
pneumonia (PJP) and antiviral therapy on or prior to Day 1 of Cycle 1. Choice of PJP and anti-viral 
Ublituximab Dose 
Total volume to be 
infused 
Infusion rate 
T0 to T30min 
T30min to T90min 
900 mg 
500 mL 
200 mL/H 
400 mL/H 

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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:  Dapsone 100 mg daily or Bactrim DS 1 tab M-W-F or equivalent.   
 
Final choice of PJP and anti-viral prophylactic therapy is per investigator discretion. 
 
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 
investigator discretion. 
 
For patients receiving acalabrutinib, consider prophylaxis in patients who are at increased risk for 
opportunistic infections per institutional standards. 
 
Participants with documented infectious complication should receive oral or IV antibiotics or other anti-
infective agents as considered appropriate by the Investigator, per institutional standards. 
Tumor lysis syndrome (TLS) prophylaxis and management 
 
Performed per institutional standards 
For patients that are considered at risk for TLS [e.g. bulky disease (a single mass with a diameter > 
10cm), or WBC count>50,000/µL, or high uric acid (≥ 7 mg/dL) at baseline], allopurinol (300 mg po daily, 
dose adjusted per renal function) may be given. If a diagnosis of TLS is established, monitoring and 
multi-disciplinary management will be per institutional practice. 
Hepatitis B reactivation 
 
For patients with a prior history of hepatitis B and for those with a positive anti-HBc with negative HBsAg 
at screening 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, 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 in Section 5.5.1. 
 
6.0 ANTICIPATED ADVERSE EVENTS 
6.1 Ublituximab 
The Investigator’s Brochure (IB) is the primary source for safety information. The ublituximab IB includes a 
summary of adverse event data and discussion on potential risks that have been observed or may be predicted to 
occur with this study drug. Refer to the most recent IB, which is updated periodically, for current information on 
ublituximab. 
The following adverse events were observed in subjects treated with single agent ublituximab and were 
considered at least possibly related to study medication. The preliminary safety data as of May 1, 2018 is provided 
for a total of 117 subjects exposed to single agent ublituximab with a maximum follow up of 2+ years.   
 
Very Common (≥ 10%) 
• 
Blood and Lymphatic System Disorders: neutropenia, thrombocytopenia 
• 
General Disorders and Administration Site Conditions: pyrexia 
• 
Injury, Poisoning and Procedural Complications: infusion related reaction 
• 
Nervous System Disorders: headache 
 
Common (≥ 2 - < 10%) 

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• 
Blood and Lymphatic System Disorders: anemia, pancytopenia 
• 
Gastrointestinal Disorders: diarrhea, abdominal pain, nausea, oral pruritus 
• 
General Disorders and Administration Site Conditions: fatigue, asthenia, chills, oedema peripheral, pain 
• 
Hepatobiliary Disorders: cytolytic hepatitis 
• 
Infections and Infestations: herpes zoster 
• 
Investigations: 
aspartate 
aminotransferase 
increased, 
blood 
bilirubin 
increased, 
gamma-
glutamyltransferase increased 
• 
Musculoskeletal and Connective Tissue Disorders: muscular weakness 
• 
Nervous System Disorders: dysgeusia 
• 
Respiratory, Thoracic and Mediastinal Disorders: throat irritation, throat tightness 
• 
Skin and Subcutaneous Tissue Disorders: pruritus, hyperhidrosis 
• 
Vascular Disorders: hypertension 
Amendment dated 12-30-20 added the potential risk of hepatitis B reactivation as a rare (less than 0.1%) but 
serious risk with ublituximab. 
6.2 Acalabrutinib 
Please refer to the investigator brochure and package insert for additional details. 
Information provided in Tables 6.2.1 and 6.2.2 is based on Acalabrutinib IB V 10.0 (Feb 2021). 
Adverse drug reactions observed in clinical studies with 1079 subjects receiving acalabrutinib monotherapy in 
hematological malignancies are summarized in Table 6.2.1. The median duration of exposure to acalabrutinib 
monotherapy treatment across the pooled dataset was 28.5 months (range, 0.0 to 65.3 months). 

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Table 6.2.1: Adverse drug reactions for acalabrutinib 
Body System 
Adverse Reaction 
No. (%) of Subjects 
(n=1079) 
All Grades 
Grade ≥ 3 
Blood and lymphatic system disorders 
Leukopenia 
Neutropenia 
Anemia 
Thrombocytopenia 
202 (18.7) 
187 (17.3) 
159 (14.7) 
102 (9.5) 
174 (16.1) 
169 (15.7) 
84 (7.8) 
52 (4.8) 
Cardiac disorders 
Atrial fibrillation/flutter 
59 (5.5) 
15 (1.4) 
Gastrointestinal disorders  
Diarrhea  
Nausea  
Constipation  
Vomiting  
Abdominal Pain  
407 (37.7) 
239 (22.2) 
160 (14.8) 
157 (14.6) 
151 (14.6) 
 32 (3.0) 
12 (1.1) 
1 (0.1) 
9 (0.8) 
10 (0.9) 
General disorders and administration site 
conditions 
Fatigue 
Asthenia 
248 (23.0) 
64 (5.9) 
19 (1.8) 
8 (0.7) 
Infections and infestations 
Infection 
770 (71.4) 
217 (20.1) 
Metabolism and nutrition disorders 
Tumor lysis syndrome* 
5 (0.5) 
4 (0.4) 
Musculoskeletal and connective tissue 
disorders 
Musculoskeletal pain  
Arthralgia  
372 (34.5) 
230 (21.3) 
22 (2.0) 
8 (0.7) 
Neoplasms begnin, malignant and 
unspecified 
Second primary malignancy 
Non-melanoma skin malignancy 
SPM excluding non-melanoma skin 
160 (14.8) 
93 (8.6) 
81 (7.5) 
55 (5.1) 
8 (0.7) 
49 (4.5) 
Nervous system disorders 
Headache 
Dizziness  
404 (37.4) 
151 (14.0) 
11 (1.0) 
2 (0.2) 
Respiratory, thoracic and mediastinal 
disorders 
Epistaxis 
    85 (7.9) 
3 (0.3) 
Skin and subcutaneous tissue disorders  
Bruising  
Rash 
376 (34.8) 
227 (21.0) 
0 
6 (0.6) 
Vascular disorders  
Hemorrhage / Hematoma 
158 (14.6) 
26 (2.4) 
* One case of drug-induced tumor lysis syndrome was observed in the acalabrutinib arm of Study ACE CL 309. 
 
Table 6.2.2 lists all serious adverse drug reactions for acalabrutinib that have occurred more than once in clinical 
studies. These adverse events are considered “expected” for regulatory purposes. All life-threatening and fatal 
SADRs are considered unexpected. 
Table 6.2.2: Serious adverse drug reactions considered expected for acalabrutinib 
Body System 
Adverse Reaction 
No. (%) of Subjects 
All Grades 
(N = 1079) n (%) 
Blood and lymphatic system disorders Anemia 
Febrile neutropenia 
Neutropenia 
Thrombocytopenia 
20 (1.9) 
16 (1.5) 
2 (0.2) 
4 (0.4) 
Cardiac disorders 
Atrial fibrillation 
13 (1.2) 
Gastrointestinal disorders  
Abdominal Pain 
Constipation 
Diarrhea 
12 (1.1) 
2 (0.2)  
9 (0.8)  

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Gastrointestinal hemorrhage 
Nausea 
Vomiting 
4 (0.4)  
2 (0.2)  
4 (0.4)  
General disorders and administration 
site conditions 
Asthenia 
Fatigue 
2 (0.2) 
4 (0.4) 
Infections and infestations 
Acute sinusitis 
Aspergillus infection 
Bacteremia 
Bronchitis 
Cellulitis 
Clostridium difficile infection 
Diverticulitis 
Epiglottitis 
Gastroenteritis 
Gastroenteritis viral 
Herpes zoster 
Infection 
Influenza 
Kidney infection 
Lower respiratory tract infection 
Lung infection 
Neutropenic sepsis 
Parainfluenzae virus infection 
Pharyngitis 
Pneumonia 
Pneumonia fungal 
Pneumonia influenzal 
Pneumonia streptococcal 
Pseudomonas infection 
Respiratory tract infection 
Rhinovirus infection 
Salmonellosis 
Sepsis 
Septic shock 
Sinusitis 
Skin infection 
Upper respiratory tract infection 
Urinary tract infection 
Urosepsis 
3 (0.3) 
2 (0.2) 
2 (0.2) 
3 (0.3) 
11 (1.0) 
2 (0.2) 
4 (0.4) 
2 (0.2) 
4 (0.4) 
2 (0.2) 
3 (0.3) 
2 (0.2) 
6 (0.6) 
2 (0.2) 
12 (1.1) 
9 (0.8) 
3 (0.3) 
2 (0.2) 
2 (0.2) 
67 (6.2) 
2 (0.2) 
2 (0.2) 
2 (0.2) 
2 (0.2) 
10 (0.9) 
2 (0.2) 
2 (0.2) 
18 (1.7) 
4 (0.4) 
2 (0.2) 
2 (0.2) 
12 (1.1) 
19 (1.8) 
4 (0.4) 
Metabolism and nutrition disorders 
Tumor lysis syndrome 
3 (0.3) 
Musculoskeletal and connective 
tissue disorders 
Back pain 
2 (0.2) 
Neoplasms benign, malignant and 
unspecified (incl. cysts and polyps) 
Basal cell carcinoma 
Glioblastoma multiforme 
Lung adenocarcinoma 
Malignant melanoma 
Metastases to meninges 
Myelodysplastic syndrome 
Neuroendocrine carcinoma of the skin 
Prostate cancer 
5 (0.5) 
2 (0.2) 
5 (0.5) 
5 (0.5) 
3 (0.3) 
3 (0.3) 
2 (0.2) 
5 (0.5) 

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Prostate cancer metastatic 
Renal cell carcinoma 
Squamous cell carcinoma 
Squamous cell carcinoma of skin 
2 (0.2) 
3 (0.3) 
2 (0.2) 
5 (0.5) 
Nervous system disorders  
Dizziness 
Hemorrhage intracranial 
Headache  
2 (0.2) 
2 (0.2) 
2 (0.2) 
Vascular disorders  
Hematoma 
3 (0.3) 
 
Contraindications 
No contraindications are known for acalabrutinib. 
Warnings and Precautions 
Table 6.2.3 summarizes the experience with acalabrutinib in hematological cancer studies. Full details regarding 
the clinical safety of acalabrutinib are presented in the acalabrutinib Investigator’s Brochure. 
Table 6.2.3: Important identified risks for acalabrutinib 
Important 
potential risks 
Description 
Hemorrhage 
Serious hemorrhagic events, including fatal events, have occurred in clinical trials with 
acalabrutinib. 
The mechanism for hemorrhage is not well understood. Patients receiving antithrombotic 
agents may be at increased risk of hemorrhage. Use caution with antithrombotic agents 
and consider additional monitoring for signs of bleeding when concomitant use is 
medically necessary.  
Consider the benefit-risk of withholding acalabrutinib for at least 3 days pre- and post-
surgery.  
Subjects with hemorrhage should be managed per institutional guidelines with supportive 
care and diagnostic evaluations as clinically indicated. 
Infections 
Serious infections (bacterial, viral, and fungal), including fatal events, have occurred in 
clinical studies with acalabrutinib. The most frequent reported Grade ≥3 infection was 
pneumonia (preferred term). Across the acalabrutinib clinical development program 
(including subjects treated with acalabrutinib in combination with other drugs), cases of 
hepatitis B virus (HBV) reactivation, aspergillosis, and progressive multifocal 
leukoencephalopathy (PML) have occurred. 
Consider prophylaxis in subjects who are at increased risk for opportunistic infections. 
Subjects should be monitored for signs and symptoms of infection and treated as 
medically appropriate. 
Subjects with infection events should be managed according to institutional guidelines 
with maximal supportive care and diagnostic evaluations as clinically indicated. 
Cytopenias  
 
Treatment-emergent Grade 3 or 4 cytopenias, including neutropenia, anaemia, and 
thrombocytopenia have occurred in clinical studies with acalabrutinib. Monitor blood 
counts as specified in the schedule of assessments and as medically appropriate. 
 

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Subjects with cytopenias should be managed according to institutional guidelines with 
maximal supportive care and diagnostic evaluations as clinically indicated.  Subjects should 
be closely monitored as appropriate.  
Second 
Primary 
Malignancies  
 
Events of second primary malignancies, including non-solid tumors and skin carcinomas, 
have occurred in clinical studies with acalabrutinib. The most frequently reported second 
primary malignancy was skin cancer (basal cell carcinoma). 
Subjects should be monitored for signs and symptoms of malignancy. Subjects who 
develop a second primary malignancy should be managed according to institutional 
guidelines with diagnostic evaluations as clinically indicated, and it may be necessary for 
subjects to permanently discontinue study treatment. Continuation of acalabrutinib 
treatment should be discussed with the medical monitor.  
Atrial fibrillation 
and Flutter 
 
Events of atrial fibrillation/flutter have occurred in clinical studies with acalabrutinib, 
particularly in subjects with cardiac risk factors, hypertension, diabetes mellitus, acute 
infections, or a previous history of atrial fibrillation. 
Monitor for symptoms of atrial fibrillation and atrial flutter (e.g., palpitations, dizziness, 
syncope, chest pain, dyspnea) and obtain an ECG as clinically indicated. Subjects with atrial 
fibrillation should be managed per institutional guidelines with supportive care and 
diagnostic evaluations as clinically indicated.  
 
6.3 Umbralisib 
The Investigator’s Brochure (IB) is the primary source for safety information. The umbralisib IB includes a summary 
of adverse event data and discussion on potential risks that have been observed or may be predicted to occur 
with this study drug. Refer to the most recent IB, which is updated periodically, for current information on 
umbralisib. 
The following adverse events were observed in subjects treated with single agent umbralisib and were considered 
at least possibly related to study medication. The preliminary safety data as of May 1, 2018 is provided for a total 
of 136 subjects exposed to single agent umbralisib with a maximum follow up of 5+ years.   
 
Very Common (≥ 10%) 
• 
Blood and Lymphatic System Disorders: neutropenia 
• 
Gastrointestinal Disorders: nausea, diarrhea, vomiting 
• 
General Disorders and Administration Site Conditions: fatigue  
 
Common (≥ 2% - < 10%) 
• 
Blood and Lymphatic System Disorders: anemia, thrombocytopenia, leukocytosis, lymphocytosis 
• 
Ear and Labyrinth Disorders: tinnitus 
• 
Eye Disorders: vision blurred 
• 
Gastrointestinal Disorders: constipation, abdominal pain, abdominal distension, dyspepsia, colitis, dry 
mouth 
• 
General Disorders and Administration Site Conditions: pyrexia, edema peripheral  
• 
Infections and Infestations: pneumonia, oral candidiasis 
• 
Injury, Poisoning and Procedural Complications: contusion 
• 
Investigations: weight decreased, alanine aminotransferase increased, aspartate aminotransferase 
increased, blood creatinine increased 
• 
Metabolism and Nutrition Disorders: decreased appetite, dehydration, hyperglycemia, hypokalemia, 
hypophosphatemia 

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• 
Musculoskeletal and Connective Tissue Disorders: muscle spasms, pain in extremity 
• 
Nervous System Disorders: dizziness, headache, dysgeusia, tremor 
• 
Psychiatric Disorders: insomnia 
• 
Respiratory, Thoracic and Mediastinal Disorders: cough 
• 
Skin and Subcutaneous Tissue Disorders: rash maculo-papular, alopecia, night sweats, pruritus, rash 
 
6.4 Ublituximab plus umbralisib 
The Investigator’s Brochure (IB) is the primary source for safety information. Refer to the most recent IB, which is 
updated periodically, for current information on ublituximab and umbralisib. 
The following adverse events were observed in subjects treated with the combination of ublituximab + umbralisib 
and were considered at least possibly related to one or both of the study medications. The preliminary safety data 
as of May 1, 2018 is provided for a total of 75 subjects exposed to ublituximab + umbralisib with a maximum follow 
up of 3+ years.   
 
Very Common (≥ 10%) 
• 
Blood and Lymphatic System Disorders: anemia, neutropenia 
• 
Gastrointestinal Disorders: diarrhea, nausea, vomiting 
• 
General Disorders and Administration Site Conditions: fatigue 
• 
Injury, Poisoning and Procedural Complications: infusion related reaction 
• 
Metabolism and Nutrition Disorders: decreased appetite 
 
Common (≥1% - < 10%) 
• 
Blood and Lymphatic System Disorders: thrombocytopenia 
• 
Cardiac Disorders: cardiac failure congestive 
• 
Ear and Labyrinth Disorders: ear congestion, ear discomfort 
• 
Eye Disorders: conjunctival pallor, conjunctivitis, corneal edema, vision blurred 
• 
Gastrointestinal Disorders: abdominal discomfort, abdominal distension, abdominal pain, constipation, 
dyspepsia, flatulence, gastrooesophageal reflux disease, haematochezia, salivary hypersecretion, 
stomatitis 
• 
General Disorders and Administration Site Conditions: asthenia, chills, face edema, infusion site pain, 
local swelling, edema peripheral, pyrexia, systemic inflammatory response syndrome 
• 
Hepatobiliary Disorders: hyperbilirubinemia 
• 
Immune System Disorders: hypogammaglobulinemia 
• 
Infections and Infestations: bronchitis, cellulitis, clostridium difficile colitis, enterocolitis infectious, oral 
candidiasis, oral herpes, otitis media, pneumonia, pneumonia streptococcal, rhinovirus infection, sepsis, 
sepsis syndrome, sinusitis, skin infection, upper respiratory tract infection, urinary tract infection 
• 
Injury, Poisoning and Procedural Complications: wound 
• 
Investigations: alanine aminotransferase increased, aspartate aminotransferase increased, blood alkaline 
phosphatase increased, blood creatinine increased, computerized tomogram thorax abnormal, 
immunoglobulins decreased, weight decreased 
• 
Metabolism and Nutrition Disorders: dehydration, failure to thrive, hyperglycemia, hyperuricemia, 
hypokalemia, hypophosphatemia 
• 
Musculoskeletal and Connective Tissue Disorders: joint swelling, muscle spasms, muscular weakness, 
myalgia, pain in extremity 
• 
Nervous System Disorders: dizziness, dysgeusia, headache, lethargy, sinus headache, somnolence 
• 
Psychiatric Disorders: agitation, anxiety 

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• 
Renal and Urinary Disorders: micturition urgency, renal failure, renal failure acute 
• 
Reproductive System and Breast Disorders: scrotal cyst, semen discoloration 
• 
Respiratory, Thoracic and Mediastinal Disorders: choking, cough, dysphonia, dyspnea, epistaxis, hypoxia, 
oropharyngeal pain, pneumonitis, productive cough, sinus congestion 
• 
Skin and Subcutaneous Tissue Disorders: alopecia, cold sweat, dermatitis acneiform, dermatitis bullous, 
dry skin, ecchymosis, pruritus, rash, maculo-papular, rosacea, urticaria 
• 
Vascular Disorders: hypertension 
7.0 DOSE DELAY / MODIFICATION GUIDELINES 
7.1 Dose Delays/ Modification 
o Toxicities will be graded using the NCI CTCAE v 5.0. 
o Baseline values are from the last values obtained prior to treatment. 
o Both acalabrutinib and umbralisib may be dose reduced for toxicity. If a toxicity occurs, both drugs (as well 
as ublituximab) may be interrupted until resolution to Grade 1, to baseline, or as noted in Table 7.1.1. 
Following that, either or both oral agents may be dose reduced based on suspected attribution. General 
guidelines for recommended dose delays and modifications are provided below. 
o No reduction in the dose of ublituximab is permitted. If Grade 4 anaphylaxis is observed at any point during 
ublituximab treatment, permanently discontinue ublituximab treatment and intervene as per investigator 
discretion. 
o All study drugs may be delayed for a maximum of 8 weeks to allow recovery of toxicities as specified in the 
tables below.   
o If one of the study drugs is discontinued for toxicity, patient may continue therapy with the other study drugs. 
o When treatment interruption is required for toxicity, all drugs are held. If ublituximab is suspected to be the 
primary reason for a recurrent toxic event, it may be discontinued only in consultation with the Study PI. 
 
Table 7.1.1 Recommended Dose Modifications 
NCI-CTCAE Grade 
Dose Delay and/or Modification 
Hematologic Adverse Event 
Neutropenia 
Grade ≤ 2 neutropenia 
Provide supportive care as warranted.   
Maintain current dose and schedule of acalabrutinib. 
Maintain current dose of umbralisib.  
If applicable, maintain full dose and schedule of ublituximab. 
Grade 3 neutropenia 
Provide supportive care as warranted. 
Maintain current dose and schedule of acalabrutinib.   
Maintain current dose of umbralisib.   
For recurrent or persistent Grade 3 neutropenia unresponsive 
to maximum supportive care: 

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• If toxicity is suspected to be related to umbralisib by the 
investigator (e. g. based on timing of toxicity occurrence 
during the cycle), reduce umbralisib to next lower dose 
level. If the lowest dose level of umbralisib is reached, 
reduce acalabrutinib to the next lower dose level. 
• If toxicity is suspected to be related to acalabrutinib by the 
investigator (e. g. based on timing of toxicity occurrence 
during the cycle), reduce acalabrutinib to the next lower 
dose level. For recurrences, umbralisib may be dose 
reduced. 
If applicable, maintain full dose and schedule of ublituximab. 
Grade 4 neutropenia or occurrence of 
neutropenic fever or infection 
Provide supportive care as warranted. 
• If toxicity is suspected to be related to umbralisib by the 
investigator (e. g. based on timing of toxicity occurrence 
during the cycle):    
1st occurrence: 
- 
Delay umbralisib until Grade ≤ 1 or baseline and, if 
present, neutropenic fever or infection is resolved; 
thereafter, resume umbralisib at current dose. 
- 
If grade 4 neutropenia lasts longer than 7 days 
(despite holding umbralisib), interrupt acalabrutinib 
until Grade ≤ 1 or baseline and, if present, neutropenic 
fever or infection is resolved; thereafter, resume 
acalabrutinib at current dose level. 
2nd occurrence (despite maximum supportive care): 
- 
Same as for 1st occurrence, but resume umbralisib at 
next lower dose level (dose reduction). 
3rd occurrence (despite maximum supportive care): 
- 
Delay umbralisib and acalabrutinib until Grade ≤ 1 or 
baseline and, if present, neutropenic fever or infection 
is resolved; thereafter, resume umbralisib and 
acalabrutinib at next lower dose level. 
4th occurrence (despite maximum supportive care): 
- 
Discontinue umbralisib. 
- 
If grade 4 neutropenia lasts longer than 7 days 
(despite umbralisib discontinuation), discontinue 
acalabrutinib.  
If applicable, delay ublituximab until Grade ≤3 and, if present, 
neutropenic fever or infection is resolved; thereafter, resume 
ublituximab at full dose and schedule. 

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• If toxicity is suspected to be related to acalabrutinib by the 
investigator (e. g. based on timing of toxicity occurrence 
during the cycle), delay acalabrutinib until Grade ≤ 1 or 
baseline, thereafter, resume acalabrutinib at current dose 
level. For recurrences, acalabrutinib and/or umbralisib may 
be dose reduced. 
If applicable, delay ublituximab until Grade ≤3 and, if present, 
neutropenic fever or infection is resolved; thereafter, resume 
ublituximab at full dose and schedule. 
   
Thrombocytopenia 
Grade ≤3 thrombocytopenia 
Provide supportive care as warranted.  
Maintain current dose and schedule of acalabrutinib. 
Maintain current dose of umbralisib.   
If applicable, maintain full dose and schedule of ublituximab. 
Grade 3 thrombocytopenia with 
bleeding, or Grade 4 
thrombocytopenia 
Provide supportive care as warranted. 
• If toxicity is suspected to be related to umbralisib by the 
investigator (e. g. based on timing of toxicity occurrence 
during the cycle):    
1st occurrence: 
- 
Delay acalabrutinib and umbralisib until Grade ≤ 1 or 
baseline; thereafter, resume both acalabrutinib and 
umbralisib at current dose level. 
2nd occurrence: 
- 
Same as for 1st occurrence, but resume umbralisib at 
next lower dose level (dose reduction). 
3rd occurrence: 
- 
Same as for 1st occurrence, but resume both 
umbralisib and acalabrutinib at next lower dose level 
(dose reduction). 
4th occurrence: 
- 
Discontinue both acalabrutinib and umbralisib. 
 
Delay ublituximab until Grade ≤3; thereafter, resume 
ublituximab at full dose and schedule.  
 

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• If toxicity is suspected to be related to acalabrutinib by the 
investigator (e. g. based on timing of toxicity occurrence 
during the cycle), delay acalabrutinib until Grade ≤ 1 or 
baseline, thereafter, resume acalabrutinib at current dose 
level. For recurrences, acalabrutinib and/or umbralisib may 
be dose reduced. 
Delay ublituximab until Grade ≤3; thereafter, resume 
ublituximab at full dose and schedule. 
Pulmonary toxicity (pneumonitis) & Related Infections* 
Grade 1 or 2 
Provide supportive care as warranted. 
 
Maintain current dose and schedule of acalabrutinib. 
Delay umbralisib. Upon complete resolution, restart 
umbralisib at next lower dose level.     
If recurrence after re-challenge, discontinue umbralisib. 
Hold ublituximab. Upon resolution, resume ublituximab at full 
dose and schedule. If recurrence after re-challenge, 
discontinue ublituximab. 
Grade ≥3 
Provide supportive care as warranted.  
Discontinue umbralisib.   
Hold acalabrutinib and ublituximab until complete resolution. 
Restart at acalabrutinib current dose level and ublituximab at 
full dose and schedule. 
If 2nd occurrence, discontinue all drugs 
* For sinopulmonary infections clearly not related to immune-mediated pneumonitis, umbralisib may 
be continued at 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. 
Diarrhea and/or Colitis 
Diarrhea Grade ≤2 
Provide supportive care as warranted. 
Maintain current dose and schedule of acalabrutinib. 
If tolerable, maintain current dose of umbralisib.  Otherwise, 
delay umbralisib until ≤ grade 1.  Resume umbralisib at current 
dose level.   
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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If recurrence after rechallenge, delay umbralisib until ≤ grade 
1; thereafter, resume umbralisib at current dose. 
If applicable, maintain full dose and schedule of ublituximab.  
If intolerable or persistent grade 2 diarrhea despite supportive 
care, delay ublituximab until ≤ grade 1; thereafter, resume 
ublituximab at full dose and schedule.   
Diarrhea Grade ≥3 
Provide supportive care as warranted. 
1st occurrence: 
- 
Delay acalabrutinib and umbralisib until Grade ≤ 1; 
thereafter, resume both acalabrutinib and umbralisib 
at current dose level. 
2nd occurrence (despite supportive care): 
- 
Same as for 1st occurrence, but resume umbralisib at 
next lower dose level (dose reduction). 
3rd occurrence (despite supportive care): 
- 
Same as for 1st occurrence, but resume both 
umbralisib and acalabrutinib at next lower dose level 
(dose reduction for both). 
4th occurrence (despite supportive care): 
Discontinue both acalabrutinib and umbralisib. 
Delay ublituximab until ≤ grade 2 (or until ≤ grade 1 for 
recurrence after rechallenge); thereafter, resume ublituximab 
at full dose and schedule.  
 
If toxicity is suspected to be related to acalabrutinib rather 
than umbralisib by the investigator, delay acalabrutinib until 
Grade ≤ 1 or baseline, thereafter, resume acalabrutinib at 
current dose level. For recurrences, acalabrutinib and/or 
umbralisib may be dose reduced. 
 
Colitis (all Grades) 
Provide supportive care as warranted.  
Delay umbralisib and interrupt acalabrutinib. Treat with 
supportive care and after resolution of colitis, resume 
acalabrutinib at current dose level and umbralisib at next 
lower dose level. 
Upon second occurrence: 
- 
Discontinue umbralisib. 
- 
Interrupt acalabrutinib. 

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- 
Treat with supportive care and after resolution of 
colitis, resume acalabrutinib at next lower dose level. 
Delay ublituximab until resolution to grade ≤1; thereafter, 
resume ublituximab at full dose and schedule. 
 
Liver Toxicity (ALT/SGPT, AST/SGOT, Bilirubin, Alkaline Phosphatase) 
Reversible liver toxicity (transaminase elevation) has been seen on study and could be attributed to 
both umbralisib and acalabrutinib. Thus, any cases of grade ≥3 toxicity should be discussed with the 
study PI. 
Grade 1 
Maintain current dose and schedule of acalabrutinib. 
Maintain current umbralisib dose. 
Assess concomitant medications and risk factors*. 
Monitor labs every 1-2 weeks. 
Maintain full dose and schedule of ublituximab***, if 
applicable. 
 
 
 
 
Grade 2  
Delay acalabrutinib, umbralisib and ublituximab***. 
Assess concomitant medications and risk factors*. 
Monitor labs at least weekly until toxicity fully resolved (Grade 
0).  Once resolved: 
o Restart acalabrutinib and umbralisib at current dose 
level. 
o Restart ublituximab*** at full dose and schedule. 
If 2nd occurrence of liver toxicity Grade 2: 
In addition to above measures, begin supportive care 
(prednisone 0.5-1.0 mg/kg/day or equivalent per investigator 
discretion) **.   
Once fully resolved (to Grade 0): 
o Restart umbralisib at next lower dose level. 
o Restart acalabrutinib at current dose. 
o Restart ublituximab*** at full dose and schedule. 
o Taper prednisone by 10 mg per week until off. 
 
If liver toxicity recurs again to Grade 2, treat as a Grade ≥3 
recurrence. 
 
 
 
Delay acalabrutinib, umbralisib and ublituximab***. 
Assess concomitant medications and risk factors*.   
Begin/continue supportive care (prednisone 0.5-1.0 
mg/kg/day or equivalent per investigator discretion) **.   

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Grade ≥3 
Discuss with the study PI. 
Monitor labs at least weekly until toxicity fully resolved 
(Grade 0). Once resolved: 
o Restart acalabrutinib at current dose level. 
o Restart umbralisib at 400 mg po daily. 
o Restart ublituximab*** at full dose and schedule. 
o Taper prednisone by 10 mg per week until off. 
If 2nd occurrence of liver toxicity Grade ≥3: 
Discontinue umbralisib. Hold acalabrutinib and ublituximab 
until resolved (Grade 0). Thereafter, resume acalabrutinib at 
current dose level and restart ublituximab*** at full dose and 
schedule; however, if liver toxicity is strongly suspected to be 
related to acalabrutinib, treat as 3rd occurrence below. 
If 3rd occurrence of liver toxicity to Grade ≥3, discontinue 
acalabrutinib and resume umbralisib at 400 mg po daily and 
ublituximab*** at full dose and schedule once toxicity 
resolves (to Grade 0). If toxicity does not recur, umbralisib may 
be escalated by one dose level after a full cycle of therapy. Re-
introduction of acalabrutinib may be attempted after 3 full 
cycles of therapy in absence of additional liver toxicity, after 
discussion with the study PI. In those circumstances, 
acalabrutinib should be given on days 8-28 of each cycle and 
liver function tests (AST, ALT, bilirubin) checked within 14±7 
days after the first dose of acalabrutinib, and as needed 
thereafter. If liver toxicity recurs to grade ≥3, acalabrutinib 
should be permanently discontinued. 
If 4th occurrence of liver toxicity Grade ≥3 (while on 
umbralisib), 
permanently 
discontinue 
umbralisib. 
Re-
introduction of acalabrutinib may be attempted after 3 full 
cycles of therapy in absence of additional liver toxicity, after 
discussion with the study PI. In those circumstances, liver 
function tests (AST, ALT, bilirubin) should be checked within 
14±7 days after the first dose of acalabrutinib, and as needed 
thereafter. If liver toxicity recurs to grade ≥3, acalabrutinib 
should be permanently discontinued. 
 
* Assess for disorders of lipids and glucose, thyroid disorders, alcohol use, viral infections, etc. 
**Supportive Care – Aggressive management of lipid, glucose, other metabolic disorders, viral 
infections, etc.   
Important: Before initiating steroids, check for viral hepatitis or CMV infection. 
*** For patients with a prior history of hepatitis B and for those with a positive anti-HBc with negative 
HBsAg at screening 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, ublituximab may be 
resumed. If reactivation of hepatitis B is confirmed, institute hepatitis B antiviral treatment.  

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Ublituximab may be resumed at investigator discretion once hepatitis B infection has resolved, with 
continued monitoring. 
All Other Non-Hematological Adverse Events 
Grade ≤2 
Provide supportive care as warranted.  
Maintain current dose and schedule of acalabrutinib. 
Maintain current dose of umbralisib. 
If applicable, maintain full dose and schedule of ublituximab. 
Grade ≥3 
Provide supportive care as warranted.  
1st occurrence: 
- 
Delay acalabrutinib and umbralisib until Grade ≤ 1 or 
baseline; thereafter, resume both acalabrutinib and 
umbralisib at current dose level. 
2nd occurrence (despite supportive care): 
- 
Same as for 1st occurrence, but resume umbralisib at 
next lower dose level (dose reduction). Investigator 
discretion may be used to maintain current dose of 
umbralisib if toxicity appears to be attributable to 
acalabrutinib. 
3rd occurrence (despite supportive care): 
- 
Same as for 1st occurrence, but resume both 
umbralisib and acalabrutinib at next lower dose level 
(dose reduction for both). If toxicity appears to be 
attributable specifically to umbralisib or acalabrutinib, 
investigator discretion may be used to maintain the 
current dose of umbralisib or acalabrutinib while 
reducing the dose of the other agent by one dose level 
based on attribution. 
4th occurrence (despite supportive care): 
- 
Discontinue both acalabrutinib and umbralisib. 
 
Delay ublituximab until ≤ grade 1; thereafter, resume 
ublituximab at full dose and schedule.   
Umbralisib and acalabrutinib Dose Reduction Recommendations 
Study Drug 
Starting Dose 
1st Dose Reduction 
2nd Dose Reduction 
Umbralisib 
(once daily, and 
according to schedule) 
800 mg 
600 mg 
400 mg 

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Acalabrutinib 
100 mg PO BID 
100 mg PO once daily (QD) 
N/A 
 A maximum of two dose level reductions are allowed for umbralisib.  
 If a subject requires a dose reduction of umbralisib (or acalabrutinib) due to study drug related 
toxicity, the dose may not be re-escalated. If further evaluation of the toxicity reveals the event was 
not related to umbralisib (or acalabrutinib), this should be recorded in the medical record and dose 
re-escalation to the previous dose may be considered in consultation with the Study PI. 
 If a subject: 1/ is already at the lowest dose level of umbralisib (or acalabrutinib) following prior dose 
reduction(s) due to study drug related toxicity, and 2/ experiences a different toxicity that would 
require a dose reduction, then, in consultation with Study PI, umbralisib (or acalabrutinib) may be 
delayed and then resumed at the same dose level when the toxicity resolves as indicated in the table 
for that particular toxicity. 
 In case of concurrent toxicities, follow the more stringent dose modification recommendations. 
 
8.0 AGENT INFORMATION 
8.1 Ublituximab 
8.1.1 
Other names 
TG-1101 
8.1.2 
Description 
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 is produced by a stable expression in a clone of the rat myeloma cell 
line YB2/0. 
Please refer to the investigator brochure for additional details. 
8.1.3 
Mechanism of action 
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. 
8.1.4 
Pharmacokinetics and Metabolism 
Please refer to the investigator brochure. 
Ublituximab is a 147 kDa glycoprotein. 
8.1.5 
Toxicology 
8.1.5.1 Expected human toxicities  
See Section 6.1 for detailed list of anticipated AEs. 
8.1.5.2 Potential effects on pregnancy and lactation 
The effects of ublituximab on pregnancy and lactation are unknown. 

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8.1.6 
Formulation 
Ublituximab is a sterile, clear to opalescent, preservative-free concentrate for solution for intravenous (IV) by 
infusion administration. 
Ublituximab will be supplied at a concentration of 25 mg/mL in 6 mL (150 mg) or 36 mL (900 mg) single-use glass 
vials. Ublituximab is packaged in either a kit containing 6 vials or in a carton containing one single vial. 
8.1.7 
Storage 
Ublituximab must be stored in a secured, limited-access, refrigerated area at a temperature ranging from +2°C / 
+ 8°C (36-46°F). Temperature should be monitored, documenting minimum and maximum daily. Ublituximab must 
not be frozen. 
Once a vial of ublituximab has been opened and/or diluted it must 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. Expiration memorandums will be provided noting 
lot expiration dates. For questions about expiry email productquality@tgtxinc.com. 
8.1.8 
Preparation and Handling 
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. 
Dilutions for ublituximab are as follows: 
 
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 
The compatibility of ublituximab with medical devices was investigated using polyvinyl chloride (PVC) and 
polyolefin (PO) infusion bags containing 0.9% NaCl and PVC and PO infusion lines. Compatibility was assessed 
using physiochemical parameters (visual appearance, protein content, protein fragmentation and aggregation) 
and biological activity. Based on this study, ublituximab is compatible in both the PVC and PO infusion bags and 
the PVC and PO infusion lines over a dosing range of 150-900 mg of ublituximab. 
Qualified personnel, familiar with procedures that minimize undue exposure to themselves and the environment, 
should undertake the preparation, handling, and safe disposal of the study agent in a self-contained and protective 
environment. 
8.1.9 
Administration 
Ublituximab is administered as an intravenous infusion. Please refer to Section 5.4.2 for administration guidelines. 
Diluted ublituximab should be checked before administration for cloudiness, color, or deposits.  Ublituximab 
should not be administered if the product does not conform to specifications. Immediately inform TG 
Therapeutics, Inc. of any product quality concerns or questions via email to productquality@tgtxinc.com. 
It is recommended that ublituximab be administered immediately after dilution. Ublituximab should NOT be 
mixed the day before and mixing should only occur once confirmed that patient is eligible for therapy on the day 
of treatment. 
No other treatment may be co-administered with ublituximab (other than for immediate intervention for adverse 
event). 

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8.1.10 Supplier 
Ublituximab will be supplied free of charge by TG Therapeutics. 
8.1.11 Ordering 
Ublituximab drug orders shall be placed using the IP Order Request form provided by TG Therapeutics and directed 
to ISTdrugorder@tgtxinc.com.  
Allow 7 to 10 business days between drug ordering and drug arrival. Order Monday through Wednesday to ensure 
shipment arrives Monday through Friday.  Ensure staff will be available to unpack shipment immediately upon 
arrival.  Immediately inform TG Therapeutics, Inc. of any product quality concerns or questions via email to 
productquality@tgtxinc.com. 
8.1.12 Accountability 
The investigator, or a responsible party designated by the investigator, must maintain a careful record of the 
inventory and disposition of the agent using a drug accountability log. 
8.1.13 Destruction and Return 
The investigator is responsible for keeping accurate records of the clinical supplies received from TG Therapeutics 
or designee, the amount dispensed to participants, and the amount remaining at the conclusion of the trial.  
Any unused agent at the end of the study, expired agent, and damaged agent will be destroyed according to 
applicable federal, state, local and institutional guidelines and procedures.  
Destruction will be documented in a drug accountability log. 
8.2 Acalabrutinib 
Acalabrutinib is an investigational product. Calquence® has been approved in the United States and other markets 
for the treatment of adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy, 
chronic lymphocytic leukemia (CLL), and small lymphocytic lymphoma (SLL).  
Please refer to the investigator brochure and package insert for additional details. 
8.2.1 
Other names 
Calquence®; ACP-196 
8.2.2 
Description 
Acalabrutinib is an inhibitor of Bruton tyrosine kinase (BTK). 
Structural formula: 
Empirical formula: 
C26H23N7O2 
Molecular weight:  465.5 g/mol 
Chemical name: 
(S)-4-(8-amino-3-(1-but-2-ynoylpyrrolidin-2-yl)-imidazo[1,5-α] pyrazin-1-yl)-N-
(pyridin-2-yl)-benzamide 

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8.2.3 
Mechanism of action 
In B cells, BTK signaling results in activation of pathways necessary for B-cell proliferation, trafficking, chemotaxis, 
and adhesion. Acalabrutinib and its major metabolite ACP-5862 inactivate BTK by forming a covalent bond with a 
cysteine residue in the kinase active site. This leads to inhibition of signaling through the BCR. In nonclinical and 
clinical studies, acalabrutinib inhibited BTK-mediated activation of downstream signaling proteins CD86 and CD69 
and inhibited malignant B-cell proliferation and survival. 
8.2.4 
Pharmacokinetics and Metabolism 
 Elimination half-life: 
Acalabrutinib: 1 hour, ACP-5862, active metabolite: 3.5 hours. 
Total body clearance: 
71 L/h 
Absorption: 
Tmax, oral: 0.9 hours 
Bioavailability, oral: 25% 
Effect of food: Cmax decreased by 73%; Tmax delayed by 1 to 2 hours 
Distribution: 
Protein binding: 97.5% 
Volume of 
distribution: 
Vd: 101 L 
Metabolism: 
Liver: Primary site 
ACP-5862 (major): Active 
Substrate of CYP3A (primary), P-glycoprotein, and BCRP 
Inhibitor of BCRP; weak inhibitor of CYP3A4/5, CYP2C8, and CYP2C9 
Weak inducer of CYP1A2, CYP2B6, and CYP3A4 
Elimination: 
Renal excretion: 12%; less than 2% as unchanged drug 
Fecal excretion: 84%; less than 2% as unchanged drug 
8.2.5 
Toxicology 
8.2.5.1 Expected human toxicities  
See Section 6.2 for detailed list of anticipated AEs. 
8.2.5.2 Potential effects on pregnancy and lactation 
Acalabrutinib may cause fetal harm and dystocia. 
No data are available regarding the presence of acalabrutinib or its active metabolite in human milk.  
8.2.6 
Standard dose adjustments 
Recommended guidelines if co-administration with a CYP3A inhibitor or inducer is unavoidable: 

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Dose Modifications for Acalabrutinib with concomitant CYP3A inhibitors or inducers 
CYP3A* 
Co-administered Drug 
Acalabrutinib Dose Modification 
Inhibition 
Strong CYP3A inhibitor 
Avoid concomitant use. 
If these inhibitors will be used short-term (such as anti-
infectives for up to 7 days), interrupt acalabrutinib. 
Moderate CYP3A inhibitor 100 mg once daily (QD) 
Induction 
Strong CYP3A inducer 
Avoid concomitant use. 
If these inducers cannot be avoided, increase the 
acalabrutinib dose to 200 mg BID during concomitant 
administration with the strong inducer and return to the 
recommended dose of 100 mg BID after stopping the 
strong CYP3A inducer. 
*Refer to Appendix E for examples of CYP3A inhibitors and inducers 
8.2.7 
Formulation 
The investigational product, acalabrutinib tablets for oral administration, is supplied as orange, oval, film-coated, 
biconvex, debossed with “ACA 100” on one side and plain on the other, containing 100 mg acalabrutinib as the 
active ingredient. 
Inactive ingredients in the tablet core are low-substituted hydroxypropyl cellulose, mannitol, microcrystalline 
cellulose, and sodium stearyl fumarate. The tablet coating consists of copovidone, ferric oxide yellow, ferric oxide 
red, hypromellose, medium-chain triglycerides, polyethylene glycol 3350, purified water and titanium dioxide.  
8.2.8 
Storage 
Acalabrutinib tablets are packaged in bottles and should be stored according to the storage conditions as indicated 
on the label. The storage condition for acalabrutinib tablets is below 20°C-25°C. 
Retain in original package until dispensing. 
8.2.9 
Administration 
Acalabrutinib is administered orally. Please refer to Section 5.4.3 for administration guidelines. 
8.2.10 Supplier 
Acalabrutinib will be supplied free of charge by AstraZeneca. 
8.2.11 Ordering 
Sites will place orders for acalabrutinib by completing a Drug Request Form.  
8.2.12 Accountability 
The investigator, or a responsible party designated by the investigator, must maintain a careful record of the 
inventory and disposition of the agent using a drug accountability log. 
8.2.13 Destruction and Return 
The investigator is responsible for keeping accurate records of the clinical supplies received from AstraZeneca or 
designee, the amount dispensed to participants, and the amount remaining at the conclusion of the trial.  

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Any unused agent at the end of the study, expired agent, and damaged agent will be destroyed according to 
applicable federal, state, local and institutional guidelines and procedures.  
Destruction will be documented in a drug accountability log. 
8.3 Umbralisib 
8.3.1 
Other names 
TGR-1202, UKONIQ™  
8.3.2 
Description and mechanism of action 
Umbralisib is a highly-specific and orally available dual inhibitor of phosphoinositide-3-kinase (PI3K) delta (δ) and 
casein kinase 1 epsilon (CK1ε) with nanomolar inhibitory potency, and high selectivity over the alpha, beta, and 
gamma Class I isoforms of PI3K. 
Please refer to the investigator brochure for additional details. 
8.3.3 
Pharmacokinetics and Metabolism 
Please refer to the investigator brochure. 
8.3.4 
Toxicology 
8.3.4.1 Expected human toxicities  
See Section 6.3 for detailed list of anticipated AEs. 
8.3.4.2 Potential effects on pregnancy and lactation 
Small molecule agents such as umbralisib are known to cross the placenta barrier, and as such, umbralisib should 
not be administered to pregnant women. No formal reproductive toxicology studies have been conducted. The 
effects of umbralisib on pregnancy and lactation are unknown. 
8.3.5 
Formulation 
Umbralisib is supplied in 200 mg oval, light green tablets with “L474” debossed on one side, for oral 
administration. The primary packaging is HDPE bottles each containing 30 tablets. 
Umbralisib is manufactured by Alembic Pharmaceuticals and supplied by TG Therapeutics, Inc. 
8.3.6 
Storage 
Umbralisib must be stored in a secured limited-access area between 20°C and 25°C. Excursions permitted between 
15°C and 30°C. Do not freeze. 
8.3.7 
Administration 
Umbralisib is administered orally. Food increases the exposure of umbralisib. Please refer to Section 5.4.4 for 
administration guidelines. 
8.3.8 
Supplier 
Umbralisib will be supplied free of charge by TG Therapeutics. 
8.3.9 
Ordering 
Umbralisib drug orders shall be placed using the IP Order Request form provided by TG Therapeutics and directed 
to ISTdrugorder@tgtxinc.com.  

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Allow 7 to 10 business days between drug ordering and drug arrival. Order Monday through Wednesday to ensure 
shipment arrives Monday through Friday.  Ensure staff will be available to unpack shipment immediately upon 
arrival. Immediately inform TG Therapeutics, Inc. of any product quality concerns or questions via email to 
productquality@tgtxinc.com. 
8.3.10 Accountability 
The investigator, or a responsible party designated by the investigator, must maintain a careful record of the 
inventory and disposition of the agent using a drug accountability log. 
8.3.11 Destruction and Return 
The investigator is responsible for keeping accurate records of the clinical supplies received from TG Therapeutics 
or designee, the amount dispensed to participants, and the amount remaining at the conclusion of the trial.  
Any unused agent at the end of the study, expired agent, and damaged agent will be destroyed according to 
applicable federal, state, local and institutional guidelines and procedures.  
Destruction will be documented in a drug accountability log. 
9.0 CORRELATIVE/ SPECIAL STUDIES 
9.1 Research Sample Collection and Dispensation 
9.1.1 
Correlative tumor tissue 
9.1.1.1 Time points of Collection 
Baseline tissue: When available, archival tissue from diagnostic tumor biopsies will be retrieved and submitted 
post-enrollment. 
Progression/ Relapse: if safe and feasible, submission of left-over tissue from a standard of care tumor biopsy 
(fresh core or excisional biopsy) for participants who progress/relapse during study is encouraged. 
9.1.1.2 Guidelines for archival specimens 
Using the formalin-fixed paraffin embedded (FFPE) tissue block, the following samples will be processed for 
correlative studies:  
o If tissue block is available submit: 
     6 paraffin scrolls measuring 10 µm thick placed into a tube and frozen at -80° C  
AND 
     10 x 5 µm thick unstained slides 
o If tissue block is unavailable submit:  
                   20 x 5 µm thick unstained slides  
9.1.1.3 Labeling of samples 
Samples will be labeled with the COH protocol #, subject ID (issued by DCC), institution, date, time point of 
collection, and if applicable patient initials. 
9.1.1.4 Sample shipment and receiving lab 
Samples will either be taken to (COH only) or batch-shipped (non-COH sites) to Dr. Danilov’s laboratory (Kaplan 
Clinical Research Building 1st floor, 158-1022). For all sites, please include the Correlative Tissue form (Appendix 
F) with your shipment. 

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Please note that samples should be batch-shipped from non-COH sites on Monday to Thursday in time for receipt 
Tuesday to Friday. Refer to Appendix G for tissue shipping details.  
9.1.2 
Bone marrow samples 
9.1.2.1 Overview and Time points 
Bone marrow aspirates will be obtained at the time points indicated in Table 9.1.2.1. 
 
Table 9.1.2.1 Overview of correlative bone marrow studies 
Time points of 
collection 
Total 
volume 
collected 
Tube type 
Type of 
analysis 
Receiving laboratory and post-collection 
instructions 
Each time a bone 
marrow biopsy is 
performed per the 
protocol or as part of 
standard 
of 
care 
(refer 
to 
Study 
Calendar, Footnote 
“p”). 
10 ml 
Purple-top 
(K+EDTA) 
Gene 
expression 
profiling, 
RNASeq, 
ATAC-Seq, 
immunoblotti
ng, MRD 
Dr. Danilov’s lab 
Please follow the same post-collection 
instructions and shipping guidelines as for 
blood samples collected in purple-top tubes 
(Table 9.1.3.3, Appendix H (collection form), 
and Appendix I). 
9.1.2.2 Labeling of bone marrow samples 
Label tubes with COH protocol #, subject ID (issued by DCC), institution, date and actual time point of collection, 
and if applicable patient initials. 
9.1.3 
Correlative blood 
9.1.3.1 Overview and Time points 
Peripheral blood will be collected prior to study treatment/procedures at the time points indicated in Table 9.1.3.1 

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Table 9.1.3.1 Overview of correlative blood studies 
Time points of 
collection 
Total 
volume 
collected 
Tube type 
Type of 
analysis 
Receiving 
laboratory 
▪ C1D1 
30 ml 
Purple-top (K+EDTA) 
FACS/Cytokine 
Clonoseq 
Dr. Danilov’s lab 
Up to 10 
mL* 
Cell-free DNA BCT® (Streck)* 
ctDNA 
▪ C2D1 
20 ml 
Purple-top (K+EDTA) 
FACS/Cytokine 
ClonoSeq 
▪ C8D1 
▪ C14D1 
▪ EOM** 
▪ At relapse 
20 ml 
Purple-top (K+EDTA) 
FACS/Cytokine 
ClonoSeq 
Up to 10 
mL* 
Cell-free DNA BCT® (Streck)* 
ctDNA 
* At least 5 mL. Cell-Free DNA BCT® (glass, 10 mL volume) tubes from Streck. Cat. No, as of April 2020, for a box 
of 100 tubes is: 218962. 
** EOM = End of maintenance. 
9.1.3.2 Labeling of blood samples 
Label tubes with COH protocol #, subject ID (issued by DCC), institution, date and actual time point of collection 
(e.g. C1D1 for Day 1 of Cycle 1), and if applicable patient initials. 
9.1.3.3 Collection and post-collection guidelines 
Refer to Table 9.1.3.3 for collection and post-collection instructions. 
Refer to Appendix H and Appendix I for blood collection form and blood shipping guidelines, respectively. 
 

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Table 9.1.3.3 Blood sample collection and post-collection instructions. 
Tube Type 
Collection details 
Post-collection instructions 
Purple-top 
1- Blood samples will be collected from an 
indwelling venous catheter or by venipuncture. 
2- Invert tubes eight times after collection. 
3- Do not freeze samples. Store samples at 15-
25oC until shipment. 
 
COH only: 
Promptly deliver the blood samples at 
ambient temperature (15-25oC) to Dr. 
Danilov’s lab (Kaplan Clinical Research 
Building 1st floor, 158-1022). 
Samples should be processed in Dr. 
Danilov’s lab within 24 hours of collection. 
 
Non-COH sites only: 
Ship overnight at ambient temperature 
(15-25oC) to Dr. Danilov’s lab. See 
Appendix I. 
Include with shipment: 
 Blood sample collection form (Appendix 
H). 
 Copy of latest CBC results (with 
differential) and date of test. 
Cell-free DNA 
BCT® (Streck)* 
1- Blood samples will be collected from an 
indwelling venous catheter or by venipuncture. 
Prevention of backflow: 
(Because cell-free DNA BCT® contain chemical 
additives)  
a. Keep patient’s arm in the downward position during 
the collection procedure. 
b. Hold the tube with the stopper in the uppermost 
position so that the tube contents do not touch the 
stopper or the end of the needle during sample 
collection.  
c. Release tourniquet once blood starts to flow in the 
tube, or within 2 minutes of application. 
2- Fill tube with up to 10 mL (but at least 5 mL) of 
blood. 
3- Remove tube from adapter and immediately 
mix by gentle inversion 8 to 10 times. 
4- Do not freeze samples. Store samples at 15-
25oC until shipment. 
* Tubes are stable when stored at 2-300C through expiration date.   
9.2 Laboratory Studies Performed 
The exploratory objectives of this study are to evaluate the mechanisms of resistance as well as T-cell repertoire 
in participants with MCL that receive the AU2 regimen. The effects of AU2 treatment on T-cell repertoire will be 
evaluated by flow cytometry.   
Peripheral blood samples will be diluted 1:1 with phosphate buffered saline (PBS) before separation of peripheral 
blood mononuclear cells (PBMCs) by density gradient centrifugation. Cells will be washed in RPMI 1640 
supplemented with 10% fetal calf serum and viably frozen for storage in liquid nitrogen. Flow cytometry will be 
used to evaluate leukocyte subpopulations (e.g., CD3, CD4, CD45, CD14, CD16, CD56). Additional surface markers 
will be used to discriminate Tregs (CD4+CD25+FoxP3+CD127low), Th17 cells (IL-17+) and other immune cell 
populations. 
Additionally, where available, tumor (MCL) cells will be isolated during the density gradient centrifugation from 
the peripheral blood and bone marrow, viably frozen and stored in liquid nitrogen. DNA, RNA and protein where 
feasible will be isolated using standard techniques and gene expression profiling, RNASeq, ATAC-Seq, 
immunoblotting and other relevant assays will be performed at a later date to explore mechanisms of drug 
resistance in MCL. 

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MRD (Minimal residual disease) 
A research version of the clonoSEQ® assay will be used to assess MRD at pre-specified time points (Adaptive 
Biotechnologies, Seattle, WA). This is a next generation sequencing (NGS) MRD assay that leverages multiplex PCR 
followed by NGS to identify and track rearrangements of IgH, V-J, D-J and IgK/L loci as well as translocations in 
Bcl1/2-IgH. 
A portion of the samples collected in purple-top tubes at the following _five_ timepoints: whole blood (C1D1, 
C8D1, C14D1, C26D1 – 5 mL) and bone marrow (at the time of suspected CR only - 5 mL) will be stored at -80C in 
Dr. Danilov’s laboratory until shipped to Adaptive Biotechnologies Inc. (Seattle, WA*) for DNA extraction and MRD 
assessment using the clonoSEQ assay. Briefly, the extracted genomic DNA will be PCR amplified using locus-
specific multiplex primer sets for IgH (VDJ, DJ), IgK and IgL receptor genes, and translocations BCL1/IgH (J) and 
BCL2/IgH (J). The amplified DNA fragments will then be sequenced using the Illumina NextSeq 500 System to 
detect and quantify the previously identified dominant clonotype sequence(s) in the sample to determine the 
sample MRD level. The dominant clonotype sequences for each patient, consistent with the presence of 
malignancy, will be identified from paired high-disease-burden FFPE tissue samples.  
cfDNA (cell free DNA) 
cfDNA will be isolated in Dr. Danilov’s laboratory and stored at -80C until analysis for tumor mutations (using NGS 
panels) and MRD. 
9.3 Collection of data from standard of care tests at screening 
Every effort should be made to collect the following data at screening on the tumor diagnostic material (lymph 
node, bone marrow, peripheral blood): 
▪ 
HopeSeq (at City of Hope) or another panel at the external institution (existing results within 6 months 
are acceptable). 
▪ 
FISH panel to include t(11;14), del(17p), del(11q), del(13q), MYC 8q24 Break Apart probe (existing results 
within 6 months are acceptable). 
▪ 
Conventional cytogenetics (existing results within 6 months are acceptable). 
▪ 
Ki-67, P53, SOX11 (by IHC – lymph node biopsy material only) 
Failure to collect such data will not preclude enrollment on the trial and do not constitute a protocol deviation. 
 

This document is confidential and for research purposes only. Do not copy, redistribute, disclose or use except as authorized.  
 
10.0  STUDY CALENDAR 
All assessments may increase in frequency as clinically indicated. 
 
 
Protocol therapy b 
Follow-up (~2 years) 
Protocol Activity 
Screening a 
Induction Phase (C1->C6) 
Maintenance Phase 
(C7->C25) c 
Optional 
Continua
tion with 
acalabru
tinib 
only 
C1 
C2 
C3 
C4 
to 
C6 
Disease 
Staging s 
C7 to 
C25 
Disease 
Staging s 
EOM* 
Safety 
30-
days 
post e 
Active 
Every 6 
months 
f 
Sur
viva
l g 
D1 d 
D2 
D8 d 
D15 d 
D1 d 
D15 z 
D1 d 
D15 z 
D1 d 
C4D1 
C7D1 
D1 d 
C14D1 
 C20D1 
  
 
Informed 
Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Registration 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Exam h 
&  Vital signs i 
X 
X 
 
 
 
X 
 
X 
 
X 
 
Every 
other 
cycle q 
 
 
X u 
X 
 
 
ECOG Status 
(Appx. A) 
X 
X 
 
 
 
X 
 
X 
 
X 
 
Every 
other 
cycle q 
 
 
X u 
X 
 
 
Con-med review 
X 
X 
 
X 
X 
X 
 
X 
 
X 
 
Every 
other 
cycle q 
 
 
X u 
X 
 
 
AE Assessment 
X 
X 
 
X 
X 
X 
 
X 
 
X 
 
cycle q  
 
 
X u 
X 
 
 
INR, PT, aPTT 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBC w/diff, plt 
X k 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
Every 
other 
cycle q 
 
 
X u 
X 
 
 
Serum 
chemistry l 
X k 
X 
X y 
X 
X 
X 
X 
X 
X 
X 
 
Every 
other 
cycle q 
 
 
X u 
X 
 
 

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Protocol therapy b 
Follow-up (~2 years) 
Protocol Activity 
Screening a 
Induction Phase (C1->C6) 
Maintenance Phase 
(C7->C25) c 
Optional 
Continua
tion with 
acalabru
tinib 
only 
C1 
C2 
C3 
C4 
to 
C6 
Disease 
Staging s 
C7 to 
C25 
Disease 
Staging s 
EOM* 
Safety 
30-
days 
post e 
Active 
Every 6 
months 
f 
Sur
viva
l g 
D1 d 
D2 
D8 d 
D15 d 
D1 d 
D15 z 
D1 d 
D15 z 
D1 d 
C4D1 
C7D1 
D1 d 
C14D1 
 C20D1 
  
 
Serology: HCV, 
HBV, CMV w 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CMV 
surveillance x  
 
 
 
 
 
 
 
 
 
(X) 
 
(X) 
 
 
(X) 
 
 
 
12-lead EKG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECHO or MUGA 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy j 
X  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Correlative 
blood m 
 
X 
 
 
 
X 
 
 
 
 
 
C8D1, 
C14D1 
 
X 
 
(X) 
(X) 
 
Ublituximab 
 
X 
 
X 
X 
X 
 
X 
 
X 
 
On D1 
of C8 
and 
every 
other 
cycle 
therea
fter r 
 
 
- 
 
 
 
Umbralisib  
 
On days 1-14  
On Days 1-7 of each cycle 
 
On 
Days 
1-7 of 
each 
cycle 
 
 
 
 
 
 
Acalabrutinib  
 
Every day of each Cycle 
 
Every 
day of 
each 
Cycle 
 
 
Every 
day of 
each 
Cycle 
 
 
 
PET-CT or CT t 
X 
 
X 
 
X 
X 
X u 
X 
X 
 
Survival status 
 
 
 
 
 
 
 
 
 
X 

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Protocol therapy b 
Follow-up (~2 years) 
Protocol Activity 
Screening a 
Induction Phase (C1->C6) 
Maintenance Phase 
(C7->C25) c 
Optional 
Continua
tion with 
acalabru
tinib 
only 
C1 
C2 
C3 
C4 
to 
C6 
Disease 
Staging s 
C7 to 
C25 
Disease 
Staging s 
EOM* 
Safety 
30-
days 
post e 
Active 
Every 6 
months 
f 
Sur
viva
l g 
D1 d 
D2 
D8 d 
D15 d 
D1 d 
D15 z 
D1 d 
D15 z 
D1 d 
C4D1 
C7D1 
D1 d 
C14D1 
 C20D1 
  
 
Correlative 
tumor tissue v 
X n 
------------------------------------------------------------------------------------------ X o------------------------------------------------------------------------------- 
Bone marrow 
biopsy/ aspirate 
p, v
X  
--------------------------------------------------------------------------------------------X-------------------------------------------------------------------------------- 
a. Screening activities to occur within 28 days prior to start of protocol therapy except for laboratory assessments. 
b. In the absence of treatment delay, each treatment cycle lasts 28 ± 3 days during Induction, and 28 ± 7 days during Maintenance. 
c. 
Maintenance phase for participants with stable disease or better response (PR or CR) at the end of Induction therapy. 
d. Activities to be performed within 72 hours prior to study drug administration. 
e. The Safety 30 days post-last dose assessments to occur 30 (±7) days post-last dose or, if > 30 days elapsed since last dose, within 7 days after decision to end 
treatment. Expedited reporting will occur during this period. Safety follow-up may be extended until resolution/ stabilization of reportable AEs. 
f. 
For participants yet to progress, Active Follow-up will occur at 6, 12, 18 and 24 months (± 30 days for all) from last on-treatment scan until disease progression 
or the initiation of a new anti-lymphoma therapy. 
g. Participants who end Active Follow-up will enter Survival Follow-up. Survival assessment to occur bi-annually or as requested by the Study PI via medical record 
review, review of social security registry, or telephone call. 
h. Standard physical exam includes weight. 
i. 
Vital signs: heart rate, blood pressure, respiration rate, and temperature. 
j. 
Women of childbearing potential: Pregnancy serum test. For the screening time point, serum pregnancy test must be performed within 3 days prior to start of 
protocol therapy. 
k. 
Screening laboratory assessments to be performed within 14 days prior to start of protocol therapy. 
l. 
Serum chemistry panel to include: glucose, Blood Urea Nitrogen (BUN), creatinine, uric acid, total protein, albumin, magnesium, bicarbonate, calcium, inorganic 
phosphorous, sodium, potassium, chloride, total bilirubin, alkaline phosphatase, ALT, AST, and LDH. 
m. Correlative blood will also be collected at time of relapse. Refer to Section 9.1.3 for additional information.  

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n. Archival tumor tissue to be submitted post-enrollment when available. Refer to Section 9.1.1. 
o. If safe and feasible, submission of left-over tissue from a standard of care tumor biopsy (fresh core or excisional biopsy) for participants who progress/relapse 
during study is encouraged. Refer to Section 9.1.1. 
p. Bone marrow biopsies will be performed at the following time points if feasible (please contact Study PI if bone marrow collection is not feasible at either time 
point to receive a waiver): 
1- At baseline (during screening). If a patient had a recent bone marrow biopsy (within 90 days), this time point may be omitted after a discussion with the Study 
PI. In this case, a correlative sample will not be submitted. 
2- At the time a CR is suspected based on imaging results (within 8 weeks after such result). 
3- At the time of disease relapse. 
At each time point, bone marrow samples will be collected for correlative studies (Section 9.1.2). 
q. Every other cycle starting on C8D1 (i.e. on days of ublituximab infusion). 
r. 
Ublituximab infusions are on Day 1 of C8, C10, C12, C14, C16, C18, C20, C22, C24, C26, C28, and C30. 
s. 
Disease assessments (imaging) to occur on Days 1 (± 7 days). 
t. 
PET-CT is strongly preferred. CT in lieu of PET-CT is allowed if patient is in CR and CR was already confirmed by PET-CT, and for patients for whom PET-CT is not 
feasible (with Study PI’s approval). 
u. Every 6 months (+/- 2 weeks) from last on treatment scan until end of protocol therapy. 
v. 
NGS panel (HopeSeq at City of Hope), FISH analysis, conventional cytogenetics and IHC should be performed on tumor diagnostic material (lymph node, bone 
marrow, peripheral blood) based on disease characteristics, per institutional practice standards at screening. Every effort should be made to collect such data 
(Section 9.3). 
w. Serum virology to include HBsAg, HBc antibody, HCV antibody and CMV IgG and IgM (or may do CMV by PCR at investigator discretion). If HBc antibody, HCV 
antibody or CMV IgG or IgM is positive, subject must be evaluated for the presence of active HBV, HCV or CMV by PCR. 
x. 
CMV screening by PCR for all subjects receiving study treatment beginning in Cycle 4 and approximately every 3 to 4 cycles thereafter aligned with study visits. 
y. 
This time point serves as TLS assessment. TLS assessment will be performed on Day 2 (+ 1 day). 
z. 
Activities to be performed on D15 +/- 3 days. 
* EOM = End of maintenance. Visit to occur at the end of Cycle 25 (with a +7 days window) and to include disease assessment (imaging). 
 

This document is confidential and for research purposes only. Do not copy, redistribute, disclose or use except 
as authorized.  
 
11.0 ENDPOINT DEFINITIONS/MEASUREMENT OF EFFECT 
11.1 Assessment of Response 
Lymphoma response/progression will be evaluated using 2014 Lugano Classification (see Appendix C). 
[51] 
Disease assessment will be performed by PET-CT. In patients in whom PET-CT is not feasible, CTs may be 
used in place of a PET-CT after discussion with the Study PI (Dr. Danilov). Patients must have a bone 
marrow biopsy performed at baseline and to confirm CR (if suspected based on imaging). After CR, 
additional bone marrow biopsy is only required if clinically indicated and at relapse. Additional necessary 
restaging studies including dedicated CT scans or MRI, are permitted at the investigator’s discretion. PET-
CT and CT results will be read by a radiologist at each study site and investigator response assessment will 
be performed. 
For patients with progression of disease on imaging, it is strongly recommended that a confirmatory 
biopsy be obtained whenever possible. 
11.2 Primary Endpoint(s) 
Complete response (CR) rate: defined as the proportion of response-evaluable participants (see Section 
12.2) that achieve a CR at the end of induction therapy. If a patient achieves CR earlier during induction 
therapy but is PD at the end of induction, the patient will be considered end of induction non-CR. If a 
patient achieves a CR earlier during induction but does not have a response evaluation at the end of 
induction for some reason (for example early termination of induction due to patient refusal), the prior 
CR will be carried over as the end of induction CR. 
11.3 Secondary Endpoint(s) 
Overall response rate (ORR): defined as the proportion of response-evaluable participants (see Section 
12.2) that achieve a best response of either CR or PR during protocol therapy. 
Progression-Free Survival (PFS): defined as the duration of time from start of protocol treatment to time 
of disease relapse/progression, start of non-protocol anti-lymphoma therapy, or death due to any cause, 
whichever occurs earlier. For patients who are alive and have not had disease relapse/progression at the 
last follow-up, it is censored at the time of last follow-up. .   
Overall Survival (OS): defined as the duration of time from start of protocol treatment to time of death 
due to any cause. For patients who are alive at last follow-up, it will be censored at the time of last follow-
up. 
Duration of Response (DOR): Defined as the time from the first achievement of PR or CR to time of PD, 
start of non-protocol anti-lymphoma therapy, or death, whichever earlier. Patients who never achieve PR 
or CR during protocol therapy are excluded. Patient who has not had any of the failure events above at 
last follow-up is censored at the time of last follow-up. 
Toxicity: Toxicity and adverse events will be recorded using the NCI CTCAE 5.0 scale. Observed toxicities 
will be summarized by type (organ affected or laboratory determination such as absolute neutrophil 
count), severity (by NCI CTCAE v5.0 and nadir or maximum values for lab measures), date of onset, 
duration, reversibility, and attribution. 

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11.4 Exploratory Endpoint(s) 
Exploratory endpoints include T-cell population and function measures, gene expression/mutation 
profiles, and MRD assessed by ClonoSeq assay. 
12.0 STATISTICAL CONSIDERATIONS 
12.1 Study Design 
This is a multicenter, single-arm Phase 2 study evaluating AU2 therapy for patients with previously 
untreated MCL. Patients will first receive 6 cycles of AU2 (acalabrutinib + umbralisib + ublituximab) 
induction; those who achieve SD or better response after induction will then receive 19 cycles of 
maintenance with the 3 agents, during which ublituximab will only be given every 2 cycles. Each cycle will 
be 28 days. Participants may continue therapy with acalabrutinib beyond 25 cycles of Induction + 
Maintenance therapy at the treating physician’s discretion. Response will be evaluated just prior to C4, 
C7 (End of Induction), C14, C20 , EOM (end of maintenance), every 6 months thereafter until end of 
protocol therapy (if patient continues with oral agents only beyond 25 cycles), and at Safety visit.  
The primary endpoint is complete response (CR) rate after AU2 induction therapy. Secondary endpoints 
include toxicities of AU2 induction and maintenance therapy, overall response rate to protocol therapy, 
duration of response, progression free survival, and overall survival.  
The study sample size is based on the desire to discriminate a promising CR rate of 50% (alternative 
hypothesis) from a disappointing CR rate of 25% (null hypothesis) after AU2 induction. These  response 
rates were chosen because 1) BR, a current standard, has been associated with an ORR of 80-90% and a 
CR rate of 40% [5, 7]; 2) In the phase 2 ACE-LY-004 trial in R/R MCL, treatment with acalabrutinib was 
associated with an ORR of 81% and a CR rate of 40% [39].  However, it is anticipated that this study will 
enroll a higher proportion of patients with high-risk MCL (TP53 aberrations, CK) where BR is ineffective.  
Simon's optimal two-stage design will be used. In the first stage, 9 evaluable patients will be accrued. If 
there are 2 or fewer CRs in these 9 patients, the study will be stopped. Otherwise, 15 additional evaluable 
patients will be accrued for a total of 24. The null hypothesis will be rejected and AU2 induction therapy 
will be considered promising if 10 or more CRs are observed in 24 evaluable patients. This design yields a 
1-sided type I error rate of 0.05 and power of 0.8. When the CR rate is disappointing (25%), there is an 
60% chance that the study will be terminated after the first stage.  
12.2 Evaluable Participants and Participant Replacement 
o Evaluable for toxicity: Patients who receive at least one dose of protocol therapy are 
evaluable for toxicity. 
o Evaluable for response endpoints:  
Evaluable patients are defined as eligible participants who have received at least one cycle of 
Induction therapy and have at least one disease evaluation post-baseline.  
Patients will be evaluable and be considered non-CR in the primary 2-stage response evaluation, 
if the reason why they did not finish at least 1 cycle of induction therapy or discontinued induction 
therapy prior to having a response assessment was progressive disease or toxicity. All other 
patients without 1+ cycle or 1+ response assessment post-baseline, such as those who terminated 
due to patient refusal or investigator decision, will be inevaluable and replaced.   

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12.3 Sample Size and Accrual Rate 
The 2-stage Simon optimal design, as described above, will require up to 24 response evaluable patients. 
Accounting for up to 10% inevaluable patients that need to be replaced, the maximum accrual for the 
study will be 27 patients. Combining all participating sites, we project that the study accrual can be 
completed within 2 years, with an estimated accrual rate of approximately 1 patient per month.  
12.4 Interim Analyses/Stopping Rules 
12.4.1 Interim Efficacy Monitoring 
The study will perform an interim analysis of CR rate per the Simon’s 2-stage rule as described above in 
Section 12.1. 
12.4.2 Toxicity Monitoring 
We will monitor the rate of the following adverse events that are at least possibly related to protocol 
treatment at any time during study treatment: 
• 
Grade ≥3 diarrhea which does not resolve within 3 days with best supportive care  
• 
Febrile neutropenia 
• 
Grade ≥2 pneumonitis 
• 
Grade ≥4 elevations of AST, ALT or Grade ≥3 elevation of bilirubin 
• 
Grade ≥4 infection 
• 
New onset grade 4 atrial fibrillation in patients without a history of atrial fibrillation 
• 
Major hemorrhage defined as serious or Grade 3 or higher bleeding or any central nervous system 
bleeding. 
• 
Severe (grade 4) cutaneous reaction 
This monitoring will include all patients who received at least 1 dose of the protocol treatment. The 
expected rate of patients having any of these toxicities should be <33%. The first monitoring will occur 
when the 6th patient completes the first induction cycle, and it will include all available cycles from the 
first 6 patients. If more than 1 patient experience any of the toxicities above at the first monitoring, accrual 
will be halted; study data will be reviewed by the study committee and the City of Hope Data and Safety 
Monitoring Committee (DSMC). Study amendment may be proposed if necessary. Accrual will not be 
resumed until approved by DSMC. If 0 or 1 patient has these toxicities at the first monitoring, accrual will 
continue as planned and the result of this first monitoring will be submitted to DSMC at the next PMT 
report. Subsequent monitoring will be performed every 6 months as part of each PMT report. If at such 
review 33% or more of the patients experience these toxicities, the study accrual will be temporarily 
halted; a full review of these events and other toxicities will be performed by the study team and DSMC. 
Patient accrual will not resume until approved by the DSMC to do so. In addition, COH DSMC will review 
all toxicities every 6 months and may make their independent assessment and recommendations. 
12.5 Statistical Analysis Plan 
Patient demographics and baseline disease characteristics will be summarized using descriptive statistics. 
For continuous variables, descriptive statistics such as number, mean, standard deviation, standard error, 

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median (range) etc. will be provided. For categorical variables, patient counts and percentages will be 
provided. 
CR rate after Induction therapy will be estimated by the proportion of response-evaluable patients 
achieving CR after Induction therapy, along with the 95% exact binomial confidence interval. ORR during 
protocol therapy will be similarly estimated. PFS and OS will be estimated using the product-limit method 
of Kaplan and Meier along with the Greenwood estimator of standard error; 95% confidence interval will 
be constructed based on log-log transformation. Median PFS/OS will be estimated when available. 
Observed toxicities of Induction therapy and Maintenance therapy will be summarized by type, severity, 
and attribution.  
For the exploratory objectives, summary statistics and graphics will be used to describe the T cell 
population and function measures, MRD status, and other correlative analyses. Exploratory correlative 
analysis will be used to explore the association between the MRD status or gene expression/mutation 
profiles and clinical outcomes.  
13.0 DATA HANDLING, DATA MANAGEMENT, RECORD KEEPING 
13.1 Source Documents 
Source documents are original documents, data, and records (e.g., medical records, pharmacy dispensing 
records, recorded data from automated instruments, laboratory data) that are relevant to the clinical trial. 
The Investigator or their designee will prepare and maintain adequate and accurate source documents. 
These documents are designed to record all observations and other pertinent data for each patient 
enrolled in this clinical trial. Source documents must be adequate to reconstruct all data transcribed onto 
the case report forms. 
13.2 Data Capture Methods and Management 
Data for this trial will be collected using City of Hope’s electronic capture system (EDC) that is compliant 
with 21 CFR Part 11.  
Study personnel will enter data from source documents corresponding to a subject’s visit into the 
protocol-specific electronic Case Report Form (eCRF).   
13.3 Case Report Forms/Data Submission Schedule 
The Investigator is responsible for all information collected on subjects enrolled in this study. All data 
collected during the course of this study must be reviewed and verified for completeness and accuracy by 
the Investigator. All case report forms must be completed by designated study personnel. The completed 
case report forms must be reviewed, signed and dated by the Investigator or designee in a timely fashion. 
All data will be collected using electronic data collection, stored as indicated in Section 13.2, and will be 
submitted according to the timelines indicated in Table 13.3. 
Table 13.3 Data Submission Schedule 
Form 
Submission Timeline 
Eligibility Checklist 
Complete prior to registration  
On Study Forms 
Within 14 calendar days of registration 
Baseline Assessment Forms 
Within 14 calendar days of registration 
Treatment Forms 
Within 10 calendar days of treatment administration 
Adverse Event Report Forms 
Within 10 calendar days of AE assessment/notification  

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Form 
Submission Timeline 
Response Assessment Forms 
Within 10 calendar days of the response assessment 
Other Assessment Forms (concomitant 
medications) 
Within 10 calendar days of the assessment 
Off Treatment/Off Study Forms 
Within 10 calendar days of end of treatment/study 
Follow up/Survival Forms 
Within 14 calendar days of the follow up activity 
13.4 Regulatory Records 
The Investigator will maintain regulatory records, including updating records in accordance with Good 
Clinical Practice guidelines and FDA regulations. 
 
14.0 REPORTING OF ADVERSE EVENTS, UNANTICIPATED PROBLEMS & OTHER EVENTS OF INTEREST 
The research team is responsible for classifying adverse events (AEs) and unanticipated problems (UPs) as 
defined in the relevant regulations and reporting to all applicable parties, including but not limited to the 
COH IRB, DSMC, Food and Drug Administration (FDA), National Institutes of Health (NIH) and other 
collaborators, e.g., pharmaceutical companies. The research team is responsible for the continued 
monitoring and tracking of all AEs in order to ensure non-reportable events are reviewed and monitored 
and do not rise to a reporting level. 
14.1 Assessment of Adverse Events 
The site Investigator will be responsible for determining the event name, and assessing the severity (i.e., 
grade), expectedness, and attribution of all adverse events as applicable per the City of Hope Clinical 
Research Adverse Event and Unanticipated Problem policy (available from the DCC). Adverse events will 
be characterized using the descriptions and grading scales found in NCI CTCAE v5.0. A copy of the scale 
can be found at: 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm.  
The following definitions will be used to determine the causality (attribution) of the event to the study 
agent or study procedure. 
• 
Unrelated – The event is clearly NOT related to study treatment, and is clearly related to other 
factors such as the participant’s clinical state, other therapeutic interventions, or concomitant 
medications administered to the participant. 
• 
Unlikely – The event is unlikely related to the study treatment, and is most likely related to other 
factors such as the participant’s clinical state, other therapeutic interventions, or concomitant 
drugs. 
• 
Possible – The event may be related to study treatment, as it follows a reasonable temporal 
sequence from the time of drug administration, but could have been produced by other factors 
such as the participant’s clinical state, other therapeutic interventions, or concomitant drugs.  
• 
Probable – The event is most likely related to the study treatment, as it follows a reasonable 
temporal sequence from the time of drug administration and a known response pattern to the 
study drug, and is unlikely related to the participant’s clinical state, other therapeutic 
interventions, or concomitant drugs.  

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• 
Definite – The event is clearly related to the study treatment, as it follows a reasonable temporal 
sequence from the time of drug administration and a known response pattern to the study drug, 
and is not reasonably explained by other factors such as the participant’s condition, therapeutic 
interventions, or concomitant drugs.  
14.2 Adverse Events of Special Interest (AESI) 
Adverse Events of Special Interest (AESI) are events that may not typically be considered to meet the 
regulatory criteria for expedited reporting, but that for a specific protocol are being reported via 
expedited means in order to facilitate the timely review of safety data and narrative. It can be e. g. a non-
serious non-specific start of an event, which may be an early manifestation of a serious potential risk. 
14.2.1 Ventricular arrhythmias 
Ventricular arrhythmias (e.g., ventricular extrasystoles, ventricular tachycardia, ventricular arrhythmia, 
ventricular fibrillation, etc.) are adverse events of special interest (AESIs) for participants exposed to 
acalabrutinib, and must be reported to AstraZeneca expeditiously, irrespective of regulatory seriousness 
criteria or causality (Sections 14.5 and 14.7). 
14.2.2 Secondary Malignancy 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., treatment with 
investigational agent/intervention, radiation or chemotherapy). A secondary malignancy is not considered 
a metastasis of the initial neoplasm. 
Refer to Section 14.7 for guidelines on reporting secondary malignancies to the industry partners. 
14.2.3 Abnormal Liver Function Tests 
Cases where a subject shows elevations in liver biochemistry may require further evaluation and 
occurrences of AST or ALT ≥ 3xULN together with total bilirubin ≥ 2xULN should be reported to 
AstraZeneca expeditiously (Sections 14.5 and 14.7). 
14.3 Overdose and Pregnancies 
14.3.1 Overdose 
Study drug overdose is the accidental or intentional use of the drug in an amount higher than the dose 
being studied. An overdose or incorrect administration of study drug is not an AE unless it results in 
untoward medical effects. 
Any study drug overdose or incorrect administration of study drug should be noted on the appropriate 
CRF even if not associated with an AE. All AEs associated with an overdose or incorrect administration of 
study drug should be recorded on the CRF. 
Any accidental or intentional overdose with ublituximab or umbralisib that is symptomatic, even if not 
fulfilling a seriousness criterion, is to be reported to TG Therapeutics as indicated in Sections 14.5 and 
14.7 on an SAE form, and following the same process described for SAEs. 
If a study drug overdose occurs, the subject should stop study drug dosing and be clinically monitored as 
appropriate, managing symptoms/side effects that may occur. 
For any participant experiencing an acalabrutinib overdose, observation for any symptomatic side effects 
should be instituted, and vital signs and biochemical and hematological parameters should be followed 

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closely (consistent with the protocol or more frequently, as needed). Appropriate supportive 
management to mitigate adverse effects should be initiated. If the overdose ingestion is recent and 
substantial, and if there are no medical contraindications, use of gastric lavage or induction of emesis may 
be considered. Refer to Sections 14.5 and 14.7 for guidelines on reporting overdose of acalabrutinib to 
AstraZeneca. 
14.3.2 Pregnancies 
14.3.2.1 
Female participants: 
Pregnancies and suspected pregnancies (including a positive pregnancy test regardless of age or disease 
state) of a female participant occurring after the participant receives the first dose of protocol therapy up 
to 2 days post-last dose of acalabrutinib and 30 days post-last dose of ublituximab or umbralisib are 
considered immediately reportable events.  Protocol therapy is to be discontinued immediately. The 
pregnancy, suspected pregnancy, or positive pregnancy test must be reported to the Study PI and the 
DCC immediately within 24 hours of awareness (Sections 14.5.1.1 and 14.5.1.2). The female subject may 
be referred to an obstetrician-gynecologist (preferably one with reproductive toxicity experience) or 
another appropriate healthcare professional for further evaluation. 
The Investigator should make every effort to follow the female participant until completion of the 
pregnancy per institutional policies, and should notify the Study PI.  
Abnormal pregnancy outcomes and neonatal deaths that occur within 28 days of birth should be reported 
as an SAE per expedited reporting guidelines. Any infant death after 28 days that the Investigator suspects 
is related to the in utero exposure to protocol therapy should also be reported as an SAE per expedited 
reporting guidelines. The Study PI or designee will subsequently inform AstraZeneca and TG therapeutics 
(Section 14.7). 
14.3.2.2 
Male participants: 
If a female partner of a male participant becomes pregnant, the male participant should notify the 
Investigator, and the pregnant female partner should be advised to call their healthcare provider 
immediately. In the event a participant’s partner becomes pregnant, the pregnancy should be reported 
to AstraZeneca and TG Therapeutics (Section 14.7). 
The Investigator should make every effort to follow the outcome of the pregnancy per institutional 
policies, and should notify the Study PI. 
14.4 Routine AE Collection and Reporting Guidelines 
AEs will be collected from the signing of informed consent until ending study participation. Routine AE 
reporting will occur via data entry into the study eCRF. AEs will be monitored by the Protocol Management 
Team (PMT). AEs reported through expedited processes (e.g., reported to the IRB, DSMC, FDA, etc.) must 
also be reported in routine study data submissions. 
AEs recorded in the eCRF include: 
o For each cycle and safety follow-up period, all grade 3 and higher AE for each type AND the 
highest grade of AE for each type (if grade 1 or 2) 
o All SAEs 
14.5 Expedited Reporting  
Table 14.5 indicates what events must be reported expeditiously. 

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Table 14.5 Criteria for Expedited Reporting 
Time point 
What to report  
From signing of the consent to study completion 
 All UPs 
From signing of the consent to treatment initiation 
 All SAEs 
For the time period beginning at treatment 
through 30 days following cessation of treatment 
 
 All SAEs* regardless of relationship to protocol therapy  
 All UPs and AEs that meet the definition of a UP 
 Ventricular arrhythmias (Section 14.2.1) 
 Abnormal liver function tests (Section 14.2.3) 
 Overdose of acalabrutinib, ublituximab or umbralisib 
(Section 14.3.1) 
 Pregnancies and lactation 
From Day 1 of protocol therapy up to 2 days post 
last dose of acalabrutinib and 30 days post last 
dose of ublituximab or umbralisib 
 Pregnancies and lactation  
Post Safety Follow-Up to removal from study  
 All SAEs* that are considered probably or definitely 
related to acalabrutinib, umbralisib or ublituximab  
NOTE: All events reported expeditiously require follow-up reporting until the event is resolved, stabilized, or 
determined to be irreversible by the investigator.  
The DCC should be consulted prior to ending the follow-up of events that have stabilized. 
* Refer to Section 14.7 for guidelines on reporting secondary malignancies to the industry partners. 
14.5.1 Expedited reporting guidelines (COH only) 
14.5.1.1 
To the COH DSMC/IRB 
Serious Adverse Events that require expedited reporting and unanticipated problems will be reported 
according to the approved City of Hope Clinical Research Adverse Event and Unanticipated Problem policy. 
This includes all SAEs and UPs that meet COH DSMC/IRB expedited reporting criteria that occurred at COH 
and non-COH sites. 
14.5.1.2 
To Participating Investigators 
▪ Report all expedited reportable AEs to participating investigators as an IND Safety Report occurring 
within 30 calendar days of receipt of sponsor (lead site) notification, and indicate whether or not a 
protocol and/or consent form change is required. A cover letter will indicate the protocol title, the 
IND#, whether the FDA was informed (if applicable), and, for non-COH sites, a statement that the 
report should be submitted to their local IRB for review if applicable per local IRB policy. 
 
▪ Forward to participating sites all IND safety reports received from AstraZeneca and TG Therapeutics, 
indicating whether a consent form or protocol change is required within 30 days of notification to Study 
PI. 

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14.5.2 Expedited reporting guidelines (non-COH sites only) 
14.5.2.1 
To the DCC/Study PI 
All events that meet the criteria specified in Table 14.5 will be reported to the DCC and Study PI within 
24 hours of notification that the event met the expedited reporting criteria. 
1. Sites are to report to their local IRB per their site’s specific institutional and IRB guidelines. As soon 
as possible, non-COH sites will provide to the COH DCC copies of the IRB submission and 
corresponding IRB response. 
2. Document/describe the AE/UP on each of the following: 
a. MedWatch 3500A or local IRB submission document* 
MedWatch 3500A is downloadable form at http://www.fda.gov/medwatch/getforms.htm 
*The local IRB submission document may be used if the document template is approved 
by the DCC 
b. Expedited Reporting Coversheet. A modifiable Microsoft Word document is available from 
the DCC. An electronic signature on the document will be accepted. 
3. Scan and email above documents to the Study PI (adanilov@coh.org) and DCC@coh.org with the 
subject title as “[AU2 for previously untreated MCL] SAE COH IRB #20459”.  
a. If available, sites may include the local IRB submission for this event in the submission.  
4. If an email receipt from DCC personnel is not received within one working day, please email 
DCC@coh.org. 
14.6 Reporting to the FDA 
The study PI (or designee) will be responsible for contacting the Office of IND Development and Regulatory 
Affairs (OIDRA) at COH to ensure prompt reporting of safety reports to the FDA. OIDRA will assist the PI 
with the preparation of the report and submit the report to the FDA in accordance with the approved City 
of Hope Clinical Research Adverse Event and Unanticipated Problem policy. 
Serious Adverse Events meeting the requirements for expedited reporting to the Food and Drug 
Administration (FDA), as defined in 21 CFR 312.32, regardless of the site of occurrence, will be reported 
as an IND safety report using the MedWatch Form FDA 3500A for Mandatory Reporting. 
The criteria that require reporting using the MedWatch 3500A are: 
o Any unexpected fatal or life threatening adverse experience associated with use of the drug must 
be reported to the FDA no later than 7 calendar days after initial receipt of the information [21 
CFR 312.32(c)(2)] 
o Any adverse experience associated with use of the drug that is both serious and unexpected must 
be submitted no later than 15 calendar days after initial receipt of the information [21 CFR 
312.32(c)(1)] 
o Any follow-up information to a study report shall be reported as soon as the relevant information 
becomes available. [21 CFR 312.32(d)(3)] 
The final IND report will be distributed to the Study PI and DCC. If it is determined that the IND safety 
report requires a change to the protocol or the consent form, the DCC will include instructions to 
participating sites for local IRB reporting. 

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In addition, on behalf of the study PI, OIDRA will submit annually within 60 days of the anniversary of the 
date the IND went into effect, an annual report to the FDA which is to include a narrative summary and 
analysis of the information of all FDA reports within the reporting interval, a summary report of adverse 
drug experiences, and history of actions taken since the last report because of adverse drug experiences. 
14.7 Reporting to Industry Partners 
The Study PI (or designee) will: 
o Report the following to AstraZeneca and TG Therapeutics per the guidelines provided in Table 
14.7 below. 
 
AstraZeneca: email: AEMailboxClinicalTrialTCS@astrazeneca.com 
 
TG Therapeutics: email: safety@tgtxinc.com, (copy gabriel.green-lemons@tgtxinc.com and 
donna.gesumaria@tgtxinc.com) 
o Assist AstraZeneca/ TG Therapeutics in investigating any SAE and will provide any follow-up 
information reasonably requested by AstraZeneca/ TG Therapeutics. 
Table 14.7 Timeframes for Reporting to AstraZeneca/ TG Therapeutics 
Type of Report 
Reporting Timeframes to AstraZeneca 
Reporting Timeframes to TG 
Therapeutics 
Pregnancy and 
suspected pregnancy 
Pregnancy and suspected pregnancy: 
Within 24 hours of being aware of the event 
using a Pregnancy Report Form 
Pregnancy 
(including 
of 
male 
participant 
partner), 
pregnancy 
outcome with 6-month follow up 
from 
end 
of 
pregnancy 
(birth, 
abortion [spontaneous, accidental or 
therapeutic], voluntary termination, 
etc.): 
Within 24 hours of being aware of the 
event using a Pregnancy Report Form 
All expedited SAE 
reports (includes 
AESIs  [specified in 
Section 14.2]) 
 
Note: See below for 
guidelines on 
reporting secondary 
malignancies. 
Within 24 hours of being aware of the event via 
a MedWatch 3500A form. 
 
Note: Overdose of acalabrutinib should be 
reported as an “overdose” report. If there is an 
associated AE/SAE, this should be reported too. 
Within 24 hours of being aware of the 
event via a MedWatch 3500A form 
including SAEs experienced during 
pregnancy 
and 
congenital 
anomalies/birth defects. 
 
Aggregate safety 
reports  
Forward to AstraZeneca at time of COH PMT 
report): 
AEMailboxClinicalTrialTCS@astrazeneca.com 
 
Forward to TG Therapeutics at time of 
COH PMT report): 
safety@tgtxinc.com 
gabriel.green-lemons@tgtxinc.com 
donna.gesumaria@tgtxinc.com 
dmarsico@tgtxinc.com 
 
o Reporting of secondary malignancies 
 
AstraZeneca: 

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Adverse Events (AEs) for malignant tumours reported during the study should generally be 
assessed as Serious AEs. If no other seriousness criteria apply, the ‘Important Medical Event’ 
criterion should be used. In certain situations, however, medical judgement on an individual 
event basis should be applied to clarify that the malignant tumour event should be assessed 
and reported as a Non-Serious AE. For example, if the tumour is included as medical history 
and progression occurs during the study, but the progression does not change treatment 
and/or prognosis of the malignant tumour, 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 tumours, 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. For studies in Early Stage and Late Stage Immuno-Oncology and 
Oncology Studies: The above instruction applies only when the malignant tumour event in 
question is a new malignant tumour (i.e., it is not the tumour for which entry into the study 
is a criterion and that is being treated by the IP under study and is not the development of 
new or progression of existing metastasis to the tumour under study). Malignant tumours 
that – as part of normal, if rare, progression – undergo transformation (e.g., Richter's 
transformation of B cell chronic lymphocytic leukemia into diffuse large B cell lymphoma) 
should not be considered a new malignant tumour. 
 
TG Therapeutics: Secondary malignancies do not need to be reported as SAEs to TG 
Therapeutics. 
o Forward to AstraZenaca and TG Therapeutics copies of initial/annual/final FDA IND submissions. 
Email: AEMailboxClinicalTrialTCS@astrazeneca.com and dmarsico@tgtxinc.com. 
 
15.0 ADHERENCE TO THE PROTOCOL & REPORTING OF PROTOCOL DEVIATIONS 
Deviations from the protocol should be avoided, except when necessary to eliminate immediate hazard(s) 
for the protection, safety, and well-being of a research participant. As a result of deviations, corrective 
actions are to be developed by the study staff and implemented promptly. All protocol deviations and 
planned protocol deviations will be reported in accordance with the City of Hope Clinical Research 
Protocol Deviation policy. 
Non-COH Sites: 
Deviations meeting the criteria specified in the City of Hope Clinical Research Protocol Deviation policy 
(available from the DCC) will be reported to the DCC and Study PI within 24 hours of notification that the 
event occurred.  
Procedure for reporting deviations to the COH DCC: 
1. Document the deviation on the Deviation Reporting Coversheet or submit your site-specific 
protocol deviation log if the log format has been approved for use by the DCC. This modifiable 
Microsoft Word document is available from the DCC. An electronic signature on this 
document will be accepted.  
2. Scan and email the Deviation Reporting Coversheet or protocol deviation log to the Study PI 
(adanilov@coh.org) and DCC@coh.org within 24 hours of notification of the deviation with 
the email subject title of “[AU2 for previously untreated MCL] Deviation COH IRB #20459”. If 

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an email receipt from the DCC is not received within one working day, please email 
DCC@coh.org.  
3. Sites are to report to their local IRB and DSMC per their site’s specific institutional and IRB 
guidelines. As soon as possible, non-COH sites will provide to the COH DCC copies of the IRB 
and/or DSMC submission and corresponding response(s). 
 
16.0 STUDY OVERSIGHT, QUALITY ASSURANCE, & DATA AND SAFETY MONITORING 
16.1 All Investigator Responsibilities 
An investigator is responsible for ensuring that an investigation is conducted according to the signed 
investigator statement, the investigational plan, and applicable regulations; for protecting the rights, 
safety, and welfare of subjects under the investigator's care; and for the control of drugs under 
investigation.  
16.2 Study Principal Investigator Responsibilities 
The Study Principal Investigator is responsible for the conduct of the clinical trial, including overseeing 
that sponsor responsibilities are executed in accordance with federal regulations.  
16.3 Protocol Management Team (PMT) 
The Protocol Management Team (PMT), minimally consisting of the study PI, collaborating investigators, 
site investigators, research nurse, clinical research associate/coordinator, and the study biostatistician, is 
responsible for ongoing monitoring of the data and safety of this study, including implementation of the 
stopping rules for safety/toxicity. 
The PMT is recommended to meet (in person or via teleconference) to review study status. The meeting 
is a forum to discuss study related issues including accrual, SAE/AE/UPs experienced, study response, 
deviations/violations, and study management issues. The appropriateness of further subject enrollment 
and the specific intervention for subsequent subject enrollment are addressed.  
16.4 Quality Assurance  
Clinical site monitoring is conducted to ensure that the rights of human subjects are protected, that the 
study is implemented in accordance with the protocol and regulatory requirements, and that the quality 
and integrity of study data and data collection methods are maintained.  Monitoring for this study will be 
performed by the City of Hope Office of Clinical Trials Monitoring (OCTM), within City of Hope’s Office for 
Safety and Data Quality.  
Details of clinical site monitoring are documented in the OCTM SOP and the Risk Based Monitoring (RBM) 
plan. These documents specify the frequency of monitoring, monitoring procedures, the amount of 
subject data to be reviewed, and the distribution of monitoring reports to the study team and the COH 
DSMC.  
16.5 Risk Determination  
This is a high risk study, as defined in the City of Hope Institutional DSMP.  This determination was made 
because this study involves a COH IND. 

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16.6 City of Hope Data and Safety Monitoring Committee 
The COH Data and Safety Monitoring Committee (DSMC) will review and monitor study progress, 
compliance, toxicity, safety, and accrual data from this trial via the PMT Progress Report (submitted by 
the Study Principal Investigator according to the frequency outlined in the City of Hope Institutional 
DSMP). The DSMC is composed of clinical specialists who have no direct relationship with the study. 
Information that raises any questions about participant safety will be addressed with the Protocol 
Management Team.  
16.7 Protocol Amendments 
Proposed amendments to the protocol require review and approval by TG Therapeutics, Inc. and 
AstraZeneca prior to implementation. After approval by TG Therapeutics, Inc. and AstraZeneca, the 
amendment will be submitted formally to the FDA by the Principal Investigator. If an amendment to the 
protocol substantially alters the study design or the potential risks to patients, patients’ consent to 
continue participation in the study should be obtained per institutional policies. 
17.0 ETHICAL AND REGULATORY CONSIDERATIONS 
17.1 Ethical Standard 
This study will be conducted in conformance with the principles set forth in The Belmont Report: Ethical 
Principles and Guidelines for the Protection of Human Subjects of Research (US National Commission for 
the Protection of Human Subjects of Biomedical and Behavioral Research, April 18, 1979) and the 
Declaration of Helsinki. 
17.2 Regulatory Compliance 
This study is to be conducted in compliance with the IRB approved protocol and according to the following 
considerations: 
o US Code of Federal Regulations (CFR) governing clinical study conduct 
 
Title 21 Part 11 – Electronic Records; Electronic Signatures  
 
Title 21 Part 50 – Protection of Human Subjects  
 
Title 21 Part 54 – Financial Disclosure by Clinical Investigators  
 
Title 21 Part 56 – Institutional Review Boards  
 
Title 21 Part 58 – Good Laboratory Practice for Nonclinical Laboratory Studies  
 
Title 21 Part 312 – Investigational New Drug Application 
 
Title 45 Part 46 – Protection of Human Subjects  
o US Federal legislation, including but not limited to 
 
Health Insurance Portability and Accountability Act of 1996  
 
Section 801 of the Food and Drug Administration Amendments Act   
o Applicable state and local laws. For research occurring in California, this includes but is not 
limited to State of California Health and Safety Code, Title 17 
o Applicable institutional research policies and procedures 
17.3 Institutional Review Board 
An Institutional Review Board (IRB) that complies with the federal regulations at 45 CFR 46 and 21 CFR 50, 
56 and State of California Health and Safety code, Title 17, must review and approve this protocol, 
informed consent form and any additional documents that the IRB may need to fulfill its responsibilities 

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(Investigator’s Brochure, information concerning patient recruitment, payment or compensation 
procedures, or other pertinent information) prior to initiation of the study. Revisions to approved 
documents will require review and approval by the IRB before the changes are implemented in the study. 
All institutional, NCI, Federal, and State of California regulations must be fulfilled. 
Each participating non-COH institution must provide for the review and approval of this protocol and the 
associated informed consent documents by an appropriate IRB holding a current US Federal wide 
Assurance issued by and registered with the Office for Human Research Protections (OHRP). The protocol 
and consent will be reviewed and approved by the COH IRB before submission to a participating site IRB. 
The IRB’s written unconditional approval of the study protocol and the informed consent document must 
be in the possession of the investigator, and, for external sites, the possession of the DCC, before the 
study is initiated. 
The IRB will be informed of serious unexpected, unanticipated adverse experiences, and unanticipated 
problems occurring during the study, and any additional adverse experiences in accordance with the 
standard operating procedures and policies of the IRB; new information that may affect adversely the 
safety of the patients of the conduct of the study; an annual update and/or request for re-approval; and 
when the study has been completed. 
All participating sites must follow the lead institution’s IRB-approved protocol. 
17.4 Informed Consent 
Each participating non-COH institution will be provided with a model informed consent form. Each 
institution may revise or add information to comply with local and/or institutional requirements, but may 
not remove procedural or risk content from the model consent form. Furthermore, prior to submission to 
the site’s IRB (initial submission and amendments), the consent and accompanying HIPAA form, if 
separate to the consent, must be reviewed and approved by the DCC. 
The Principal Investigator or IRB approved named designee will explain the nature, duration, purpose of 
the study, potential risks, alternatives and potential benefits, and all other information contained in the 
informed consent document. In addition, they will review the experimental subject’s bill of rights if 
applicable, and the HIPAA research authorization form. Prospective participants will be informed that they 
may withdraw from the study at any time and for any reason without prejudice, including as applicable, 
their current or future care or employment at City of Hope or participating institution or any relationship 
they have with City of Hope or participating institution. Prospective participants will be afforded sufficient 
time to consider whether or not to participate in the research. 
After the study has been fully explained, written informed consent will be obtained from either the 
prospective participant or his/her guardian or legal representative before study participation. The method 
of obtaining and documenting the informed consent and the contents of the consent must comply with 
the ICH-GCP and all applicable regulatory requirements. 
A copy of the signed informed consent will be given to the participant or his/her legally authorized 
representative. The original signed consent must be maintained by the site investigator and available for 
inspection by sponsor designated representatives, or regulatory authority at any time. 
Informed consent is a process that is initiated prior to the individual agreeing to participate in the study 
and continues throughout study participation. 

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17.5 Participant Withdrawal 
Participants may withdraw from the study at any time and for any reason without prejudice. The 
withdrawal must be documented per institutional policies. The COH DCC should be promptly notified of 
the change in participant status.   
Participant withdrawal may consist of any of the following with regard to study procedures and data 
collection: 
o Withdrawal from study treatment, but agreement to continue with active study procedures 
and chart review and survival follow-up. 
o Withdrawal from study treatment and all active procedures, but agreement for chart review 
and survival follow-up. 
o Withdrawal from study treatment, all active procedures, and any future data collection. 
Participants who agreed to the collection of research blood samples may withdraw consent to use their 
specimens, if they are not yet processed as detailed in the consent form. Once the PI and site PI is notified 
of this withdrawal of informed consent, the research specimens will not be used in any research. At that 
time, any of the existing specimens will be destroyed. 
17.6 Special and Vulnerable Populations 
17.6.1 Women and Minorities 
The study is open to anyone regardless of gender, race or ethnicity. Efforts will be made to extend the 
accrual to a representative population. If differences in outcome that correlate to gender, racial, or ethnic 
identity are noted, accrual may be expanded or additional studies may be performed to investigate those 
differences more fully. 
Pregnant women are excluded because the effects of study drugs on embryogenesis and reproduction are 
unknown. Acalabrutinib may cause fetal harm.   
17.6.2 Pediatric Population 
The incidence of mantle cell lymphoma is rare in the pediatric population. 
17.6.3 HIV Positive Individuals 
Participants with HIV are excluded due to concerns about inadvertent augmentation of infectious and/or 
inflammatory activity. 
17.6.4 Vulnerable Populations 
Per 45 CFR §46.111 (a)(3) and 45 CFR §46, Subparts B-D identifies children, prisoners, pregnant women, 
mentally incapacitated persons, and economically or educationally disadvantaged persons as vulnerable 
populations.  
Adults lacking capacity to consent are not excluded from participation. This study does not pose additional 
risks for adults lacking capacity than for the general population. In such instances, informed consent will 
be sought and documented from the prospective participant’s legally authorized representative in 
agreement with institutional policies and local IRB approval. 
Economically/educationally disadvantaged persons are not actively targeted for participation, nor are 
they excluded from participation. This study does not pose additional risks for economically/educationally 
disadvantaged persons than for the general population. 

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17.7 Participant Confidentiality 
Participant confidentiality is strictly held in trust by the investigators, study staff, and the sponsor(s) and 
their agents. This confidentiality is extended to cover testing of biological samples in addition to any study 
information relating to participants.  
This research will be conducted in compliance with federal and state requirements relating to protected 
health information (PHI), including the requirements of the Health Insurance Portability and 
Accountability Act of 1996 (HIPAA). HIPAA regulations require a signed subject authorization informing 
the subject of the nature of the PHI to be collected, who will have access to that information and why, 
who will use or disclose that information, and the rights of a research participant to revoke their 
authorization for use of their PHI. In the event that a subject revokes authorization to collect or use PHI, 
the investigator, by regulation, retains the ability to use all information collected prior to the revocation 
of subject authorization. For subjects that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect at least vital status (i.e. that the subject is alive) at the end 
of their scheduled study period. 
Release of research results should preserve the privacy of medical information and must be carried out in 
accordance with Department of Health and Human Services Standards for Privacy of Individually 
Identifiable Health Information, 45 CFR 164.508. When results of this study are reported in medical 
journals or at meetings, identification of those taking part will not be disclosed and no identifiers will be 
used.  
Medical records of subjects will be securely maintained in the strictest confidence, according to current 
legal requirements. Data will be entered, analyzed and stored in encrypted, password protected, secure 
computers that meet all HIPAA requirements. All data capture records, drug accountability records, study 
reports and communications will identify the patient by initials and the assigned patient number.  
Source documents provided to the DCC for the purpose of auditing or monitoring will be de-identified and 
labeled with the study number, subject ID, and if applicable patient initials. 
The Investigator/Institution will permit direct access to source data and documents by sponsor 
representatives, the FDA, and other applicable regulatory authorities. The access may consist of trial-
related monitoring, including remote monitoring, audits, IRB/IEC reviews, and FDA/regulatory authority 
inspections. The patient’s confidentiality will be maintained and will not be made publicly available to the 
extent permitted by the applicable laws and regulations. 
Participant specimens will be de-identified (coded) prior to submission to research laboratories. The 
specimens will be labeled with the study number, subject (accession) ID, date and time point of collection. 
The key to the code will be maintained in the COH clinical trials management system which is a secure 
environment.  
17.8 Use of Unused (Leftover) Specimens Collected for this Trial  
Unused samples in existence at study completion (i.e. completion of all research activities under this 
study) will either be: (a) placed in a COH IRB approved biorepository with some clinical information and 
potentially PHI attached or (b) discarded. 
With regard to which option will apply, each site IRB may choose to either: (a) leave the determination to 
the participant via a question in the informed consent document, which would be communicated to the 
study registrar (DCC) at the time of participant registration, OR b) may choose to make a single 
determination on behalf of their respective participants, and communicate that determination to their 
respective participants via the informed consent. 

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Samples may only be used for correlative analyses described in the protocol approved by TG Therapeutics, 
Inc. Unused samples may not be used for other purposes without prior approval by TG Therapeutics. 
Investigators and institution may not provide samples taken from study subjects to anyone outside of 
their institution for any purpose without written pre-approval by TG Therapeutics, Inc.  
17.9 Conflict of Interest 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, or financial 
gain greater than the minimum allowable by their institution, etc.) must have the conflict reviewed by a 
properly constituted Conflict of Interest Committee with a Committee-sanctioned conflict management 
plan that has been reviewed and approved by the study Sponsor (City of Hope) prior to participation in 
this study. All City of Hope investigators will follow the City of Hope conflict of interest policy. 
17.10 Financial Obligations, Compensation, and Reimbursement of Participants 
Acalabrutinib, ublituximab, and umbralisib will be provided free of charge to participants.  
Neither the research participant nor the insurance carrier will be responsible for the research procedures 
related to this study. 
Standard of care drugs or procedures provided during the course of study participation will be the 
responsibility of the research participant and/or the insurance carrier. The participant will be responsible 
for all copayments, deductibles, and other costs of treatment and diagnostic procedures as set forth by 
the insurance carrier. The participant and/or the insurance carrier will be billed for the costs of treatment 
and diagnostic procedures in the same way as if the participant were not in a research study.   
In the event of physical injury to a participant resulting from research procedures, appropriate medical 
treatment will be available at City of Hope or at the non-COH site to the injured participant. There are no 
plans for City of Hope to provide financial compensation in the event of physical injury to a participant.  
The research participant will not receive reimbursement or payment for taking part in this study. 
17.11 Publication/ Data Sharing 
Neither the complete nor any part of the results of the study carried out under this protocol, nor any of 
the information provided by City of Hope for the purposes of performing the study, will be published or 
passed on to any third party without the written approval of the Study PI. Any investigator involved with 
this study is obligated to provide City of Hope with complete test results and all data derived from the 
study. 
The preparation and submittal for publication of manuscripts containing the study results shall be in 
accordance with a process determined by mutual written agreement between City of Hope, AstraZeneca, 
TG therapeutics, and participating non-COH institutions. The publication or presentation of any study 
results shall comply with all applicable privacy laws, including, but not limited to, the Health Insurance 
Portability and Accountability Act of 1996.  
In accordance with the U.S. Public Law 110-85 (Food and Drug Administration Amendments Act of 2007 
or FDAAA), Title VIII, Section 801, this trial will be registered onto ClinicalTrials.gov. Results will be 
reported on ClinicalTrials.gov generally within 12 months after the completion date unless criteria to delay 
submission are met per the final rule. 

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18.0 REFERENCES 
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Tiemann, M., et al., Histopathology, cell proliferation indices and clinical outcome in 304 patients with 
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Vogt, N., et al., The molecular pathogenesis of mantle cell lymphoma. Leuk Lymphoma, 2017. 58(7): p. 1530-
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Flinn, I.W., et al., Randomized trial of bendamustine-rituximab or R-CHOP/R-CVP in first-line treatment of 
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Chen, R.W., et al., RB but not R-HCVAD is a feasible induction regimen prior to auto-HCT in frontline MCL: 
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8. 
Eskelund, C.W., et al., TP53 mutations identify younger mantle cell lymphoma patients who do not benefit 
from intensive chemoimmunotherapy. Blood, 2017. 130(17): p. 1903-1910. 
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Greenwell, I.B., et al., Complex karyotype in patients with mantle cell lymphoma predicts inferior survival 
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Lim, K.H., Y. Yang, and L.M. Staudt, Pathogenetic importance and therapeutic implications of NF-kappaB in 
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de Rooij, M.F., et al., The clinically active BTK inhibitor PCI-32765 targets B-cell receptor- and chemokine-
controlled adhesion and migration in chronic lymphocytic leukemia. Blood, 2012. 119(11): p. 2590-4. 
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Honigberg, L.A., et al., The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell activation and is 
efficacious in models of autoimmune disease and B-cell malignancy. Proc Natl Acad Sci U S A, 2010. 107(29): 
p. 13075-80. 
13. 
Cinar, M., et al., Bruton tyrosine kinase is commonly overexpressed in mantle cell lymphoma and its 
attenuation by Ibrutinib induces apoptosis. Leuk Res, 2013. 37(10): p. 1271-7. 
14. 
Wang, M.L., et al., Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma. N Engl J 
Med, 2013. 369(6): p. 507-16. 
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Wang, M.L., et al., Long-term follow-up of MCL patients treated with single-agent ibrutinib: updated safety 
and efficacy results. Blood, 2015. 126(6): p. 739-45. 
16. 
Rule, S., et al., Outcomes in 370 patients with mantle cell lymphoma treated with ibrutinib: a pooled analysis 
from three open-label studies. Br J Haematol, 2017. 179(3): p. 430-438. 
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Jain, P., et al., Four-year follow-up of a single arm, phase II clinical trial of ibrutinib with rituximab (IR) in 
patients with relapsed/refractory mantle cell lymphoma (MCL). Br J Haematol, 2018. 
18. 
Wang, M.L., et al., Frontline Treatment with Ibrutinib Plus Rituximab (IR) Followed By Short Course R-
Hypercvad/MTX Is Extremely Potent and Safe in Patients (age ≤ 65 years) with Mantle Cell Lymphoma (MCL) 
- Results of Phase-II Window-1 Clinical Trial. Blood, 2019. 134(Supplement_1): p. 3987-3987. 
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Cheah, C.Y., et al., Patients with mantle cell lymphoma failing ibrutinib are unlikely to respond to salvage 
chemotherapy and have poor outcomes. Ann Oncol, 2015. 26(6): p. 1175-9. 

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Martin, P., et al., Postibrutinib outcomes in patients with mantle cell lymphoma. Blood, 2016. 127(12): p. 
1559-63. 
21. 
Woyach, J.A., et al., Resistance Mechanisms for the Bruton's Tyrosine Kinase Inhibitor Ibrutinib. N Engl J 
Med, 2014. 
22. 
Woyach, J.A., et al., BTKC481S-Mediated Resistance to Ibrutinib in Chronic Lymphocytic Leukemia. J Clin 
Oncol, 2017. 35(13): p. 1437-1443. 
23. 
Chiron, D., et al., Cell-cycle reprogramming for PI3K inhibition overrides a relapse-specific C481S BTK 
mutation revealed by longitudinal functional genomics in mantle cell lymphoma. Cancer Discov, 2014. 4(9): 
p. 1022-35. 
24. 
Zhao, X., et al., Unification of de novo and acquired ibrutinib resistance in mantle cell lymphoma. Nat 
Commun, 2017. 8: p. 14920. 
25. 
Kahl, B.S., et al., A phase 1 study of the PI3Kdelta inhibitor idelalisib in patients with relapsed/refractory 
mantle cell lymphoma (MCL). Blood, 2014. 123(22): p. 3398-405. 
26. 
de Rooij, M.F., et al., Ibrutinib and idelalisib synergistically target BCR-controlled adhesion in MCL and CLL: 
a rationale for combination therapy. Blood, 2015. 125(14): p. 2306-9. 
27. 
Mathews Griner, L.A., et al., High-throughput combinatorial screening identifies drugs that cooperate with 
ibrutinib to kill activated B-cell-like diffuse large B-cell lymphoma cells. Proc Natl Acad Sci U S A, 2014. 
111(6): p. 2349-54. 
28. 
Yahiaoui, A., et al., PI3Kdelta inhibitor idelalisib in combination with BTK inhibitor ONO/GS-4059 in diffuse 
large B cell lymphoma with acquired resistance to PI3Kdelta and BTK inhibitors. PLoS One, 2017. 12(2): p. 
e0171221. 
29. 
Niemann, C.U., et al., Combined BTK and PI3Kdelta Inhibition with Acalabrutinib and ACP-319 Improves 
Survival and Tumor Control in CLL Mouse Model. Clin Cancer Res, 2017. 23(19): p. 5814-5823. 
30. 
Burris, H.A., et al., Umbralisib, a novel PI3Kδ and casein kinase-1ε inhibitor, in relapsed or refractory chronic 
lymphocytic leukaemia and lymphoma: an open-label, phase 1, dose-escalation, first-in-human study. The 
Lancet Oncology, 2018. 19(4): p. 486-496. 
31. 
Deng, C., et al., Silencing c-Myc translation as a therapeutic strategy through targeting PI3Kδ and CK1ε in 
hematological malignancies. Blood, 2017. 129(1): p. 88-99. 
32. 
Lampson, B.L. and J.R. Brown, PI3Kδ-Selective and PI3Kα/δ-Combinatorial Inhibitors in Clinical Development 
for B-Cell Non-Hodgkin Lymphoma. Expert opinion on investigational drugs, 2017. 26(11): p. 1267-1279. 
33. 
Burris, H.A., 3rd, et al., Umbralisib, a novel PI3Kdelta and casein kinase-1epsilon inhibitor, in relapsed or 
refractory chronic lymphocytic leukaemia and lymphoma: an open-label, phase 1, dose-escalation, first-in-
human study. Lancet Oncol, 2018. 19(4): p. 486-496. 
34. 
Davids, M.S., et al., An Integrated Safety Analysis of the Next Generation PI3Kδ Inhibitor Umbralisib (TGR-
1202) in Patients with Relapsed/Refractory Lymphoid Malignancies. Blood, 2017. 130(Supplement 1): p. 
4037-4037. 
35. 
Davids, M.S., 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. Lancet Haematol, 2019. 
6(1): p. e38-e47. 
36. 
Nastoupil, L.J., 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. 
Lancet Haematol, 2019. 6(2): p. e100-e109. 
37. 
Byrd, J.C., et al., Acalabrutinib (ACP-196) in Relapsed Chronic Lymphocytic Leukemia. The New England 
journal of medicine, 2016. 374(4): p. 323-332. 

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38. 
Barf, T., et al., Acalabrutinib (ACP-196): A Covalent Bruton Tyrosine Kinase Inhibitor with a Differentiated 
Selectivity and In Vivo Potency Profile. The Journal of pharmacology and experimental therapeutics, 2017. 
363(2): p. 240-252. 
39. 
Wang, M., et al., Acalabrutinib in relapsed or refractory mantle cell lymphoma (ACE-LY-004): a single-arm, 
multicentre, phase 2 trial. The Lancet, 2018. 391(10121): p. 659-667. 
40. 
Acalabrutinib, Prescribing Information: Revised 10/2017. 
41. 
Markham, A. and S. Dhillon, Acalabrutinib: First Global Approval. Drugs, 2018. 78(1): p. 139-145. 
42. 
Woyach, J., et al., Resistance to Acalabrutinib in CLL Is Mediated Primarily By BTK Mutations. Blood, 2019. 
134(Supplement_1): p. 504-504. 
43. 
de Romeuf, C., et al., Chronic lymphocytic leukaemia cells are efficiently killed by an anti-CD20 monoclonal 
antibody selected for improved engagement of FcgammaRIIIA/CD16. Br J Haematol, 2008. 140(6): p. 635-
43. 
44. 
Le Garff-Tavernier, M., et al., Analysis of CD16+CD56dim NK cells from CLL patients: evidence supporting a 
therapeutic strategy with optimized anti-CD20 monoclonal antibodies. Leukemia, 2011. 25(1): p. 101-9. 
45. 
Ferrero, S. and M. Dreyling, Minimal residual disease in mantle cell lymphoma: are we ready for a 
personalized treatment approach? Haematologica, 2017. 102(7): p. 1133-1136. 
46. 
Pott, C., et al., Molecular remission is an independent predictor of clinical outcome in patients with mantle 
cell lymphoma after combined immunochemotherapy: a European MCL intergroup study. Blood, 2010. 
115(16): p. 3215-23. 
47. 
Colomer, D. and E. Campo, Unlocking New Therapeutic Targets and Resistance Mechanisms in Mantle Cell 
Lymphoma. Cancer Cell, 2014. 25(1): p. 7-9. 
48. 
Jares, P., D. Colomer, and E. Campo, Molecular pathogenesis of mantle cell lymphoma. The Journal of clinical 
investigation, 2012. 122(10): p. 3416-3423. 
49. 
Kluin-Nelemans, H.C., et al., Treatment of Older Patients with Mantle-Cell Lymphoma. New England Journal 
of Medicine, 2012. 367(6): p. 520-531. 
50. 
Le Gouill, S., et al., Rituximab after Autologous Stem-Cell Transplantation in Mantle-Cell Lymphoma. New 
England Journal of Medicine, 2017. 377(13): p. 1250-1260. 
51. 
Cheson, B.D., et al., Recommendations for Initial Evaluation, Staging, and Response Assessment of Hodgkin 
and Non-Hodgkin Lymphoma: The Lugano Classification. Journal of Clinical Oncology, 2014. 32(27): p. 3059-
3067. 
52. 
Oken, M.M., et al., Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin 
Oncol, 1982. 5(6): p. 649-55. 
53. 
Dolgin, M., et al., Nomenclature and Criteria for Diagnosis of Diseases of the Heart and Great Vessels. 9 edn 
(Boston, Little, Brown and Company). 1994. 
54. 
Cheson, B.D., et al., Recommendations for Initial Evaluation, Staging, and Response Assessment of Hodgkin 
and Non-Hodgkin Lymphoma: The Lugano Classification. J Clin Oncol, 2014. 
 
 
 
 

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APPENDIX A: ECOG PERFORMANCE STATUS SCALE 
ECOG Performance Scale [52] 
Grade 
Descriptions 
0 
Normal activity. Fully active, able to carry on all pre-
disease performance without restriction. 
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). 
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. 
3 
In bed >50% of the time. Capable of only limited self-care, 
confined to bed or chair more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on 
any self-care. Totally confined to bed or chair. 
5 
Dead. 
 
 
 

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APPENDIX B: NYHA CARDIAC GRADING CRITERIA 
Modified from Dolgin et al., 1994 [53] 
 
New York Heart Association Classification of Heart Failure 
Class I 
No symptoms. Ordinary physical activity such as walking and climbing stairs does not cause fatigue 
or dyspnea. 
Class II 
Symptoms with ordinary physical activity. Walking or climbing stairs rapidly, walking uphill, walking 
or stair climbing after meals, in cold weather, in wind or when under emotional stress causes undue 
fatigue or dyspnea. 
Class III 
Symptoms with less than ordinary physical activity. Walking one to two blocks on the level and 
climbing more than one flight of stairs in normal conditions causes undue fatigue or dyspnea. 
Class IV 
Symptoms at rest. Inability to carry on any physical activity without fatigue or dyspnea. 
 
 

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APPENDIX C: LYMPHOMA RESPONSE CRITERIA [54] 
Response 
Site 
CT-Based Response 
PET-CT Based Response 
Complete 
Response 
 
Complete radiologic response (all 
of the following) 
Complete metabolic response (even 
with a persistent mass) 
Lymph nodes and 
extralymphatic sites 
 
Target nodes/nodal masses 
must regress to ≤1.5 cm in 
longest diameter (LDi).  
 
 
No extralymphatic sites of 
disease. 
 
Score ≤ 3* with or without a 
residual mass on 5-point scale†. 
 
 
It is recognized that in Waldeyer’s 
ring or extranodal sites with high 
physiologic uptake or with 
activation within spleen or 
marrow (e.g., with chemotherapy 
or myeloid colony-stimulating 
factors), uptake may be greater 
than normal mediastinum and/or 
liver. In this circumstance, 
complete metabolic response may 
be inferred if uptake at sites of 
initial involvement is no greater 
than surrounding normal tissue 
even if the tissue has high 
physiologic uptake. 
Nonmeasured 
lesion 
Absent 
Not applicable 
Organ enlargement 
Regress to normal 
Not applicable 
New lesions 
None 
None 
Bone marrow 
Normal by morphology; if 
indeterminate, IHC negative 
No evidence of FDG-avid disease in 
marrow 
Partial 
Response 
 
Partial remission (all of the 
following) 
Partial metabolic response 
Lymph nodes and 
extralymphatic sites 
 
≥ 50% decrease in SPD of up 
to 6 target measurable nodes 
and extranodal sites 
 
When a lesion is too small to 
measure on CT, assign 5 mm 
X 5 mm as the default value 
 
When no longer visible, 0 X 0 
mm 
 
For a node > 5 mm X 5 mm, 
but smaller than normal, use 
actual measurement for 
calculation 
 
Score 4 or 5† with reduced uptake 
compared with baseline and 
residual mass(es) of any size 
 
At interim, these findings suggest 
responding disease 
 
At end of treatment, these 
findings indicate residual disease 
Nonmeasured 
lesion 
Absent/normal, regressed, but 
no increase 
Not applicable 
Organ enlargement 
Spleen must have regressed by 
> 50% in length beyond normal 
Not applicable 
New lesions 
None 
None 

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Response 
Site 
CT-Based Response 
PET-CT Based Response 
Bone marrow 
Not applicable 
Residual uptake higher than uptake 
in normal marrow but reduced 
compared with baseline (diffuse 
uptake compatible with reactive 
changes from chemotherapy 
allowed). If there are persistent focal 
changes in the marrow in the context 
of a nodal response, consideration 
should be given to further evaluation 
with MRI or biopsy or an interval 
scan 
No response or 
stable disease 
 
Stable disease 
No metabolic response 
Target nodes/nodal 
masses, extranodal 
lesions 
< 50% decrease from baseline 
in SPD of up to 6 dominant, 
measurable nodes and 
extranodal sites; no criteria for 
progressive disease are met 
Score 4 or 5† with no significant 
change in FDG uptake from baseline 
at interim or end of treatment 
Nonmeasured 
lesion 
No increase consistent with 
progression 
Not applicable 
Organ enlargement 
No increase consistent with 
progression 
Not applicable 
New lesions 
None 
None 
Bone marrow 
Not applicable 
No change from baseline 
Progressive 
disease 
 
Progressive disease requires at 
least 1 of the following 
Progressive metabolic disease 
Individual 
target 
nodes/nodal masses 
PPD progression: 
Score 4 or 5† with an increase in 
intensity of uptake from baseline 
and/or 
Extranodal lesions 
An individual node/lesion must be 
abnormal with: 
 
Longest diameter (LDi) > 1.5 
cm and 
 
Increase by ≥ 50% from PPD 
nadir and 
 
An increase in LDi or shortest 
diameter (SDi) from nadir 
 
0.5 cm for lesions ≤ 2 cm 
 
1.0 cm for lesions > 2 cm 
 
In the setting of 
splenomegaly, the splenic 
length must increase by > 
50% of the extent of its prior 
increase beyond baseline 
(e.g., a 15-cm spleen must 
increase to >16 cm). If no 
prior splenomegaly, must 
 
New FDG-avid foci consistent with 
lymphoma at interim OR 
 
end-of-treatment assessment 

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Response 
Site 
CT-Based Response 
PET-CT Based Response 
increase by at least 2 cm 
from baseline 
 
New or recurrent 
splenomegaly 
Nonmeasured 
lesion 
New or clear progression of 
preexisting nonmeasured 
lesions 
None 
New lesions 
 
Regrowth of previously 
resolved lesions 
 
A new node > 1.5 cm in any 
axis 
 
A new extranodal site > 1.0 
cm in any axis; if < 1.0 cm in 
any axis, its presence must 
be unequivocal and must be 
attributable to lymphoma 
 
Assessable disease of any 
size unequivocally 
attributable to lymphoma 
 
New FDG-avid foci consistent with 
lymphoma rather than another 
etiology (eg, infection, 
inflammation).  
 
If uncertain regarding etiology of 
new lesions, biopsy or interval 
scan may be considered. 
Bone marrow 
New or recurrent involvement 
New or recurrent FDG-avid foci 
 
Measured dominant lesions:  
Up to six of the largest dominant nodes, nodal masses, and extranodal lesions selected to be clearly 
measurable in two diameters. Nodes should preferably be from disparate regions of the body and should 
include, where applicable, mediastinal and retroperitoneal areas.  
Non-nodal lesions include those in solid organs (e.g., liver, spleen, kidneys, lungs), GI involvement, cutaneous 
lesions, or those noted on palpation.  
Nonmeasured lesions:  
Any disease not selected as measured, dominant disease and truly assessable disease should be considered 
not measured. These sites include any nodes, nodal masses, and extranodal sites not selected as dominant or 
measurable or that do not meet the requirements for measurability but are still considered abnormal, as well 
as truly assessable disease, which is any site of suspected disease that would be difficult to follow 
quantitatively with measurement, including pleural effusions, ascites, bone lesions, leptomeningeal disease, 
abdominal masses, and other lesions that cannot be confirmed and followed by imaging. In Waldeyer’s ring or 
in extranodal sites (e.g., GI tract, liver, bone marrow), FDG uptake may be greater than in the mediastinum 
with complete metabolic response, but should be no higher than surrounding normal physiologic uptake (eg, 
with marrow activation as a result of chemotherapy or myeloid growth factors). 
*A score of 3 in many patients indicates a good prognosis with standard treatment, especially if at the time of 
an interim scan. However, in trials involving PET where de-escalation is investigated, it may be preferable to 
consider a score of 3 as inadequate response (to avoid undertreatment).  
†PET 5-point scale:  
1, no uptake above background; 2, uptake ≤ mediastinum; 3, uptake > mediastinum but ≤ liver; 4, uptake 
moderately > liver; 5, uptake markedly higher than liver and/or new lesions; X, new areas of uptake unlikely to 
be related to lymphoma. 
Abbreviations:   
CT, computed tomography; FDG, fluorodeoxyglucose; IHC, immunohistochemistry; LDi, longest transverse 
diameter of a lesion; MRI, magnetic resonance imaging; PET, positron emission tomography; PPD, cross 

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product of the LDi and perpendicular diameter; SDi, shortest axis perpendicular to the LDi; SPD, sum of the 
product of the perpendicular diameters for multiple lesions. 
 
 
 
 

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APPENDIX D: REGISTRATION COVERSHEET  
COH IRB# 20459: A Phase 2 Study of Acalabrutinib and PI3Kδ inhibitor Umbralisib in Combination 
with Ublituximab (AU2) in Patients with Previously Untreated Mantle Cell Lymphoma 
Data Coordinating Center:   
City of Hope 
1500 Duarte Road 
Duarte, CA 91010  
Tel:  (626)-218-7904 
Email:  DCC@coh.org (use #secure# in subject line) 
Site Principal Investigator  
Name: 
 
CRA/Study Coordinator:     
Contact Number:   
Patient’s Initials: (F M L): 
Institution: 
PI/ Sub-Investigator: 
Patient’s DOB: 
IRB approval valid until (date): 
Sex: 
______Male 
______Female 
Date Informed Consent Signed: 
Projected start date of treatment: 
Race 
Ethnicity 
Method of 
Payment:_______________________ 
 
Black 
 Hispanic 
Codes: 
 
Caucasian 
 Non-Hispanic 
01 Private 
06 Military or Veterans 
Adm. sponsored 
 
Asian 
 Other_________________ 
02 Medicare 
07 Self-pay (no 
insurance) 
 
American Indian 
 
03 Medicare & 
private ins. 
08 No means of 
payment  (no insurance) 
 
Native Hawaiian/Pacific 
Islander 
04 Medicaid 
09 Unknown 
 
Other_______________
____________________ 
05 Medicaid & Medicare 
Reason for Screen Failure:  
 
Reason for Failing to Initiate Protocol Therapy: 
 
 
 
 

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APPENDIX E: PROTON PUMP INHIBITORS AND CYP3A INHIBITORS AND INDUCERS 
Examples of proton pump inhibitors, and CYP3A inhibitors and inducers 
Proton-pump inhibitors1 
Omeprazole, Lansoprazole, Pantoprazole, Rabeprazole, Esomeprazole, Dexlansoprazole 
Strong CYP3A Inhibitors1,2 
Ketoconazole, Clarithromycin, Itraconazole, Nefazodone, Saquinavir, Ritonavir, Indinavir, Nelfinavir, 
Voriconazole, Lopinavir, Telithromycin, Conivaptan, Posaconazole, Boceprevir, Telaprevir, Cobicistat, 
Idelalisib, Grapefruit, Starfruit, Seville Oranges 
Moderate CYP3A Inhibitors1,2 
Erythromycin, Verapamil, Diltiazem, Cyclosporine, Ciprofloxacin, Fluvoxamine, Fluconazole, Aprepitant, 
Imatinib, Nilotinib, Dronedarone, Crizotinib, Atazanavir, Letermovir, Duvelisib 
Strong CYP3A Inducers1,2 
Phenytoin, Carbamazepine, Rifampin, Mitotane, Fosphenytoin, St John's Wort, Enzalutamide  
Lumacaftor 
1This is not an exhaustive list. Investigators should consult additional resources (e.g., website, drug 
label) for a full list or for more info on individual drugs. 
2Refer to Flockhart Table™ for a more detailed list of CYP3A inducers and inhibitors  
(https://drug-interactions.medicine.iu.edu/Main-Table.aspx). 
 
 

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APPENDIX F: CORRELATIVE TISSUE FORM (FOR ALL SITES) 
 
A copy of this form should accompany the sample shipments to Dr. Danilov’s laboratory. 
Non-COH sites: refer to Appendix G for shipping instructions. 
 
COH IRB number: 20459 
Shipping date (MM-DD-YYYY):   ________/________/________ 
Subject ID (issued by DCC):   
Participant Initials (F, M, L) (if applicable): 
Institution: 
Date of collection/ biopsy (MM-DD-YYYY):    ________/________/________ 
Time point:     
  Baseline       
  Progression 
Diagnosis: 
Tissue type (FFPE scrolls, slides, biopsies): 
Number of scrolls: 
Number of slides: 
 
 
 
 
 
 
CRA/Study Coordinator/Nurse Printed Name:   
CRA/Study Coordinator/Nurse Signature:   
Contact Number: 
 
 
 
 
 
 
 
 
 
 
 

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APPENDIX G: TISSUE SHIPPING GUIDELINES TO DR. DANILOV’S LABORATORY 
 
These guidelines apply to non-COH sites only. 
All biological material must be shipped according to applicable government and International Air 
Transport Association (IATA) regulations.  
Shipping guidelines can also be found on the FedEx website. 
 
1. Aim to ship samples on a Monday through Thursday. If this is not feasible, advance arrangements 
should be made with Dr. Danilov or his representative (DL-danilovlab@coh.org).   
2. Notify Dr. Danilov or his representative (DL-danilovlab@coh.org) of impending shipment. Sites 
must create their own FedEx shipping labels. 
3. Slides/ Blocks: Batch ship at room temperature via FedEx. During extreme heat, include 
refrigerated (not frozen) gel packs or gel insulators. 
It is recommended to ship samples via FedEx overnight (for a delivery by 3 pm or earlier the next 
day) or FedEx 2-day (with a morning delivery). During extreme heat, ship via FedEx overnight (for 
a delivery ideally by 10.30 am, or 3 pm the next day). 
4. Frozen samples should be batch shipped on dry ice via FedEx overnight (for a delivery by 10.30 
am the next day). The shipment should contain enough dry ice to last at least 72 hours. 
5. On the day of shipment, email the sample shipment information to Dr. Danilov or his 
representative (DL-danilovlab@coh.org). 
6. Ship samples with a copy of the correlative tissue form (Appendix F) and a copy of the pathology 
report to: 
 
Dr. Alexey Danilov MD, PhD 
Kaplan Clinical Research Building 1st floor, 158-1022 
City of Hope National Medical Center 
1500 E. Duarte Road 
Duarte, CA 91010 
Telephone: 626-218-1959 
 
 
 
 
 

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APPENDIX H: CORRELATIVE BLOOD/ BONE MARROW COLLECTION FORM FOR NON-COH SITES ONLY 
COH IRB number: 20459 
Participant Initials (F, M, L) (if applicable): 
Subject ID (issued by DCC):   
Institution: 
To be used by non-COH sites for the following blood/bone marrow samples being sent to Dr. Danilov’s 
lab: 
Blood Samples 
Blood 
Sample # 
Time point of 
Collection 
Expected 
Volume 
Tube Type Used 
Collected 
Volume 
Time of Collection 
Date of 
Collection 
Indicate 
which sample 
was collected 
1. 
 
Cycle 1, Day 1 
30 mL 
Purple-top 
_____ mL 
____:____ AM/ PM 
____/____/____ 
 
Up to 10 mL 
Cell-free DNA BCT 
_____ mL 
____:____ AM/ PM 
____/____/____ 
 
2. 
 
Cycle 2, Day 1 
20 mL 
Purple-top 
______mL 
____:____ AM/ PM 
____/____/____ 
 
3. 
 
Cycle 8, Day 1 
20 mL 
Purple -top 
_____ mL 
____:____ AM/ PM 
____/____/____ 
 
Up to 10 mL 
Cell-free DNA BCT 
_____ mL 
____:____ AM/ PM 
____/____/____ 
 
4. 
 
Cycle 14, Day 1 
20 mL 
Purple -top 
_____ mL 
____:____ AM/ PM 
____/____/____ 
 
Up to 10 mL 
Cell-free DNA BCT 
_____ mL 
____:____ AM/ PM 
____/____/____ 
 
5. 
 
EOM (End of maintenance) 
20 mL 
Purple -top 
_____ mL 
____:____ AM/ PM 
____/____/____ 
 
Up to 10 mL 
Cell-free DNA BCT 
_____ mL 
____:____ AM/ PM 
____/____/____ 
 
6. 
 
At relapse 
20 mL 
Purple -top 
_____ mL 
____:____ AM/ PM 
____/____/____ 
 
Up to 10 mL 
Cell-free DNA BCT 
_____ mL 
____:____ AM/ PM 
____/____/____ 
 
 
Bone Marrow Samples 
Indicate 
which 
sample 
was 
collected 
Time point of 
Collection 
Expected 
Volume 
Tube Type Used 
Collected 
Volume 
Time of Collection 
Date of 
Collection 
 
Baseline 
10 mL 
Purple -top 
_____ mL 
____:____ AM/ PM 
____/____/____ 
 
Suspected CR 
10 mL 
Purple -top 
_____ mL 
____:____ AM/ PM 
____/____/____ 
 
Relapse 
10 mL 
Purple -top 
_____ mL 
____:____ AM/ PM 
____/____/____ 
 
A copy of this form should accompany the sample shipments to Dr. Danilov’s lab. 
Refer to the blood/bone marrow shipping guidelines for shipping instructions (Appendix I). 
 
CRA/Study Coordinator/ Nurse:   
Contact Number: 
CRA/Study Coordinator/ Nurse Signature:   
Date: 
 
 

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APPENDIX I: BLOOD & BONE MARROW SHIPPING GUIDELINES TO DR. DANILOV’S LABORATORY 
These guidelines apply to non-COH sites only. 
All biological material must be shipped according to applicable government and International Air 
Transport Association (IATA) regulations.  
Shipping guidelines can also be found on the FedEx website. 
 
1. Aim to ship samples on a Monday through Thursday. If this is not feasible, advance arrangements 
should be made with Dr. Danilov or his representative (DL-danilovlab@coh.org). Sites must create 
their own FedEx shipping labels. 
1. Blood/bone marrow samples in purple-top tubes will be sent overnight at ambient temperature 
(15-25oC) in an appropriate container via FedEx. Cell-free BCT tubes should be shipped as soon 
as possible but no more than 3 days after being drawn via overnight courier at ambient 
temperature. All tubes must be stored at room temperature while awaiting shipment as cold 
temperatures can affect future analyses. 
2. On the day of shipment, email Dr. Danilov or his representative (DL-danilovlab@coh.org) the 
FedEx shipment #. 
3. Ship samples with a copy of the correlative blood/bone marrow collection form (Appendix H) 
and a copy of the latest CBC results (with differential) and the date of the test to: 
 
Dr. Alexey Danilov MD, PhD 
Kaplan Clinical Research Building 1st floor, 158-1022 
City of Hope National Medical Center 
1500 E. Duarte Road 
Duarte, CA 91010 
Telephone: 626-218-1959 
 
 
 

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APPENDIX J: HEPATITIS B SEROLOGIC TEST RESULTS 
 
 
 

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APPENDIX K: HIGHLY EFFECTIVE CONTRACEPTION METHODS 
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 of a female subject’s male partner (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) 
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 
country/region. 
 
 

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APPENDIX L-1: PATIENT DRUG DIARY INSTRUCTIONS 
COH IRB number: 20459 
Participant Initials (F, M, L) (if applicable): 
Subject ID (issued by DCC):   
Institution: 
 
 
 
 
General Instructions: 
1. Record the date and number of tablets that you took. 
2. Record any comments, side effects, missed, vomited or skipped doses in the Comments column. 
3. Bring this diary, all study drug bottles, and any unused tablets to each clinic visit. Do not throw 
away empty study drug bottles or unused tablets. 
4. Do not share your drug supply or transfer it to any other container. 
 
Umbralisib Specific Instructions: 
 
Take umbralisib once a day within 30 minutes of starting a meal, at approximately the same time 
each day. 
 
Tablets should be swallowed whole. The tablets should not be broken or chewed. 
 
If you miss a dose by less than 12 hours, take the missed dose right away. If you missed a dose by 
more than 12 hours, skip the missed dose and take the next dose at the usual time. 
 
If you vomit a dose, wait until the next scheduled dose; do not take extra medicine to make up 
the vomited dose. 
 
Acalabrutinib Specific Instructions: 
 
Take acalabrutinib twice a day (about 12 hours apart) with or without food, at approximately 
the same time each day. 
 
Tablets should be swallowed whole. The tablets should not be opened, broken or chewed. 
 
If you miss a dose by less than 3 hours, take the missed dose right away. If you missed a dose by 
more than 3 hours, skip the missed dose and take the next dose at the usual time. 
 
If you vomit a dose, wait until the next scheduled dose; do not take extra medicine to make up 
the vomited dose. 
 
 
 
Study Contact Information 
Study Doctor 
Phone: 
Name: 
 
Study Nurse 
Phone: 
Name: 
 
 

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APPENDIX L-2: PATIENT DRUG DIARY *** FOR CYCLE 1 ONLY *** 
COH IRB number: 20459 
Participant Initials (F, M, L) (if applicable): 
Subject ID (issued by DCC):   
Institution: 
Cycle #: 1 
Cycle start date: _________________ 
 
***For clinic staff use only*** 
Umbralisib daily dose: _____ mg ( _____ tablets) 
Acalabrutinib dose: _____ mg ( _____ tablets) ________ a day 
 
 
CYCLE 1 
Cycle 
Day 
Week 
Day 
Date 
Umbralisib 
# of tablets 
taken 
Acalabrutinib 
# of tablets 
taken 
Comments 
Write down missed/ vomited doses, 
side-effects (e.g. nausea, vomiting etc.) 
1 
 
 
 
AM: 
 
PM: 
 
 
2 
 
 
 
AM: 
 
PM: 
 
 
3 
 
 
 
AM: 
 
PM: 
 
 
4 
 
 
 
AM: 
 
PM: 
 
 
5 
 
 
 
AM: 
 
PM: 
 
 
6 
 
 
 
AM: 
 
PM: 
 
 
7 
 
 
 
AM: 
 
PM: 
 
 
8 
 
 
 
AM: 
 
PM: 
 
 
9 
 
 
 
AM: 
 
PM: 
 
 
10 
 
 
 
AM: 
 
PM: 
 
 
11 
 
 
 
AM: 
 
PM: 
 
 
12 
 
 
 
AM: 
 
PM: 
 
 
13 
 
 
 
AM: 
 
PM: 
 
 
14 
 
 
 
AM: 
 
PM: 
 
 
15 
 
 
 
AM: 
 
PM: 
 
 
16 
 
 
 
AM: 
 
PM: 
 
 

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COH IRB number: 20459 
Participant Initials (F, M, L) (if applicable): 
Subject ID (issued by DCC):   
Institution: 
 
CYCLE 1 (continued) 
Cycle 
Day 
Week 
Day 
Date 
Umbralisib 
# of tablets 
taken 
Acalabrutinib 
# of tablets 
taken 
Comments 
Write down missed/ vomited doses, 
side-effects (e.g. nausea, vomiting etc.) 
17 
 
 
 
AM: 
 
PM: 
 
 
18 
 
 
 
AM: 
 
PM: 
 
 
19 
 
 
 
AM: 
 
PM: 
 
 
20 
 
 
 
AM: 
 
PM: 
 
 
21 
 
 
 
AM: 
 
PM: 
 
 
22 
 
 
 
AM: 
 
PM: 
 
 
23 
 
 
 
AM: 
 
PM: 
 
 
24 
 
 
 
AM: 
 
PM: 
 
 
25 
 
 
 
AM: 
 
PM: 
 
 
26 
 
 
 
AM: 
 
PM: 
 
 
27 
 
 
 
AM: 
 
PM: 
 
 
28 
 
 
 
AM: 
 
PM: 
 
 
 
***For clinic staff use only*** 
 
# of Umbralisib tablets dispensed: ________             # of Umbralisib tablets returned: ________ 
 
# of Acalabrutinib tablets dispensed: ________     # of Acalabrutinib tablets returned: ________ 
 
Compare with drug diary entries made by participant/guardian. 
If there is a discrepancy, please reconcile. 
 
STUDY STAFF SIGNATURE/ INITIALS:                                            DATE: 
 
 
 

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APPENDIX L-3: PATIENT DRUG DIARY *** FOR ALL OTHER CYCLES *** 
COH IRB number: 20459 
Participant Initials (F, M, L) (if applicable): 
Subject ID (issued by DCC):   
Institution: 
Cycle #: ____ 
Cycle start date: _________________ 
 
***For clinic staff use only*** 
Umbralisib daily dose: _____ mg ( _____ tablets) 
Acalabrutinib dose: _____ mg ( _____ tablets)  ________ a day 
 
 
ALL OTHER CYCLES 
Cycle 
Day 
Week 
Day 
Date 
Umbralisib 
# of tablets 
taken 
Acalabrutinib 
# of tablets 
taken 
Comments 
Write down missed/ vomited doses, 
side-effects (e.g. nausea, vomiting etc.) 
1 
 
 
 
AM: 
 
PM: 
 
 
2 
 
 
 
AM: 
 
PM: 
 
 
3 
 
 
 
AM: 
 
PM: 
 
 
4 
 
 
 
AM: 
 
PM: 
 
 
5 
 
 
 
AM: 
 
PM: 
 
 
6 
 
 
 
AM: 
 
PM: 
 
 
7 
 
 
 
AM: 
 
PM: 
 
 
8 
 
 
 
AM: 
 
PM: 
 
 
9 
 
 
 
AM: 
 
PM: 
 
 
10 
 
 
 
AM: 
 
PM: 
 
 
11 
 
 
 
AM: 
 
PM: 
 
 
12 
 
 
 
AM: 
 
PM: 
 
 
13 
 
 
 
AM: 
 
PM: 
 
 
14 
 
 
 
AM: 
 
PM: 
 
 
15 
 
 
 
AM: 
 
PM: 
 
 
16 
 
 
 
AM: 
 
PM: 
 
 

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COH IRB number: 20459 
Participant Initials (F, M, L) (if applicable): 
Subject ID (issued by DCC):   
Institution: 
 
ALL OTHER CYCLES (continued) 
Cycle 
Day 
Week 
Day 
Date 
Umbralisib 
# of tablets 
taken 
Acalabrutinib 
# of tablets 
taken 
Comments 
Write down missed/ vomited doses, 
side-effects (e.g. nausea, vomiting etc.) 
17 
 
 
 
AM: 
 
PM: 
 
 
18 
 
 
 
AM: 
 
PM: 
 
 
19 
 
 
 
AM: 
 
PM: 
 
 
20 
 
 
 
AM: 
 
PM: 
 
 
21 
 
 
 
AM: 
 
PM: 
 
 
22 
 
 
 
AM: 
 
PM: 
 
 
23 
 
 
 
AM: 
 
PM: 
 
 
24 
 
 
 
AM: 
 
PM: 
 
 
25 
 
 
 
AM: 
 
PM: 
 
 
 
***For clinic staff use only*** 
 
# of Umbralisib tablets dispensed: ________             # of Umbralisib tablets returned: ________ 
 
# of Acalabrutinib tablets dispensed: ________     # of Acalabrutinib tablets returned: ________ 
 
Compare with drug diary entries made by participant/guardian. 
If there is a discrepancy, please reconcile. 
 
STUDY STAFF SIGNATURE/ INITIALS:                                            DATE: