A Phase 2 Trial of Acalabrutinib for the Treatment of Relapsed/Refractory Autoimmune Hemolytic Anemia
Phase: PHASE2
Conditions: Autoimmune Hemolytic Anemia, Chronic Lymphocytic Leukemia, Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, Warm Antibody Autoimmune Hemolytic Anemia
Sponsor: City of Hope Medical Center

 
IRB #20311 
 
03/21/2022 
Packet: 04 
CITY OF HOPE MEDICAL CENTER 
1500 E. DUARTE ROAD 
DUARTE, CA 91010 
 
DEPARTMENT OF HEMATOLOGY AND HEMATOPOIETIC CELL TRANSPLANTATION 
 
TITLE: A phase 2 trial of acalabrutinib for the treatment of relapsed/refractory autoimmune hemolytic 
anemia 
 
CITY OF HOPE PROTOCOL NUMBER: 
 IRB #20311 
Protocol date: 03/21/2022 
 
Initial Submission  
Protocol dated 1/21/2020 
Packet: 00 
Protocol Amendment 01 
Protocol dated 3/18/2021 
Packet: 01 
Protocol Amendment 02 
Protocol dated 3/18/2021(TP) 
Packet: 02 
Protocol Amendment 03 
Protocol dated 03/21/2022 
Packet: 03 
Protocol Amendment 04 
Protocol dated 03/21/2022 (TP, PAP) 
Packet: 04 
 
 
 
DISEASE SITE: 
 
 
 
 
  
 
STAGE: 
 
 
 
 
 
 
 
MODALITY(IES): 
 
 
 
 
  
 
TYPE:  
 
 
 
 
 
  
 
PRINCIPAL INVESTIGATOR: 
 
 
Alexey Danilov, M.D., Ph.D.  
 
COLLABORATING INVESTIGATOR: 
 
Tanya Siddiqi, M.D. 
 
 
PARTICIPATING CLINICIANS: 
 
 
Elizabeth Budde, M.D., Ph.D. 
Alex Herrera, M.D. 
Matthew Mei, M.D. 
Liana Nikolaenko, M.D. 
Leslie Popplewell, M.D. 
Steven Rosen, M.D. 
Geoffrey Shouse, D.O. 
Jasmine Zain, M.D. 
Swetha Kambhampati, M.D. 
John Baird, M.D. 
 
  
Biostatistician:  
 
 
 
 
Lu Chen, Ph.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 
Protocol Title: A phase 2 trial of acalabrutinib for the treatment of relapsed/refractory 
autoimmune hemolytic anemia 
Version Date: 03/21/2022 
Protocol Version: 02 
 
City of Hope #: 20311 
Agents: Acalabrutinib 
IND Number: Exempt 
Sponsor/IND Holder: City of Hope 
Industry Partner: AstraZeneca 
Industry Partner Protocol ID: Pending … 
NCT Number: NCT04657094 
Participating Sites: City of Hope (Duarte), Ohio State University 
Short Title …Acalabrutinib in AIHA… 
 
 
Principal Investigator 
Alexey Danilov, MD, PhD 
City of Hope National Medical Center 
Dept. of Hematology 
T: (626) 218-2405 
Email: adanilov@coh.org  
Coordinating Center 
Data Coordinating Center 
City of Hope National Medical Center 
T: (626)-218-7904 
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: 626-218-6626 
Email: lchen@coh.org 
Protocol Development Scientist 
D. Lynne Smith, PhD 
City of Hope National Medical Center 
Toni Stephenson Lymphoma Center 
T: 626 218-1134 
Email: lysmith@coh.org 
  
 
Co-Investigator 
Tanya Siddiqi, MD 
City of Hope National Medical Center 
Dept. of Hematology 
T: 626-218-2405 
Email: tsiddiqi@coh.org 
 
Participating non-COH sites 
Site Lead Investigator 
Kerry A. Rogers, MD 
Ohio State University  
Dept. of Internal Medicine 
T: 614 366-9338 
Fax: 614 293-7526 
Email: kerry.rogers@osumc.edu 
 
Site Lead Investigator 
Philip A. Thompson, MBBS 
University of Texas M.D. Anderson 
Cancer Center 
Dept. Leukemia 
T: 713 792-7305 
Fax: 713 563-7746 
Email: 
PAThompson2@mdanderson.org 
 
 
 
 
 
 

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STUDY SCHEMA 
 
 
 
 
 
 

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PROTOCOL SYNOPSIS 
Protocol Title 
A phase 2 trial of acalabrutinib for the treatment of relapsed or refractory autoimmune hemolytic anemia 
Study Detail 
Population/Indication(s): 
AIHA in patients with CLL 
Phase: 
Phase 2 
Sample Size: 
22 
Estimated Accrual Duration: 
36 months 
Estimated Study Duration 
60 months 
Participant Duration: 
24 months (12 months treatment, 12 months follow-up) 
Participating Sites: 
 City of Hope Duarte, CA 
 Ohio State University, OH 
Study Agents: 
Acalabrutinib 
Sponsor: 
City of Hope 
Industry Partner:  AstraZeneca 
 
 
 
 
Rationale for this Study 
Autoimmune hemolytic anemia (AIHA) is a life-threatening disease with an incidence of 1-3 per 100,000 persons per 
year. In addition to idiopathic AIHA, a number of underlying conditions have been associated with this disorder, including 
viral infections, autoimmune and connective tissues diseases, and lymphoproliferative disorders. AIHA is particularly 
common among patients with chronic lymphocytic leukemia (CLL) with an incidence of ~2.3% as reported in a recent 
retrospective analysis of 1750 patients. First-line therapy of AIHA typically consists of corticosteroids, which induce initial 
responses in 70%-85% of patients with warm AIHA; however, only one-third of patients remain in long-term remission 
after stopping corticosteroids, and a further 50% require maintenance doses. Subsequent lines of immunosuppressive 
therapy carry initial response rates from 40-60%, though relapses are similarly common. Therefore, in the 
relapsed/refractory setting, safe and effective treatments for AIHA are needed. Ibrutinib, a small molecule inhibitor of 
Bruton tyrosine kinase (BTK), inhibits B-cell activity and has been shown to inhibit production of auto-antibodies in 
murine models of autoimmunity, suggesting their potential efficacy in multiple autoimmune conditions. Preliminary 
evidence suggests that ibrutinib may be efficacious in treatment of CLL-associated AIHA, as 50% of patients who 
presented with hemolysis and received therapy with the BTK inhibitor were able to discontinue immunosuppressive 
therapy. A second-generation selective BTK inhibitor, acalabrutinib, may be associated with fewer off-target effects 
including diminished frequency of side effects including bleeding and atrial fibrillation, and showed increased efficacy 
against AIHA in a murine model. This study will assess if acalabrutinib can increase hemoglobin and reduce transfusion 
requirements in patients with relapsed or refractory AIHA. 
Treatment Description 
Eligible participants enrolled in this study will receive acalabrutinib (100 mg, PO BID) for 12 cycles.  Participants that 
experience disease progression or unacceptable toxicities will discontinue study drug and be removed from study.  
Treatment with acalabrutinib may be continued beyond 12 cycles, for a maximum of 36 cycles, if the study participant 
might benefit from ongoing therapy in the opinion of treating physician (e.g., ongoing therapy for CLL is required). 
Objectives 
Primary Objective(s) 
 
Assess the efficacy of acalabrutinib in patients with relapsed or refractory AIHA 
Secondary Objective(s) 
 
Evaluate acalabrutinib’s ability to induce short term and sustained hemoglobin response 

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 
Assess the toxicity of acalabrutinib 
 
Evaluate efficacy of acalabrutinib in CLL  
Exploratory Objective(s) 
 
Assess the effect of acalabrutinib on T-cell functionality in an autoimmune disorder. 
Study Design 
This is a phase 2, single-arm, open-label study to assess the efficacy and safety of acalabrutinib in the treatment of CLL 
patients with relapsed/refractory AIHA.  
Evaluation Criteria and Endpoints 
Primary Endpoint(s):  
 
AIHA Overall Response Rate (ORR) after 6 cycles, including complete and partial response 
Secondary Endpoint(s):  
 
AIHA ORR after 3 and 12 cycles of therapy; frequency of PRBC (packed red blood cell) transfusion; Incidence of 
toxicity [per CTCAE v5.0] and IWCLL 20181 (hematologic) criteria; CLL ORR after 6 and 12 cycles of therapy; 
duration of AIHA respose and duration of CLL response 
Exploratory Endpoint 
 
Percentage of T-cell subsets among study participants 
Statistical Considerations 
A sample size of 20 achieves an approximate 87% power using a one-sided binomial exact test with a significance level 
(alpha) of 0.05 for detecting improvement of 0.3 (0.6 from 0.3) in response rate, based upon the assumption that a 
response of 30% or less indicates no benefit.  The actual type I error is 0.048 and the exact binomial test will require 10 
or more responders in 20 patients evaluable for the primary endpoint to reject the null hypothesis of 0.3. Anticipating up 
to 10% patients not evaluable for the primary endpoint, a total of 22 participants will be enrolled. 
Abbreviated Eligibility Criteria 
Main Inclusion Criteria 
 
Men and women, aged >18 years 
 
“Warm" or "cold" AIHA in patients with CLL, relapsed/refractory (RR) after first line treatment with oral 
prednisone (with or without rituximab), defined by: 
- anemia (Hgb≤10 g/dL; or Hgb>10 g/dL dependent on transfusions to maintain this level of hemoglobin), and  
- laboratory evidence of hemolysis: 3 of 4 markers present (increased reticulocyte count, increased indirect 
bilirubin, increased lactate dehydrogenase, haptoglobin < institutional lower limit of normal)  
 
Positive DAT (score ≥ 1+) – either IgG DAT, C3 DAT, or both. Eligibility of patients with Coombs-negative AIHA 
should be confirmed by the trial investigator at each respective study site. 
 
ECOG performance status grade ≤2 
 
Histologically or flow cytometry confirmed diagnosis of CLL/SLL 
 
Prior to starting study agent, participant must have organ function as defined below: 
- 
Direct bilirubin ≤3 X institutional upper limit of normal (ULN) or 1 mg/dL, whichever is higher, if deemed 
related to hemolysis by the investigator 
- 
AST or ALT ≤3 X institutional ULN  
- 
Estimated CrCL using the Cockroft-Gault equation (or an alternative equation, per institutional standard) 
≥30 mL/min.   
- 
Absolute neutrophil count (ANC) ≥500/mm3, platelet count ≥30,000/mm3. 
- 
PT/INR or aPTT <2 x ULN. Exception: subjects receiving warfarin are excluded; however, those receiving 
other anticoagulant therapy who have a higher INR/aPTT are permitted to enroll 

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Main Exclusion Criteria 
 
Prior therapeutic intervention with any of the following: 
o 
Therapeutic anticancer antibodies within 2 weeks;  
o 
Radio- or toxin-immunoconjugates within 10 weeks;  
o 
BH3-mimetic venetoclax, PI3K inhibitors and other “targeted” therapy– within 6 half-lives;  
o 
Treatment with ibrutinib, acalabrutinib or another BTK inhibitor within 12 months  
 
All other chemotherapy, radiation therapy within 3 weeks prior to initiation of therapy. 
 
Inadequate recovery from adverse events related to prior therapy to grade 1 or baseline (excluding Grade 2 
alopecia and neuropathy). 
 
Chronic use of corticosteroids in excess of prednisone 60 mg/day or its equivalent.  
 
Allogeneic stem cell transplant within the past 12 months or ongoing immunosuppressive therapy. 
 
History of prior malignancy except:  
o 
malignancy treated with curative intent and no known active disease present for ≥ 2 years prior to 
initiation of therapy on current study;  
o 
adequately treated non-melanoma skin cancer or lentigo maligna (melanoma in situ) without evidence 
of disease;  
o 
adequately treated in situ carcinomas (e.g., breast, cervical, esophageal, etc.) without evidence of 
disease;  
o 
asymptomatic prostate cancer managed with “watch and wait” strategy;  
 
History of Human Immunodeficiency Virus (HIV) infection or active hepatitis B or C. 
 
Major surgery (requiring general anesthesia) within 28 days prior to initiation of therapy. 
 
Patients with clinically significant medical condition of malabsorption, inflammatory bowel disease, chronic 
conditions which manifest with diarrhea, refractory nausea, vomiting or any other condition that will interfere 
significantly with drug absorption.  
 
Requires treatment with strong CYP3A inhibitors or inducers.   If the patient requires a strong CYP3A 
inhibitor/inducer, they should not be enrolled even if it could be held for  14 days before the first dose of study 
drug.  
 
Requirement for concurrent therapy with vitamin K antagonists (e.g., warfarin) 
 
Active uncontrolled infection 
 
Positive pregnancy test or breastfeeding 
Investigational Product Dosage and Administration 
 Acalabrutinib, 100 mg by mouth every 12 hours daily on a 28-day cycle for 12 cycles; however, particpants deriving 
clinical benefit may, at the discretion of the Pincipal Investigator, receive additional cycles of this treatment. 
Clinical Observations and Tests to be Performed 
 
Safety assessments (CBCs with differential, comprehensive chemistry panel, and coagulation) 
 
Response assessments 
 
CT/PET scans  
 
Correlative tumor blood samples. 
 
 

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TABLE OF CONTENTS 
SECTION ....................................................................................................................................................................... PAGE 
Protocol Team ..................................................................................................................................................................... 2 
Study Schema ...................................................................................................................................................................... 3 
Protocol Synopsis ................................................................................................................................................................ 4 
Table of Contents ................................................................................................................................................................ 7 
Abbreviations ...................................................................................................................................................................... 9 
1.0 
Objectives ............................................................................................................................................................ 11 
1.1 
Primary Objective(s) 
11 
1.2 
Secondary Objective(s) 
11 
1.3 
Exploratory Objective(s) 
11 
2.0 
Background .......................................................................................................................................................... 11 
2.1 
Introduction/Rationale for Development 
11 
2.2 
Overview of Acalabrutinib (ACP-196) 
13 
2.3 
Background for Correlative Studies 
15 
2.4 
Overview and Rationale of Study Design 
15 
3.0 
Eligibility Criteria .................................................................................................................................................. 16 
3.1 
Inclusion Criteria 
16 
3.2 
Exclusion Criteria 
17 
4.0 
Participant Enrollment ......................................................................................................................................... 20 
4.1 
Pre-Enrollment Informed Consent and Screening Procedures 
20 
4.2 
Participant Enrollment 
20 
4.3 
Screen Failures and Registered Participants Who Do Not begin Study Treatment 
21 
5.0 
Treatment Program ............................................................................................................................................. 21 
5.1 
Treatment Program Overview 
21 
5.2 
Cycle Definition 
21 
5.3 
Treatment Plan 
21 
5.4 
Agent Administration 
21 
5.5 
Assessments and Special Monitoring 
22 
5.6 
Duration of Therapy and Criteria for Removal from Protocol Therapy 
22 
5.7 
Follow-Up 
22 
5.8 
Duration of Study Participation 
22 
5.9 
Prohibited and Concomitant Therapies/Medications 
22 
5.10 
Supportive care 
23 
6.0 
Anticipated Adverse Events ................................................................................................................................. 25 
6.1 
Acalabrutinib 
25 
7.0 
Dose Delay / Modification Guidelines .................................................................................................................. 27 
7.1 
Dose Delays 
27 
7.2 
Dose Modifications 
27 
8.0 
Agent Information ............................................................................................................................................... 28 
8.1 
Acalabrutinib (Calquence, ACP-196) 
28 
9.0 
Correlative/ Special Studies ................................................................................................................................. 30 
9.2 
Laboratory Studies Performed 
31 
10.0 
Study Calendar ..................................................................................................................................................... 32 
11.0 
Endpoint Definitions/Measurement of Effect ...................................................................................................... 35 
11.1 
Primary Endpoint(s) 
35 
11.2 
Secondary Endpoint(s) 
35 
11.3 
Exploratory Endpoint(s) 
37 
12.0 
Statistical Considerations ..................................................................................................................................... 37 
12.1 
Study Design 
37 

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12.2 
Sample Size and Power 
37 
12.3 
Study Stopping Rules 
37 
12.4 
Statistical Analysis Plan 
38 
12.5 
Handling of Missing Data 
38 
13.0 
Data Handling, Data Management, Record Keeping ............................................................................................ 39 
13.1 
Source Documents 
39 
13.2 
Data Capture Methods and Management 
39 
13.3 
Case Report Forms/Data Submission Schedule 
39 
13.4 
Regulatory Records 
39 
14.0 
Reporting of Adverse Events, Unanticipated Problems & Other Events of Interest .............................................. 39 
14.1 
Assessment of Adverse Events 
40 
14.2 
Adverse Events of Special Interest (AESI) 
40 
14.3 
Pregnancies 
41 
14.4 
Routine AE Collection and Reporting Guidelines 
42 
14.5 
Expedited Reporting 
42 
14.6 
Reporting to the FDA 
44 
14.7 
Reporting to Acerta Pharma/AstraZeneca 
44 
15.0 
Adherence to the Protocol & Reporting of Protocol Deviations ........................................................................... 45 
15.1 
Reporting by COH 
45 
15.2 
Reporting by non-COH Sites: 
45 
16.0 
Study Oversight, Quality Assurance, & Data and Safety Monitoring .................................................................... 46 
16.1 
All Investigator Responsibilities 
46 
16.2 
Study Principal Investigator Responsibilities 
46 
16.3 
Protocol Management Team (PMT) 
46 
16.4 
Quality Assurance 
46 
16.5 
Risk Determination 
46 
16.6 
City of Hope Data and Safety Monitoring Committee (DSMC) 
46 
17.0 
Ethical and Regulatory Considerations ................................................................................................................. 47 
17.1 
Ethical Standard 
47 
17.2 
Regulatory Compliance 
47 
17.3 
Institutional Review Board 
47 
17.4 
Informed Consent 
48 
17.5 
Participant Withdrawal 
48 
17.6 
Special and Vulnerable Populations 
49 
17.7 
Participant Confidentiality 
49 
17.8 
Use of Unused (Leftover) Specimens Collected for this Trial 
50 
17.9 
Conflict of Interest 
50 
17.10 
Financial Obligations, Compensation, and Reimbursement of Participants 
50 
17.11 
Publication/ Data Sharing 
51 
18.0 
References ........................................................................................................................................................... 52 
Appendix A: Performance Status Scales............................................................................................................................. 55 
Appendix B: AIHA Response Criteria .................................................................................................................................. 56 
Appendix C: CLL/SLL Response Criteria .............................................................................................................................. 57 
APPENDIX D-1: Acalabrutinib Medication Diary Instructions ............................................................................................. 58 
Appendix D-2: Medication Diary ........................................................................................................................................ 59 
Appendix E: Registration Coversheet ................................................................................................................................. 61 
Appendix F: Expedited Reporting CoverSheet ........................................................................... Error! Bookmark not defined. 
 
 
 

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ABBREVIATIONS  
 
Abbreviation 
Meaning 
AE 
Adverse event 
AIHA 
Autoimmune hemolytic anemia 
AIC 
Autoimmune cytopenia 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
AST 
Aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical (Classification System) 
AUC 
Area under the curve 
BUN 
Blood urea nitrogen 
CBC 
Complete blood cell (count) 
CFR 
United States Code of Federal Regulations  
CLL 
Chronic lymphocytic leukemia 
CoC 
National Institutes of Health (NIH) Certificate of Confidentiality 
CR 
Complete response 
CRMS 
Clinical research management system 
CRQA 
Clinical Research Quality & Administration 
CRRC 
Clinical Research Review Committee (OHSU) 
CRF 
Case report form 
CT 
Computerized tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTMS 
Clinical Trial Management System 
DSMC 
Data and Safety Monitoring Committee 
DSMP 
Data and Safety Monitoring Plan 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
eCRIS 
Electronic Clinical Research Information System 
EDC 
Electronic data capture 
FDA 
United States Food and Drug Administration 
GCP 
Good Clinical Practice 
HBeAg 
Hepatitis B “e” antigen 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human immunodeficiency virus 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IND 
Investigational new drug application 
IRB 
Institutional Review Board 
iwCLL 
International Workshop on Chronic Lymphocytic Leukemia 
IV 
Intravenous 
LDH 
Lactate dehydrogenase 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic resonance imaging 
N/A 
Not applicable 

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NCI 
National Cancer Institute 
OHRP 
Office for Human Research Protections 
OHSU 
Oregon Health & Science University 
ORR 
Overall response rate 
PET 
Positron emission tomography 
PI 
Principal Investigator 
PO 
Per os (by mouth, orally) 
PR 
Partial response 
RNI 
Reportable new information 
RR 
Relapsed/refractory 
SAE 
Serious adverse event 
SLL 
Small lymphocytic lymphoma 
ULN 
Upper limit of normal 
UP 
Unanticipated problem 

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1.0 OBJECTIVES 
1.1 Primary Objective(s)  
o Assess the efficacy of acalabrutinib in CLL patients with relapsed or refractory AIHA 
1.2 Secondary Objective(s) 
o Evaluate acalabrutinib’s ability to induce short term and sustained hemoglobin response 
o Assess the toxicity of acalabrutinib 
o Evaluate efficacy of acalabrutinib in CLL 
1.3 Exploratory Objective(s) 
o Assess the effect of acalabrutinib on T-cell functionality in an autoimmune disorder. 
2.0 BACKGROUND 
2.1 Introduction/Rationale for Development 
2.1.1 
Overview of Autoimmune hemolytic Anemia (AIHA) 
Autoimmune hemolytic anemia (AIHA) is a life-threatening autoimmune disease characterized by autoantibodies 
targeting antigens on erythrocytes.  This process subsequently results in the destruction of erythrocyte by either 
extravascular phagocytosis in the spleen, liver, and bone marrow, or via intravascular complement-mediated 
lysis.2  The incidence of AIHA is approximately 1-3 per 100,000 persons per year, and though often cases are often 
idiopathic (~50% of cases), they can also occur secondary to another disease such as viral infections, autoimmune 
diseases (~20% of cases), and lymphoproliferative disorders (~20% of cases).2-4   
Warm AIHA (wAIHA) is the most common subtype, accounting for 65% to 70% of AIHA.2  The warm subtype of 
AIHA is characterized by immunoglobulin G (IgG) autoantibodies binding to erythrocytes at 37°C, resulting in their 
destruction via tissue macrophages (i.e., extravascular phagocytosis).  Depending on the IgG subtype, warm 
antibody hemolytic anemia may also promote intravascular hemolysis by binding complement to erythrocytes.  
Accounting for approximately 20% to 25% of AIHAs, cold agglutinin disease (CAD) is characterized by production 
of IgM autoantibodies that optimally fix to complement at 4°C, and prevalently causes intravascular hemolysis.2,5,6  
Another 8% of patients with AIHA have both warm IgG and cold IgM antibodies and are termed mixed 
autoantibody hemolytic anemias.7  
2.1.2 
Management of AIHA in Chronic Lymphocytic Leukemia 
Autoimmune cytopenias (AIC) are frequently observed in patients with chronic lymphocytic leukemia (CLL), and 
include AIHA, immune thrombocytopenia (ITP), pure red cell aplasia (PRCA) and autoimmune granulocytopenia 
(AIG).8  AIHA is common among patients with chronic lymphocytic leukemia (CLL), with warm AIHA being the most 
common subtype in these patients.  The incidence of CLL-associated AIHA is ~2.3% conservatively and as high as 
15% in some cohorts.9,10  Patients with CLL developing AIHA may carry prognostic significance as this subset of 
patients is linked to poor survival11, with the late onset of AIHA in the course of CLL associated with inferior 
outcomes compared to early onset of AIHA.8  Reasons for such inferior survival may, in part, be explained by AIHA 
patients having higher risk infections, and bleeding and cardiovascular complications.8  
The treatment of AIHA has typically included use of corticosteroids, splenectomy and conventional 
immunosuppressive drug.2  Importantly, the therapeutic strategy is largely dependent on the AIHA subtype. Use 
of corticosteroids in the frontline is widely adopted for treating warm antibody AIHA, but are relatively ineffective 
for cases of cold AIHA.  For warm AIHA, initial treatment with prednisone is associated with responses in 70%-85% 
of patients; however, even this is short-lived as only 15% to 20% of patients achieve long-term remission upon 

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withdrawal of corticosteroid.4  Subsequent lines of immunosuppressive therapy (e.g., cyclophosphamide, 
rituximab) carry initial response rates from 40-60%, but durable responses occur in only 20% to 30% treated 
patients.2,12,13  For example, in a cohort of 14 steroid‐refractory patients with AIHA secondary to CLL, rituximab 
monotherapy was associated with a complete response (CR) and partial response (PR) of 3 (22%) and 7 (50%) 
patients, respectively.14  Of the 8 patients still alive at the mean follow‐up of 17 months, only 6 (40%) were 
transfusion‐free.   
Many treatment approaches have also examined the use of corticosteroids in combination with 
cyclophosphamide and rituximab.9  Using a combination regimen of dexamethasone (12 mg), rituximab (375 
mg/m2) and cyclophosphamide (750 mg/m2) (RCD) in a cohort of 48 CLL patients including 26 with AIHA, 9 with 
immune thrombocytopenia (ITP), and 8 with Evans syndrome.  Overall, the RCD regimen achieved a response rate 
of 89.5% for AIHA, but relapse occurred in nearly 40% of patients with a median response duration of 24 months.15 
2.1.3 
Bruton Tyrosine Kinase Inhibitors for Treating AIHA 
Bruton’s tyrosine kinase (BTK) mediates B-cell signaling and is also present in innate immune cells, but not T cells.16  
Specifically, activation of the B-cell receptor (BCR) in response to antigen-binding, and/or other stimulation (e.g., 
CD40, toll-like receptors [TLRs], Fc receptors [FCRs] and chemokine receptors) elicits activation of Src family 
kinases, SYK (spleen tyrosine kinase) and LYN, which in turn activates BTK.16  As such, BTK plays a central role in 
modulation of BCR signaling, and while overexpression of BTK can result in autoimmunity, decreased BTK 
expression improves the outcomes of autoimmune diseases.16-18  Moreover, unlike normal B cells, autoreactive B 
cells appear to be more dependent upon BTK for survival.19  
Ibrutinib, a small molecule inhibitor of BTK, inhibits B-cell activity and has been shown to inhibit production of 
auto-antibodies in murine models of autoimmunity suggesting their potential efficacy in multiple autoimmune 
conditions.16,20,21  Additionally, ibrutinib also inhibits IL-2 inducible T-cell kinase (ITK), and thereby can modulate 
activation of certain T-cell subsets that contribute to the development of humoral autoimmunity.22  As Th1 
cytokines (IFN-gamma, IL-12 and TNF-alpha) are reduced in AIHA, the ability of BTK inhibitors to potentiate Th1-
mediated immune responses may play an important role in their activity in this condition.22,23   
While AIHA is a common complication of CLL, many clinical trials with BTK inhibitors have typically excluded 
patients with uncontrolled hemolysis; recent clinical findings, however, point to the utility of BTK inhibition in the 
treatment of AIHA.10,24-26  Rogers et al10 conducted a retrospective cohort review of 301 patients that participated 
in several clinical trials investigating ibrutinib (with or without anti-CD20 monoclonal antibody therapy) for 
treatment of CLL. Of these 301 patients, 78 patients had a history of autoimmune cytopenias (AIC), of which 44 
(56%) were AIHA.  Of those with AIC, 22 were receiving AIC therapy prior to start of ibrutinib. Notably, of these 22 
patients, 19 (86%) were able to discontinue the AIC therapy after a median of 4.7 months from start of ibrutinib.  
Though not statistically significant, the treatment emergent cases of AIC was decreased from 13 AIC episodes per 
1000 patient-years of ibrutinib exposure for those receiving ibrutinib alone to 7 episodes per 1000 patient-years 
of ibrutinib treatment for those receiving concomitant anti-CD20 monoclonal antibody treatment.  
Montillo et al25 retrospectively assessed data from the phase 3 RESONATE trial, in which patients with previously 
treated CLL were randomized to receive treatment with ibrutinib (n=195) or ofatumumab (n=191).  Median 
treatment duration was 18.3 months for patients on ibrutinib versus 5.3 months for ofatumumab.  A total of 38 
and 42 patients with a history of AIHA or ITP were identified in the ibrutinib and ofatumumab treatment arms, 
respectively.  While no new AIC were observed among those treated with ibrutinib, 4 patients randomized to the 
ofatumumab arm developed AIC (n = 2 AIHA and n = 2 ITP).   
A retrospective cohort study27 done at Mayo Clinic included 193 patients who received ibrutinib for CLL outside 
of a clinical trial had 11 cases of treatment-emergent AIC which is 6% of the cohort and consistent with the findings 
in the cohort reported by Rogers et al.10  In this cohort 29/193 (15%) had a prior history of AIC and 12 were on a 
chronic therapy for AIC.  Of these 12, 8 (67%) were able to discontinue their chronic AIC therapy while taking 
ibrutinib with no relapses or worsening of AIC.28 

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Manda et al24 published a case report of a 70 year-old man with asymptomatic CLL (with del(17p)) that presented 
12 months later with fatigue, generalized weakness, dyspnea and chest pain on mild exertion.  Warm AIHA was 
confirmed using a direct antiglobin test (DAT), and the patient was initially treated with prednisone (1 mg/kg), but 
remained symptomatic at 2 week follow-up. A subsequent 2-week treatment with cyclophosphamide (500 
mg/m2) and vincristine (2 mg) in addition to steroid therapy also failed to improve symptoms.  The patient was 
then started on ibrutinib (420 mg daily), which after 3 weeks, was associated with a complete resolution of AIHA 
and CLL-related symptoms.  
The above findings provide clinical data that targeting of the BTK pathway may have a role in controlling AIHA in 
CLL.  Among the new agents, acalabrutinib has gained increasing favor as a second-generation selective BTK 
inhibitor. It is hoped that fewer off target effects will result in a better safety profile compared to ibrutinib.   
Supporting this, laboratory studies in the rat-RBC inducible murine model of AIHA demonstrate that 
pharmacologic BTK inhibition reduces anti-RBC autoantibody production (Rogers et al20, unpublished).  In this 
study C3H/B6 F1 WT mice were treated with either vehicle (10% β-cyclodextrin), acalabrutinib (0.16 mg/mL) or 
ibrutinib (0.16 mg/mL) via drinking water for 2 weeks then injected intraperitoneally with washed rat RBCs weekly 
for 4 weeks while the drug water was continued.  The rat RBC injections induce a measurable autoimmune 
response starting around 14 days after the first injection and peaking around days 28-35.  Autoantibody 
production was measured by a flow cytometry assay which detects IgG on the surface of RBCs taken from the 
circulation of the treated mice.  Treatment with acalabrutinib reduced anti-RBC autoantibody compared to both 
vehicle and ibrutinib (see figure).  There was a trend towards decreased autoantibody production compared to 
vehicle in the mice treated with ibrutinib that did not reach statistical significance.  This supports that acalabrutinib 
may be more beneficial for the treatment of AIHA compared to ibrutinib.   
 
2.2 Overview of Acalabrutinib (ACP-196) 
2.2.1 
Acalabrutinib in Treating CLL 
Acalabrutinib (CALQUENCE, ACP-196) is a second-generation BTK inhibitor that shows higher selectivity for BTK, 
while simultaneously lacking irreversible inhibition of activities of other kinases such as epidermal growth factor 
Figure 1. Quantitation of immunoglobulin on mouse RBCs by direct enzyme-linked anti-globulin test. 

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receptor (EGFR), interleukin-2-inducible T-cell kinase (ITK), and T cell X chromosome kinase (Txk), among 
others.29,30  This higher target selectivity is expected to contribute to the improved safety profile over that of 
ibrutinib.31  In the phase II ACE-LY-004 trial consisting of 124 patients with mantle cell lymphoma (MCL), 
administration of acalabrutinib (100 mg PO twice daily [bid]) was associated with an objective response rate (ORR) 
of 80.6%, including a complete response (CR) rate of 42.7% and a partial response (PR) rate of 37.9%. The 
estimated duration of response (DOR) rates at 12 and 24 months were 73.2% and 52.4%, respectively; and the 
median DOR was 25.7 months.32 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%).31  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.33,34   
Acalabrutinib has received FDA approval in therapy of CLL based on two large randomized trials, ASCEND and 
ELEVATE TN, in patients with R/R and TN CLL, respectively, which were conducted after encouraging results of the 
phase I/II ACE-CL-001 trial (NCT02029443) evaluating the safety and efficacy of acalabrutinib for patients with 
relapsed CLL.35  A total of 61 patients that had received a median of 3 previous therapies were enrolled and 
assigned to receive oral acalabrutinib dose of 100, 175, 250 or 400 mg once daily in the phase I dose-escalation 
portion, or 100 mg (bid) in the phase II portion of the study.  The authors reported an ORR of 95% (57 of 60 
evaluable patients). Notably, ORR was 100% (n = 18) in patients with chromosome 17p13.1 deletion.  Additional 
sub-analyses of patient subgroups from the ACE-CL-001 trial have reported that among study participants that 
were intolerant to treatment with ibrutinib (i.e., experienced ibrutinib-related AEs), the ORR was 76% (22 of 29 
evaluable patients), including 1 complete, 14 partial and 7 partial responses with lymphocytosis.  A median time 
of 3.7 months to at least partial response was observed.36 Additionally, in a sub-group of patients with Richter 
Transformation (n = 29), the ORR was 38%, with the median duration of response reported as 5.7 months.37 
The efficacy of acalabrutinib in patients with relapsed or refractory CLL was based upon a multicenter, 
randomized, open-label trial (ASCEND; NCT02970318). The trial enrolled 310 patients with relapsed or refractory 
CLL after at least 1 prior systemic therapy but excluded patients who had previous treatment with either 
venetoclax, a BTK inhibitor, or a phosphoinositide-3 kinase inhibitor. Patients were randomized in a 1:1 ratio to 
receive either: acalabrutinib 100 mg or Investigator’s choice of idelalisib plus a rituximab product (IR) or 
bendamustine plus a rituximab product (BR). Acalabrutinib monotherapy was found to significantly improve PFS 
with a more tolerable safety profile versus IdR/BR in R/R CLL patients.38 At a median follow-up of 16.1 months, 
PFS in the acalabrutinib arm vs the IdR/BR arm was significantly prolonged (median NR versus 16.5 months; HR 
0.31, 95% CI 0.20 - 0.49, P<0.0001). Twelve-month PFS rates were 88% vs 68% with acalabrutinib vs IdR/BR. ORR 
and 12-month OS rates were both similar with acalabrutinib and IdR/BR arms (ORR: 81% and 75%, 12-month OS: 
94% and 91%). The most common AEs with acalabrutinib were headache (22%), neutropenia (19%); diarrhea 
(18%), anemia and cough (15% each). Grade ≥3 AEs (≥5%) with acalabrutinib were neutropenia (16%), anemia 
(12%) and pneumonia (5%). AEs of interest were atrial fibrillation (5.2% on acalabrutinib vs 3.3% on IdR/BR), 
bleeding AEs (26% vs 7.2%), Grade ≥3 infections (15% vs 24%) and second primary malignancies (excluding NMSC; 
6.5% vs 2.6%).  
In the ELEVATE TN trial in treatment-naïve CLL patients with a median follow-up of 28 months acalabrutinib + 
obinutuzumab (O) significantly prolonged PFS vs O + chlorambucil (Clb) (median not reached [NR] vs 22.6 mo; HR 
0.10, 95% CI 0.06-0.18, P<0.0001), reducing the risk of progression or death by 90%. Acalabrutinib also prolonged 
PFS vs O + Clb (HR 0.20, 95% CI 0.13-0.31, P<0.0001). Estimated 30-mo PFS rates with acalabrutinib + O, 
acalabrutinib, and O + Clb were 90%, 82%, and 34%, respectively.39 
2.2.2 
Rationale for Acalabrutinib in AIHA 
Second-line therapy of AIHA with cytotoxic and immunosuppressive drugs such as azathioprine, 
cyclophosphamide, and cyclosporine is reported to provide a 40%-60% response rate, but their use is often 
associated with serious side effects.2,12,13  Anti-CD20 targeting with rituximab for the treatment of 

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relapsed/refractory AIHA achieves a 60-70% response rate, with a median duration of response of 19 months.40  
However, most of these patients inevitably relapse.  Although splenectomy remains an option in this setting, 
surgical morbidity and risk for serious infectious complications are inherent challenges to this treatment 
approach.2,4  Likewise, other treatment options such as plasmapheresis, and danazol have not proved effective.4  
Altogether, these findings highlight the need for novel treatment approaches, especially in CLL-associated AIHA 
where there is little prospective or retrospective data on these approaches and immunosuppression will have 
higher risks due to the already increased risk for infection in patients with CLL.   
Preclinical and preliminary clinical evidence strongly suggests that BTK inhibition modulates the immune system 
and may be efficacious in the treatment CLL-associated AIHA.10,16-18,24-26  A second generation BTK inhibitor, 
acalabrutinib, provides a novel approach to evaluate the impact of BTK inhibition on treating AIHA, as well as 
control the underlying autoimmune or lymphoproliferative disorder that may be driving AIHA.  Moreover, 
acalabrutinib has gained increasing favor as a second-generation BTK inhibitor with potentially fewer off-target 
effects leading to side effects such as bleeding and atrial fibrillation.29  This makes acalabrutinib an attractive 
option for treatment of AIHA.  The aim of this study is to investigate whether acalabrutinib will be effective in the 
treatment of relapse or refractory AIHA, and assess its effect on T-cell function in patients with CLL.   
2.3 Background for Correlative Studies 
Recent data suggests that ibrutinib increased CD4 and CD8 T-cell numbers, resulting in an increased Tcon/Treg 
ratio in CLL patients, but this effect was not observed with acalabrutinib.41  However, both ibrutinib and 
acalabrutinib reduced expression of PD-1 and CTLA-4, suggesting that an immunolodulatory effect may still be 
observed with acalabrutinib.  Thus, this study will evaluate the effects of acalabrutinib on T-cell populations.  
Particularly, these in vitro studies will measure T-cell activation across participant samples pre-acalabrutinib, then 
3 and 6 months after initiating therapy with acalabrutinib.  
2.4 Overview and Rationale of Study Design 
Refer to Section 12.0 Statistical Considerations for additional information regarding statistical methods used in 
this study. 
This is a single-arm, open label, phase II study to assess the efficacy of acalabrutinib in controlling relapsed or 
refractory AIHA in a setting of CLL.  Participants must meet the inclusion criteria, have none of the exclusion 
criteria, and have provided written informed consent before the conduct of any screening tests not performed 
routinely in their treatment. 
In this study, eligible participants will have a diagnosis of wAIHA or CAD (cold agglutinin disease) who had a 
recurrence, did not respond to, or did not tolerate at least one prior AIHA treatment with corticosteroid.  Eligible 
participants will be administered acalabrutinib (100 mg PO BID) daily for 12 cycles (each cycle is 28 days). 
Treatment with acalabrutinib may be continued beyond 12 cycles if the study participant might benefit from 
ongoing therapy in the opinion of treating physician (e.g., ongoing therapy for CLL is required); the maximum 
number of cycles allowed on this study in such situations is 36 cycles.  At the end of this treatment period (i.e. 
after acalabrutinib is discontinued), participants will be considered off-treatment and undergo follow-up 
evaluations in accordance with institutional standards (refer to Section10.0 Study Calendar).   
A total of 22 participants are planned for enrollment to this study over a period of 36 months.  After 6 patients 
are enrolled on study, investigators will discuss whether it is reasonable to continue accrual based on overall drug 
safety profile seen in the first 6 patients.  Further enrollment will be held if two or more patients (of the first 6 
patients) develop any grade 4 toxicity (assessed as possibly, probably,  or definitely related to study drug) during 
cycle 1 of treatment, or if ≥3/6 patients need to discontinue therapy with acalabrutinib during cycle 1 of treatment 
due to perceived lack of efficacy. Accrual will also be paused any time if any death possibly, probably, or definitely 
attributed to study treatment occurred.  

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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 
Age Criteria, Performance status 
__2. Age: ≥ 18 years 
__3. ECOG ≤ 2 
Nature of Illness and Illness Related Criteria 
__4. “Warm" or "cold" AIHA in patients with CLL, relapsed/refractory (RR) after first line treatment with oral 
prednisone (with or without rituximab), defined as: 
 
anemia (Hgb≤10 g/dL; or Hgb>10 g/dL dependent on transfusions or maintenance therapy (rituximab, 
cyclosporin, etc) to maintain this level of hemoglobin, and 
 
laboratory evidence of hemolysis – presence of 3 of 4 markers (increased reticulocyte count, increased indirect 
bilirubin, increased lactate dehydrogenase, absent haptoglobin)  
__5. Positive DAT (score ≥ 1+) – either IgG DAT, C3 DAT, or both. Eligibility of patients with Coombs-negative 
AIHA should be confirmed by the trial investigator at each respective study site. 
__6. Histologically or flow cytometry confirmed diagnosis of CLL/SLL 
__7. Participant must be able to swallow tablets or capsules. 
Clinical Laboratory and Organ Function Criteria (To be performed within 30 days prior to Day 1 of protocol therapy unless 
otherwise stated) 
__8. ANC ≥ 500/mm3 unless due to disease involvement in the bone 
marrow or autoimmune neutropenia. 
ANC: 
Date: 
__9. Platelets ≥ 30,000/mm3 unless due to disease involvement in the 
bone marrow or autoimmune thrombocytopenia (Evans 
syndrome). 
Plts: 
 
Date: 
__10. Direct bilirubin ≤ 3.0 X ULN, or 1 mg/dL, whichever is higher, if 
deemed related to hemolysis by the investigator. 
ULN: 
Bil: 
Date: 
__11. AST ≤ 3.0 x ULN 
ULN: 
AST: 
Date: 
__12. ALT ≤ 3.0 x ULN 
ULN: 
ALT: 
Date: 

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__13. Creatinine clearance of ≥ 30 mL/min per 24 hour urine test or the 
Cockcroft-Gault formula or  
 
Serum Cr: 
 
Cr Clearance: 
Date: 
__14. If not receiving anticoagulants: International Normalized Ratio 
(INR) OR Prothrombin (PT) < 2 x ULN 
If on anticoagulant therapy: PT must be within therapeutic range 
of intended use of anticoagulants 
ULN: 
INR: 
PT: 
Date: 
__15. If not receiving anticoagulants: Activated Partial Thromboplastin 
Time (aPTT) < 2 x ULN 
If on anticoagulant therapy: aPTT must be within therapeutic 
range of intended use of anticoagulants 
ULN: 
 
aPTT: 
Date: 
__16. Seronegative for HIV Ag/Ab combo, HCV*, active HBV (Surface 
Antigen Negative), and syphilis (RPR) 
*If positive, Hepatitis C RNA quantitation must be performed. 
HIV: 
HCV: 
HBV: 
Syphilis: 
Date: 
__17. Women of childbearing potential (WOCBP): negative urine or 
serum pregnancy test within the screening window prior to 
receiving the first dose of study medication. 
If the urine test is positive or cannot be confirmed as negative, a 
serum pregnancy test will be required 
Urine: 
Serum: 
Date: 
 
 
 
 
 
 
 
Contraception 
__18. Agreement by females of childbearing potential to use highly effective methods of birth control or abstain 
from heterosexual activity starting with the first dose of study therapy through 2 days after the last dose of 
protocol therapy.  
* 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.  therapeutic anticancer antibodies within 2 weeks;  
__2.  radio- or toxin-immunoconjugates within 10 weeks;  
__3.  BH3-mimetic venetoclax, PI3K inhibitors and other “targeted” therapy– within 6 half-lives;  
__4.  Ibrutinib, acalabrutinib or another BTK inhibitor within 12 months 
__5.  Patients on stable chronic AIHA treatments are allowed provided the dose has not changed in the 4 weeks 
prior to enrollment 
__6.  Allogeneic stem cell transplant within 1 year prior to Day 1 of protocol therapy, or ongoing 
immunosuppressive therapy for cGVHD 
__7.  Chemotherapy, radiation therapy, biological therapy, immunotherapy within 21 days prior to Day 1 of 
protocol therapy  

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__8.  Strong CYP3A4 inducers/ inhibitors. If the patient requires a strong CYP3A inhibitor/inducer, they should 
not be enrolled even if it could be held for 14 days before the first dose of study drug. 
__9.  Proton pump inhibitors (but patients who switch to H2-receptor antagonists or antacids are eligible for 
enrollment). 
__10.  Chronic use of corticosteroids (>2 weeks) in excess of prednisone 60 mg/day or its equivalent within 4 
weeks prior to start of study therapy. Rescue steroids are allowed during trial. 
__11.  Vitamin K antagonists 
Other illnesses or conditions 
__12.  Known intolerance to acalabrutinib 
__13.  History of bleeding disorders or with active bleeding. 
__14.  Patients with suspected or confirmed progressive multifocal leukoencephalopathy (PML) 
__15.  Patients with history of stroke or intracranial hemorrhage within 6 months. 
__16.  Inadequate recovery from adverse events related to prior therapy to grade 1 or baseline (excluding Grade 
2 alopecia and neuropathy).  
__17.  Active uncontrolled infection 
__18.  Known history of immunodeficiency virus (HIV) infection 
 
Subjects who have an undetectable or unquantifiable HIV viral load with CD4 > 300 and are on HAART 
medication are allowed. Testing to be done only in patients suspected of having infections or exposures. 
__19.  Active infection with hepatitis B virus (HBV) or hepatitis C virus (HCV). 
 
Participants who are hepatitis B core antibody (anti-HBc) positive and who are surface antigen negative will 
need to have a negative polymerase chain reaction (PCR).  Those who are hepatitis B surface antigen (HbsAg) 
positive or hepatitis B PCR positive will be excluded.  Note that IVIG administration may lead to positive anti-
HBc test result. 
 
Subjects who are hepatitis C antibody positive will need to have a negative PCR result.  Those who are hepatitis 
C PCR positive will be excluded. 
__20.  Major surgery (requiring general anesthesia) within 28 days prior to initiation of therapy. 
__21.  Has difficulty with or is unable to swallow oral medication, or has significant gastrointestinal disease that 
would limit absorption of oral medication. 
__22.  History of prior malignancy except: 
 
Malignancy treated with curative intent and no known active disease present for ≥ 2 years prior to initiation of 
therapy on current study;  
 
Adequately treated non-melanoma skin cancer or lentigo maligna (melanoma in situ) without evidence of 
disease;  
 
Adequately treated in situ carcinomas (e.g., breast, cervical, esophageal, etc.) without evidence of disease;  
 
Asymptomatic prostate cancer managed with “watch and wait” strategy;  
__23.  Significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart 
failure, or myocardial infarction within 6 months of screening, or any Class 3 or 4 cardiac disease as defined by 
the New York Heart Association Functional Classification, or left ventricular ejection fraction (LVEF) ≤ 40%. 
__24.  Psychiatric illness/social situations that would limit compliance with study requirements. 
__25.  Participant is pregnant or breastfeeding, or expecting to conceive or father children within the projected 
duration of the trial. 

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__26.  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 
__27.  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. 
 
 

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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 E) 
o Completed eligibility checklist (printed from Section 3.0 of the protocol) with required 
signature(s) 
o Signed Informed Consent  
o Signed HIPAA authorization form (if separate from informed consent) 
o Signed subject’s bill of Rights (California only) 
3. When all source documents are received, the DCC will review and work with the study team to resolve 
any missing elements. Any missing documents may delay review and registration.  A participant failing to 
meet all requirements will not be registered and the study team will be immediately notified. 
4. The DCC will send a Confirmation of Registration Form, including the Subject Study Number to:  
o The study team: Site Lead Investigator, treating physician/ sub-investigator, protocol nurse, CRC 
and pharmacy (as needed). 

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o The COH Study PI and COH study team designees (including but not limited to study monitor(s) 
and statistician(s)). 
5. 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 E) 
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-arm Phase 2 trial with acalabrutinib for patients with CLL with relapsed or 
refractory AIHA. Treatment will be administered on an out-patient basis (in-patient administration is allowed if 
deemed necessary by the Investigator). Participants will be followed at least every 4 months after removal from 
study drug until 12 months after end of treatment, introduction of next treatment (including standard-of-care BTK 
inhibitors) for AIHA or CLL, or death, whichever occurs first. 
5.2 Cycle Definition 
The treatment cycle will be 28 days. Cycle 1 Day 1 is defined as the first day of acalabrutinib administration, and 
should occur within 30 days of consent. The cycle day count will continue despite a hold in acalabrutinib 
administration due to toxicities (See Section 7.2). However, the next cycle will be delayed as long as acalabrutinib 
is held and will start once acalabrutinib is restarted. 
5.3 Treatment Plan 
Eligible participants enrolled in this study will receive acalabrutinib (100 mg PO BID) on an out-patient basis 
(however, treatment may also be given inpatient). On-study treatment with acalabrutinib will continue for up to 
12 28-day cycles. Participants will be considered off-treatment once study drug is permanently stopped.  
Treatment with acalabrutinib may be continued beyond 12 cycles, for a maximum of 36 cycles, if the study 
participant might benefit from ongoing therapy in the opinion of treating physician (e.g., ongoing therapy for CLL 
with R/R AIHA is required). Participants will be followed for an additional 12 months from time of last 
administration of study drug.  
 
5.4 Agent Administration 
Acalabrutinib capsules should be taken orally twice daily with 8 ounces (approximately 240 mL) of water. The 
capsules should be swallowed whole and participants should not attempt to open capsules or dissolve them in 
water.  If a dose is missed by more than 3 hours, participants should wait and take next dose at regularly scheduled 
time. Do not make up for missed dose. 
Participants will self-administer oral study agent, acalabrutinib, and are required to maintain a medication diary 
to assess compliance (refer to Appendix D).  Participants will receive instruction on how to administer study drug 
Regimen Description 
Agent 
Dose 
Route* 
Schedule 
Cycle Length 
Acalabrutinib  
100 mg 
PO, every 12 hours 
Continuous 
28 days 

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from a physician, clinical research nurse, or other designated, qualified healthcare provider.  Participants will be 
provided with a medical diary and are required to record the date, dose, and the time of the ingestion. 
5.5 Assessments and Special Monitoring 
For a detailed list of all study procedures including timing and windows, see Section 10.0.  
Note: Initiate a new cycle after all procedures/safety assessments have been completed. 
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 Completed protocol therapy (see Section 5.3) 
o AIHA relapse or progressive disease for CLL  
o Participant is deemed intolerant to protocol therapy because of toxicity, despite dose modification/ 
delay  
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 End of 
Treatment assessments, and then to follow-up (Refer to the Follow-Up section below). 
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 
All participants will enter follow-up after completing End of Treatment assessments (per Study Calendar in Section 
10.0 footnote d), until one of criteria in Section 5.8 below is met.  
Assessment time points and windows are detailed in Section 10.0. 
5.8 Duration of Study Participation 
Study participation may conclude when any of the following occur:  
o Completion of study activities (treatment and 12 months of follow-up after protocol treatment) 
o Withdrawal of consent (See Section 17.5) 
o Start of new therapy for either AIHA or CLL (including standard-of-care BTK inhibitors) 
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 
Medications required to treat AEs, manage cancer symptoms, concurrent diseases and supportive care agents, 
such as pain medications, anti-emetics and anti-diarrheals are allowed in general.  The participant must be told to 

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notify the investigational site about any new medications begun after the start of the study treatment.  Each 
participant’s medication and supplement profile should be reviewed by investigator and/or an oncology trained 
pharmacist to ensure compliance with this aspect of care. 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.  
5.9.2 
Prohibited medications, treatments and procedures 
Patients will not receive any other therapy for CLL besides the study therapy. 
Participants are prohibited from receiving the following therapies during screening and for the duration of their 
participation in this study: 
o Any anti-cancer systemic chemotherapy (e.g., bendamustine, cyclophosphamide, pentostatin, or 
fludarabine), or targeted agents (venetoclax, duvelisib, etc.)  
o Any immunotherapy (e.g., rituximab, GA101, alemtuzumab, or ofatumumab) 
o Bone marrow transplant or CAR T-cells 
o Any other experimental therapy, or radiation therapy while receiving acalabrutinib 
o Vitamin K antagonists (e.g., warfarin) 
5.9.3 
Cautionary medications, treatments and procedures 
Co-administration of acalabrutinib with a proton pump inhibitor should be avoided.  Co-administration of 
acalabrutinib with a strong or moderate CYP3A inhibitors 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 Table 5.9.1 for examples of proton pump inhibitors, and CYP3A inhibitor and inducers. 
Table 5.9.1. 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 ). 
5.10 Supportive care 
With the exception of prohibited therapies (refer to Prohibited therapies sub-section above), participants should 
receive prophylactic or supportive as clinically indicated per institutional policies. 

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5.10.1 Corticosteroids 
Participants are not permitted to be receiving chronic corticosteroids (>2 weeks within the 4 week period prior to 
first dose of study medication; at dosages equivalent to prednisone >60 mg/day) at time of screening and 
enrollment on to this study – see Section 3.2.  Concomitant use of corticosteroids for management of AIHA in 
conjunction with study drug is permitted at this dose, but it is anticipated that a taper will occur while patient is 
receiving acalabrutinib, and should be completed by the end of 8 weeks on study to a dose of ≤20 mg/day of 
prednisone or equivalent. The use of corticosteroids for treating AIHA should be in accordance with institutional 
standards.  
5.10.2 Infection prophylaxis and treatment 
Participants receiving acalabrutinib are at risk for infection, and appropriate prophylaxis in accordance with 
institutional standards is recommended.  In general, participants with documented infectious complication should 
receive oral or IV antibiotics or other anti-infective agents as considered appropriate by the Investigator for a 
given infectious condition, according to standard institutional practice.   
5.10.3 Nausea/vomiting 
No routine prophylactic anti-emetic treatment is required at the start of treatment; however, participants should 
receive appropriate anti-emetic treatment at the first onset of nausea or vomiting and as required thereafter per 
institutional guidelines.  
5.10.4 Diet 
Participants should maintain a normal diet unless modifications are required to manage an AE such as diarrhea, 
nausea or vomiting. 
5.10.5 Gastric acid reducing agents 
Co-administration of acalabrutinib and a proton pump inhibitor should be avoided. If treatment with a gastric acid 
reducing agent is required, investigators should consider using a H2-receptor antagonist (e.g., ranitidine or 
famotidine) or an antacid (e.g., calcium carbonate).   
In the case of antacids, acalabrutinib dosing should be separated by at least 2 hours.  For use of H2-receptor 
antagonists, acalabrutinib dosing should be taken 2 hours before administration of H2-receptor antagonist.   
5.10.6 Transfusions of platelets and red blood cells  
Platelet transfusions are permitted as medically necessary per institutional guidelines (e.g., for platelets 
<10,000/μL in the absence of clinical bleeding). Each transfusion event (and number of units given) will recorded 
in the CRF.   
Red blood cell transfusion should be considered for all participants with anemia, especially those with hemoglobin 
values ≤6 g/dL. Each transfusion event (and number of units given) will be recorded in the CRF. 
5.10.7 Anti-platelet agents and anticoagulants 
Use of vitamin K antagonists (e.g., warfarin) is prohibited while on study. 
Other anticoagulants (direct anticoagulants, heparin products) and antiplatelet agents may be used in participants 
who have controlled coagulopathy at baseline, as well as those who develop a coagulopathy on study.  Participants 
who develop a requirement for therapeutic anticoagulation while on study (e.g., new atrial fibrillation, or venous 
thrombosis) may stay on study, and will be carefully monitored for bleeding risks. 

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5.10.8 Tumor Lysis Syndrome 
Tumor lysis syndrome associated with CLL should be monitored (e.g., uric acid) and appropriate hydration 
measure and therapy with anti-hyperuricemic (e.g., allopurinol) should be performed as clinically indicated per 
institutional guidelines.  
5.10.9 Study Drug Overdose 
In the event of participant ingestion of more than the prescribed dosage of acalabrutinib (100 mg BID), 
observation for any symptomatic side effects should be instituted, and vital signs, biochemical and hematologic 
parameters should be followed closely (consistent with the protocol or more frequently, as needed).  Appropriate 
supportive management to mitigate adverse effects should be initiated per institutional guidelines.  If the 
overdose ingestion of acalabrutinib is recent and substantial, and if there are no medical contraindications, use of 
gastric lavage or induction of emesis may be considered.  Overdoses should be reported by the Investigator to the 
Sponsor and AstraZeneca as described in Section 14.4.1. 
6.0 ANTICIPATED ADVERSE EVENTS 
6.1 Acalabrutinib 
Per the Investigator Brochure edition 9.0 dated Feb 2020 32the expected toxicities for acalabrutinib are: 
System Organ Class 
Adverse Reactions 
Infections and infestationsa  
 
Very common 
 
Common 
Infectionb, upper respiratory tract infection, lower respiratory tract 
infectionc, urinary tract infection 
Herpesvirus infection 
Blood and lymphatic system disordersd  
 
Very common 
Neutropeniae, anemiaf, thrombocytopeniag, lymphocytosish 
Nervous system disorders  
 
Very common 
 
Rare 
Headache, dizziness 
Progressive multifocal leukoencephalopathy 
Gastrointestinal system disorders 
 
Very common 
Diarrhea, nausea 
Musculoskeletal and connective tissue disorders 
 
Very common 
Musculoskeletal paini, arthralgia 
Metabolism and nutrition disorders 
 
Rare 
Tumor lysis syndrome 
General disorders and administration site conditions 
 
Very common 
Fatiguej 
Skin and subcutaneous tissue disorders 
 
Very common 
Bruisingk, rashl 
Vascular disorders 
 
Very common 
Hemorrhagem 
Cardiac disorders 
 
Common 
Atrial fibrillation or flutter, hypertension 
Laboratory abnormality 
 
Very common 
Uric acid increase, ALT increase, AST increase, bilirubin increase 
Neoplasms, benign, malignant, and unspecified 

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System Organ Class 
Adverse Reactions 
 
Common 
Second primary malignancy, non-melanoma skin cancer 
a. Includes any adverse reactions involving infection or febrile neutropenia 
b. Upper respiratory tract infection, nasopharyngitis and sinusitis 
c. 
Includes pneumonia, lower respiratory tract infection, bronchitis, bronchiolitis, tracheitis, and lung infection 
d. Derived from adverse reaction and laboratory data 
e. Includes neutropenia, neutrophil count decreased, and related laboratory data 
f. 
Includes anemia, red blood cell count decreased, and related laboratory data 
g. Includes thrombocytopenia, platelet count decreased, and related laboratory data 
h. Includes lymphocytosis, lymphocyte count increased, and related laboratory data 
i. 
Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal pain, musculoskeletal discomfort, 
myalgia, neck pain, pain in extremity and spinal pain 
j. 
Includes asthenia, fatigue, and lethargy 
k. 
Includes bruise, contusion, and ecchymosis 
l. 
Includes rash, dermatitis, and other related terms 
m. Includes hemorrhage, hematoma, hemoptysis, hematuria, menorrhagia, hemarthrosis, and epistaxis 
Very common (≥1/10); Common (≥1/100 to <1/10); Uncommon (≥1/1,000 to <1/100); Rare (≥1/10,000 to <1/1,000); Very rare 
(<1/10,000); not known (cannot be estimated from the available data). 
The important risks of acalabrutinib are the following: 
Hemorrhage 
Serious hemorrhagic events, including central nervous system, respiratory, and gastrointestinal hemorrhage, have 
been reported in clinical trials with acalabrutinib; some of these bleeding events resulted in fatal outcomes.  Grade 
3 or higher bleeding events, including gastrointestinal, intracranial, and epistaxis have been reported in 2% of 
patients. Overall, bleeding events including bruising and petechiae of any grade occurred in approximately 50% of 
patients with hematological malignancies. 
The mechanism for hemorrhage is not well understood.  Acalabrutinib may further increase the risk of 
hemorrhage in patients receiving antiplatelet or anticoagulant therapies and patients should be monitored for 
signs of bleeding.  Consider the benefit-risk of withholding acalabrutinib for 3-7 days pre- and post-surgery 
depending on the surgery and the risk of bleeding.   
Infections 
Serious infections (bacterial, viral or fungal), including fatal events and opportunistic infections, have been 
reported in clinical studies with acalabrutinib.  The most frequently reported Grade 3 or 4 infection was 
pneumonia.  Across the acalabrutinib clinical development program (including subjects treated with acalabrutinib 
in combination with other drugs), cases of hepatitis B virus (HBV) reactivation (resulting in liver failure and death 
in 1 case) and cases of progressive multifocal leukoencephalopathy have occurred in subjects with hematologic 
malignancies.  Monitor patients for signs and symptoms of infection and treat as medically appropriate. 
Cytopenias 
Treatment-emergent Grade 3 or 4 cytopenias including neutropenia, anemia, and thrombocytopenia have 
occurred in clinical studies with acalabrutinib.   Subjects should be closely monitored as appropriate. 
Second primary malignancies 
Second primary malignancies, including solid tumors and skin cancers, have been reported in patients treated 
with acalabrutinib.  The most frequent 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 

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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 primary investigator. 
Atrial fibrillation 
Events of atrial fibrillation/flutter have been reported in clinical studies with acalabrutinib, particularly in subjects 
with cardiac risk factors, hypertension, diabetes mellitus, acute infections, and a previous history of atrial 
fibrillation. The mechanism for atrial fibrillation is not well understood. 
7.0 DOSE DELAY / MODIFICATION GUIDELINES 
7.1 Dose Delays 
Any toxicity observed during the course of the study could be managed by an interruption of the study drug 
treatment.  Repeat dose interruptions are allowed as required, for a maximum of 4 weeks on each occasion. Please 
refer to Tables 7.2.1 and 7.2.2 for dosing delays and modifications. 
In general, dosing interruptions are permitted in the case of medical / surgical events or logistical reasons (i.e., 
elective surgery, unrelated medical events) not related to study therapy.  Participants should be placed back on 
study therapy within 4 weeks of the scheduled interruption, unless otherwise discussed with the investigator.  The 
reason for interruption should be documented in the participant's study record. 
7.2 Dose Modifications 
Please refer to Acalabrutinib Investigator Brochure edition 9.032 for dosing delays and modifications. 
Unavoidable use of strong CYP3A inhibitor or inducer may also require a reduction or increase of acalabrutinib 
dose (refer to Table 7.2.2). 
Table 7.2.1 Recommended Dose Modifications for Adverse Reactions 
Event 
AE Occurrence 
Dose Modification 
Grade 3 or greater non-hematologic 
toxicities, 
 
Grade 3 thrombocytopenia 
with bleeding, 
Grade 4 thrombocytopenia 
or 
Grade 4 neutropenia lasting 
longer than 7 days 
1st or 2nd occurrence:  
Interrupt acalabrutinib until resolved to 
Grade 1 or baseline and resume at 100 mg 
PO BID. 
3rd occurrence: 
Interrupt acalabrutinib until resolved to 
Grade 1 or baseline and resume at 100 mg 
PO once daily (QD) 
4th occurrence: 
Discontinue study drug. Remove participant 
from study 
Table 7.2.2 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 QD 
Induction 
Strong CYP3A inducer 
Avoid concomitant use. 
If these inducers cannot be avoided, increase acalabrutinib 
dose to 200 mg BID. 
*Refer to Section 5.9 for examples of CYP3A inhibitor and inducers 
 

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8.0 AGENT INFORMATION 
8.1 Acalabrutinib (Calquence, ACP-196) 
Acalabrutinib has been FDA approved for adult patients with CLL or SLL or mantle cell lymphoma (MCL) with have 
received at least one prior therapy. 
8.1.1 
Description 
Structural Formula 
 
Molecular Formula 
C26H23N7O2 
Molecular Weight 
465.51 kDa 
 
Acalabrutinib is a white to yellow powder with pH-dependent solubility. It is freely soluble in water at pH values 
below 3 and practically insoluble at pH > 6.  Acalabrutinib supplied as yellow and blue hard capsules for oral 
administration, where each capsule contains 100 mg acalabrutinib and the following inactive ingredients: silicified 
microcrystalline cellulose, partially pregelatinized starch, magnesium stearate, and sodium starch glycolate.  The 
capsule shell contains gelatin, titanium dioxide, yellow iron oxide, FD&C Blue 2 and is imprinted with edible black 
ink stating “ACA 100 mg”. 
8.1.2 
Mechanism of action 
Acalabrutinib is a small-molecule inhibitor of BTK. Acalabrutinib and its active metabolite, ACP-5862, form a 
covalent bond with a cysteine residue in the BTK active site, leading to inhibition of BTK enzymatic activity. BTK is 
a signaling molecule of the B cell antigen receptor (BCR) and cytokine receptor pathways. In B cells, BTK signaling 
results in activation of pathways necessary for B-cell proliferation, trafficking, chemotaxis, and adhesion. In 
nonclinical studies, acalabrutinib inhibited BTK-mediated activation of downstream signaling proteins CD86 and 
CD69 and inhibited malignant B-cell proliferation and tumor growth in mouse xenograft models. 
8.1.3 
Pharmacokinetics and Metabolism 
Half-life: 1 hr acalabrutinib, 3.5 h ACP-5862 
Distribution: Highly bound to plasma protein 
Metabolism: Predominantly metabolized by CYP3A enzymes; ACP-5862 is a major metabolite 
Excretion: 84% feces, 12% urine 

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8.1.4 
Toxicology 
See Section 6.1 for detailed list of anticipated AEs. 
8.1.5 
Storage 
Store at 20°C-25°C (68°F-77°F).  Excursions are permitted to 15°C-30°C (59°F-86°F). 
8.1.6 
Handling 
National Institute for Occupational Safety and Health (NIOSH) recommends the use of single gloves by anyone 
handling intact tablets or capsules or administering from a unit-dose package.  Use caution when handling 
acalabrutinib, avoid eye or skin contact with the drug product.  If there is exposure to the drug product, the 
individual should be treated for physical exposure (skin washing) or inhalation (move to fresh air, as necessary), 
and, if needed, seek medical advice. 
8.1.7 
Administration 
See Section 5.4 
8.1.8 
Supplier 
Acalabrutinib will be supplied by the manufacturer, Astra Zeneca, and prepared by the local site pharmacy per 
manufacturer instructions.  Following submission and approval of the required regulatory documents, a supply of 
acalabrutinib may be ordered from Astra Zeneca by completing a Drug Request Form. 
8.1.9 
Accountability 
The Investigator, or a responsible party designated by the Investigator, must maintain a careful record of the 
inventory and disposition of the study agent. (See the NCI Investigator’s Handbook for Procedures for Drug 
Accountability and Storage).   
Responsibility for drug accountability at the study site rests with the Investigator; however, the Investigator may 
assign some of the drug accountability duties to an appropriate pharmacist or designee. Inventory and 
accountability records must be maintained and readily available for inspection by the study monitor and are open 
to inspection at any time by any applicable regulatory authorities or other oversight bodies. 
The Investigator or designee will collect and retain all used, unused, and partially used containers of study 
medication until full accounting has been completed. The Investigator or designee must maintain records that 
document: 
• 
Investigational product delivery to the study site. 
• 
The inventory at the site. 
• 
Use by each participant including pill/unit counts from each supply dispensed. 
• 
Return of investigational product to the Investigator or designee. 
• 
Destruction or return of investigational product for final disposal. 
These records should include dates, quantities, batch/serial numbers (if available), and the unique code numbers 
(if available) assigned to the investigational product and study participants. 
The investigational product must be used only in accordance with the protocol. The Investigator will also maintain 
records adequately documenting that the participants were provided the correct study medication specified. 
Completed accountability records will be archived by the site. At the completion of the study, the Investigator or 
designee will oversee shipment of any remaining study drug back to Astra Zeneca for destruction according to 
institutional standard operating procedures. If local procedures mandate site destruction of investigational 
supply, prior written approval must be obtained from Astra Zeneca. 

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8.1.10 Destruction and Return 
At the end of the study, or earlier upon approval from study management, unused supplies of study drug should 
be destroyed according to institutional policies.  Drug supplies will be counted and reconciled in full at the site 
with all monitoring procedures complete before destruction.  Destruction will be documented in the Drug 
Accountability Record Form. 
9.0 CORRELATIVE/ SPECIAL STUDIES 
The exploratory objectives of this study are to evaluate the T-cell repertoire in participants with AIHA-associated 
CLL that receive acalabrutinib.  The effects of acalabrutinib treatment on T-cell repertoire will be evaluated by 
flow cytometry. Plasma cytokine level will be measured by relevant methods (for example, ELISA Research Sample 
Collection and Dispensation 
9.1.1 
Correlative blood 
9.1.1.1 Overview and Time points 
Peripheral blood will be collected prior to study treatment/procedures at the time points indicated in Table 9.1.2.1 
Table 9.1.2.1 Overview of correlative blood studies 
Time points of 
collection 
Total 
volume 
collected 
Tube type 
Receiving 
laboratory 
Type of analysis 
C1D1, C4D1, C7D1, 
C13D1 
15-20 ml 
Green-top (sodium or lithium 
heparin) 
Investigator 
Laboratory 
FACS/Cytokine 
 
9.1.1.2 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. 
9.1.1.3 Collection and post-collection guidelines 
Refer to Table 9.1.2.3 for collection and post-collection instructions. 

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Table 9.1.2.3 Blood sample collection and post-collection instructions. 
Tube Type 
Collection details 
Site of 
collection 
Post-collection instructions 
Green-top 
1- Blood samples will be collected 
from an indwelling venous catheter or 
by venipuncture. 
2- Invert tubes eight times after 
collection. 
3- Immediately place the tubes on ice. 
COH 
Only 
Promptly deliver the blood samples for 
processing within 4 hours to: 
Alexey Danilov Laboratory 
Kaplan Clinical Research Bldg 1st Floor, 158-
1022 
City of Hope National Medical Center  
1500 E Duarte Rd, Duarte, CA. 
OSU 
Site Only 
Promptly deliver the blood samples for 
processing within 4 hours to: 
Kerry Rogers Laboratory 
Ohio State University  
460 West 10th Ave 
Columbus, OH 
MDACC 
Site Only 
Ship whole blood samples on day of collection 
overnight at room temp to: 
Alexey Danilov Laboratory 
Kaplan Clinical Research Bldg 1st Floor, 158-
1022 
City of Hope National Medical Center  
1500 E Duarte Rd, Duarte, CA 91010. 
 
Please refer to Appendix F and Appendix G 
Peripheral blood mononuclear cells (PBMCs) and plasma will be separated by density gradient centrifugation.  
Cells will be frozen and stored in liquid nitrogen.  Plasma will be stored at -70°C.  
9.2 Laboratory Studies Performed 
Flow cytometry will be used to evaluate leukocyte subpopulations (e.g., CD3, CD4, CD45, TCRγδ, CD14, CD16, 
CD56). Additional surface markers will be used to discriminate different maturation stages of effector cells (CD28, 
CD27, CD45RA, CD3, CD8, CCR7, CD4, CD45): naive T cells, central memory, effector memory and CD45RA 
expressing effector memory cells; Tregs (CD4+CD25+FoxP3+CD127low); Th17 (IL-17positive). To assess activation 
levels of circulating T-cells, a panel of activation markers will be used (e.g., CD38, CD25, CD69, HLA-DR). The 
immunology panel may be expanded to include other markers. Plasma cytokine levels will be measured by ELISA. 
  

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. 
Treatment or Assessment (± 7 days)a 
Screeningb 
Cycle 1 
C2-3 
C4 
C5-6 
C7 
C8-12 
C13 & every 
3 Cyclesc 
EoTd 
Follow-upe 
D1 
D8 
D15 
D22 
D1 
D1 
D1 
D1 
D1 
D1 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical historyg  
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteriah 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Registrationi  
X 
 
 
 
 
 
 
 
 
 
 
 
 
Other anti-cancer treatmentj. 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Concurrent med review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Physical examl 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Vital signsm 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
ECOG Performance Status (Appendix A)  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Adverse Event Evaln 
 
X 
12-lead EKGoa 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy testp 
X 
X 
 
 
 
 
 
 
 
 
 
X 
 
Hematologyq 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Biochemistryr 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum Immunoglobulinss 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
Hemolysis parameterst 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PT, aPTT, INR 
X 
 
 
 
 
 
 
 
 
 
 
 
 
HBsAg, HBcAb, HCVAb, RPR 
X 
 
 
 
 
 
 
 
 
 
 
 
 
HIV test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
CT Imaging and CLL assessment (Appendix C)u 
X 
 
 
 
 
 
 
 
X 
 
X 
 
 
Bone Marrow Biopsyv 
 
 
 
 
 
 
 
 
 
 
X 
 
 
AIHA disease assessment (Appendix B) 
X 
 
 
 
 
 
X 
 
X 
 
X 
 
X 

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Molecular and Genetic Testsw 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Acalabrutinibx 
 
Orally, every 12 hours 
 
 
Medication diaryy 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Research blood collectionz 
 
X 
 
 
 
 
X 
 
X 
 
X 
 
 
a. Ideally the clinic visit and all the study requirements should be performed on Day 1 of each cycle as indicated, but may be performed within 7 days before or after 
the scheduled day. Each treatment cycle is 28 days 
b. Screening activities to occur within 30 days prior to the start of protocol therapy. 
c. 
Protocol therapy may last up to 12 cycles, until unacceptable toxicity or disease progression (see Section 5.6 for more comprehensive list). At the end of 12 cycles, 
treatment with acalabrutinib may be continued if the study participant might benefit from the ongoing therapy in the opinion of the treating physician. 
d. An End of Treatment (EOT) visit is required for safety assessments for any subjects who permanently discontinue study drug for any reason, including disease 
progression.  This visit should occur at 30 (±7) days from time of the last dose of study drug to monitor for resolution or progression of AEs and to document the 
occurrence of any new events, regardless of whether the subject receives a new CLL therapy or demonstrates disease progression within this timeframe  Subjects 
who withdraw consent for study treatment should still be encouraged to complete the EOT assessments, but these assessments cannot be mandated if subject 
consent for further study participation is withdrawn. 
e. Follow-up assessment are to occur in accordance with standard of care, with participants visits occurring at least every 4 months, up to 12 months from time last 
dose of study drug. 
f. 
Informed consent process to be fully documented (see Section 17.4). Informed consent must occur prior to any research only (non-SOC) screening procedures. 
g. 
A medical history will be obtained by the investigator or qualified designee. To include information on demographics, all active conditions, and any condition 
diagnosed within the prior 10 years that are considered to be clinically significant by the Investigator.  Details regarding the participant’s cancer will be recorded 
separately and not listed as medical history. 
h. Eligibility criteria are detailed in Section 3.0. 
i. 
Registration into a COH clinical trial management system (CTMS) 
j. 
Document the following disease-specific information: number of prior treatment regimens for CLL and AIHA; drugs previously used in the therapy of CLL and AIHA; 
including (if available): therapy dates, and response, concomitant autoimmune disorders, including hematologic (immune thrombocytopenia, immune-mediated 
neutropenia) and non-hematologic (e.g., rheumatoid arthritis and other rheumatologic conditions; inflammatory bowel disease [Crohn’s disease, ulcerative colitis]), 
History of ibrutinib intolerance (present versus not), Rai stage at diagnosis (if known) and the time of study entry. 
k. 
Current list of medications will be acquired concurrent with medical history. See Section 5.9 for concomitant medication restrictions and guidelines. Baseline 
transfusion requirements must be assessed prior to start of study drug. Transfusion requirements prior to study start up to 6 months will be collected/documented, 
if available. Transfusion requirement will be assessed on day 1 of each cycle and number of units of PRBCs and platelets transfused during the previous cycle will be 
documented. Enter new medications started during the trial through the end of treatment visit. Record all medications taken for grade 3 and 4 SAEs. 
l. 
Physical examination must be performed by a medically qualified individual such as a licensed physician, Physician’s Assistant or advanced Registered Nurse 
Practitioner as local law permits. Baseline complete physical exam per institutional standards and may include evaluating: weight, general appearance, head, ears, 
eyes, nose, throat, neck, skin, cardiovascular system, respiratory system, gastrointestinal system, and nervous system.  Height is only required as part of screening. 
Weight should be recorded at each visit. More extensive physical exams will be performed if guided by the development of new symptoms.  
m. Vital signs: blood pressure, heart rate, temperature, and oxygen saturation by pulse oximetry.  

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n. Adverse events will be assessed using the CTCAE v5.0 (non-hematologic) and IWCLL 2018 (hematologic). SAEs related to study procedures will be recorded and 
reported from the time the participant signs the Consent Form.  Please see Section 14 for routine AE assessing and reporting (Section 14.6) and SAE reporting 
(Section 14.7).  
o. Electrocardiogram (ECG): resting 12-lead ECGs will be recorded at screening, and as clinically indicated throughout the study. 
p. A serum or urine pregnancy test is required during screening for women of childbearing potential. If urine pregnancy results cannot be confirmed as negative, a 
serum pregnancy test is required. For Day 1 Cycle 1, a pregnancy test may be omitted if previously obtained within 72 hours prior to first dose of trial treatment.  
Pregnancy tests (serum and/or urine tests) should be repeated, if required, per institutional guidelines. A serum or urine pregnancy test will be done for women of 
childbearing potential any time for missed or late menses, and at the end of treatment.  If the urine pregnancy test is positive, a serum pregnancy test must be 
performed per institutional standards.  
q. Hematology: Hemoglobin; hematocrit; mean corpuscular volume (MCV); reticulocyte count (absolute and relative); leukocyte count; differential count; platelets.  
Additional hematology may be performed thereafter as clinically indicated 
r. 
Biochemistry: Comprehensive metabolic panel (CMP), including: Na, K, Cl, CO2, BUN, Creatinine, Ca, glucose, Albumin, Alkaline Phosphatase, total bilirubin, AST, ALT, 
total protein. 
s. 
Serum immunoglobulins, IgG, IgM, and IgA are required at screening and on cycle 13 D1.  
t. 
Hemolysis parameters: Reticulocytes, lactate dehydrogenase (LDH), bilirubin (direct/indirect), haptoglobulin and DAT. 
u. Computed tomography (CT) scan of neck, chest, abdomen and pelvis per institutional guidelines (with intravenous contrast, wherever possible) will be performed for 
response assessment at screening, C7D1, C13D1 and annually thereafter. CLL response will be evaluated every time imaging is performed. A bone marrow biopsy will 
be performed only if CR is suspected.  Positron emission tomography with CT (PET-CT) and/or magnetic resonance imaging studies may be performed as clinically 
indicated, per institutional guidelines, and is acceptable in place of CT, if performed.   
v. 
Bone Marrow Biopsy - A bone marrow biopsy will be performed to document CR within 90 days of the imaging test where CR was suspected. - A bone marrow biopsy 
may be performed at screening per investigator discretion, but is not required. 
w. Molecular and Genetic Assays: testing results are not required to proceed with study enrollment.  Cellular and molecular assays will be performed according to 
institutional standards, at screening on specimens obtained within 6 months if no intervening therapy. The following assays will be planned as per standard of care: 
CLL FISH Panel (as per institutional standards), immunoglobulin heavy chain (IGVH) mutational status (unless already known), prognostic gene panel (e.g., HopeSeq 
panel performed at COH). 
x. 
Participants will self-administer oral study agent, acalabrutinib. Participants will receive instruction on how to administer study drug from a physician, clinical 
research nurse, or other designated, qualified healthcare provider 
y. 
Assessment of study agent adherence.  Participants will be provided with a medical diary (Appendix D) and are required to record the date, dose, and the time of the 
ingestion. This will be reviewed at each clinic visit to assess compliance. 
z. 
Research blood may be collected as part of any planned blood draw that is performed per institutional standard. 
 

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 Primary Endpoint(s) 
Objective 
Endpoint 
Start  
End  
Assess the efficacy of acalabrutinib 
in CLL patients with relapsed or 
refractory AIHA 
AIHA ORR after 6 cycles [ORR defined as 
proportion of patients who achieve 
complete and partial response; refer to 
Appendix B ] 
First dose of 
study drug [i.e. 
C1 Day 1] 
After 6 cycles  of 
therapy 
Primary endpoint of AIHA ORR after 6 cycles will be defined as the proportion of patients achieving AIHA 
complete or partial response after 6 cycles. Patients evaluable for this endpoint include: 1) those who 
receive at least 6 cycles of treatment and have AIHA response evaluation after 6 cycles (each cycle = 28 
days); 2) patients who terminate acalabrutinib prior to completing 6 cycles due to AIHA or CLL progressive 
disease (they will be counted as non-responders).  
11.1.1 Response Criteria for AIHA 
See Appendix B: AIHA Response Criteria 42for the definition of clinical response for AIHA. 
11.2 Secondary Endpoint(s) 
Objective 
 
Endpoint 
Start  
End  
Evaluate acalabrutinib’s 
ability to induce short term 
and sustained hemoglobin 
response 
AIHA ORR after 3 and 12 cycles 
First dose of study 
drug [i.e., C1 Day 
1] 
After 12 cycles of 
treatment  
Frequency of PRBC transfusion 
while receiving acalabrutinib 
Up to 30 days after last 
dose 
AIHA-specific Relapse-Free Survival 
(RFS) 
Until time of AIHA relapse, 
death, or end of follow-up, 
whichever occurs first. 
[up to 12 months after the 
last dose of study drug] 
AIHA Sustained Response 
Assess the toxicity of 
acalabrutinib  
Incidence and type of treatment-
related toxicity [per CTCAE v5.0 and 
IWCLL 2018 criteria1]  
Up to 30 days after last 
dose of study drug 
Evaluate efficacy of 
acalabrutinib in CLL 
CLL ORR after 6, 12 cycles, per 
standard IWCLL criteria 
First dose of study 
drug [i.e., C1 Day 
1] 
After 6 or 12 cycles from 
treatment start  
CLL-specific event-free survival (EFS) 
Until time of progression, 
death, start of new 
therapy, or end of follow-
up, whichever occurs first. 
[up to 12 months after the 
last dose of study drug] 
Duration of CLL response 
When CR/PR is 
first documented 
AIHA ORR after 3 and 12 cycles: it will be defined as the proportion of patients achieving AIHA CR/PR after 
3 or 12 cycles respectively. Patients evaluable for this endpoint include: : 1) those who receive at least 3 
or 12 cycles of acalabrutinib treatment and have AIHA response evaluation after 3 or 12 cycles; 2) patients 

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who terminate acalabrutinib prior to completing 3 or 12 cycles due to relapse of AIHA or CLL progressive 
disease (they will be counted as non-responders). 
Frequency of PRBC transfusion: it will be defined as the number of PRBC transfusions from start of 
protocol treatment through EOT. 
AIHA-specific Relapse-Free Survival (RFS): it will be defined as the time from start of acalabrutinib 
treatment until death, or relapse of AIHA.42 Patients without death, or AIHA relapse will be censored at 
the last follow-up or when they begin new therapy for CLL or AIHA. Relapse of AIHA will be determined 
by the investigator. A minimal requirement is Hgb<10 g/dL and evidence of hemolysis per laboratory 
parameters. Investigators will document the criteria by which relapse was assessed. 
Toxicity: incidence, type, severity, and attribution of toxicities on the study will be assessed by CTCAE v5.0 
(non-hematologic) and IWCLL 2018 (hematologic). All patients who receive at least 1 dose of acalabrutinib 
will be included in the toxicity analysis.  
CLL ORR after 6 or 12 cycles: it will be defined as the proportion of patients achieving CLL CR /PR after 6 
or 12 cycles respectively. Patients evaluable for this endpoint include: 1) those who receive at least 6 or 
12 cycles of acalabrutinib and have a CLL response evaluation at those timepoints; 2) patients who 
terminate acalabrutinib treatment prior to completing 6 or 12 cycles due to CLL progressive disease (they 
will be counted as non-responders).  
CLL-specific Event-free Survival (EFS): it will be defined as the time from start of acalabrutinib treatment 
until death, time of CLL progression, or start of new therapy for CLL, whichever earlier. Patients without 
death, CLL recurrence/progression, or start of new therapy for CLL will be censored at the last follow-up. 
Duration of CLL-response: it will be estimated among patients who achieve CLL CR/PR on protocol 
treatment. It will be defined as the time from the first documented CLL CR/PR until death, time of CLL 
recurrence/progression, or start of new therapy for CLL, whichever earlier. Patients without death, CLL 
recurrence/progression, or start of new therapy for CLL will be censored at the last follow-up. 
AIHA sustained response: it will be estimated among patients who achieve AIHA CR/PR on protocol 
treatment. It will be defined as the time from the first documented AIHA CR/PR until death or relapse of 
AIHA, whichever is earlier. Patients without death or AIHA relapse will be censored at the last follow-up 
or when they begin new therapy for AIHA or CLL. 
11.2.1 Response Criteria for AIHA and for CLL 
See Appendix B: AIHA Response Criteria for the definition of clinical response for AIHA.  
CLL response will be determined per the investigators’ assessment, according to Hallek et al1 (see 
Appendix C: CLL/SLL Response Criteria).  Response assessments are to coincide with CT measurements.   
11.2.2 CLL Evaluation 
Physical examination – physical exams will focus on documenting a change in the number of sites and 
sizes of lymphadenopathies, hepatomegaly and splenomegaly at the scheduled time points defined 
above.  More extensive physical exams will be performed if guided by the development of new symptoms.  
CBC – white blood cell count, hemoglobin and hematocrit, platelet count, and differential count, including 
both percent and absolute number of lymphocytes. CBC with differential should be assessed at schedule 
time points defined above.  
CT scan of neck, chest, abdomen and pelvis with contrast, will be performed at scheduled time points 
defined above.   

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11.3 Exploratory Endpoint(s) 
Objective 
Endpoint 
Start  
End  
Assess the effect of 
acalabrutinib on T-cell 
functionality in an 
autoimmune disorder. 
Percentage of T-cell subsets 
among study participants 
Baseline values (prior 
start of study 
therapy) 
After 3, 6 and 12 
cycles 
 
 
12.0 STATISTICAL CONSIDERATIONS 
12.1 Study Design 
This is a Phase 2, single-arm, open-label study to assess the efficacy and safety of acalabrutinib in the 
treatment of CLL patients with AIHA. Refer to Section 2.4 Overview and Rationale of Study Design for a 
detailed description of the study design and endpoints. 
12.2 Sample Size and Power 
For warm AIHA, initial treatment with prednisone is associated with responses in 70%-85% of patients; 
however, even this is short-lived as only 15% to 20% of patients achieve long-term remission upon 
withdrawal of corticosteroids.4 Subsequent lines of immunosuppressive therapy (e.g., cyclophosphamide, 
rituximab) carry initial response rates from 40-60%, but durable responses occur in only 20% to 30% 
treated patients.2,12,13  
A sample size of 20 achieves an approximate 87% power using a one-sided binomial exact test with a 
significance level (alpha) of 0.05 for detecting improvement of 0.3 (0.6 from 0.3) in response rate , based 
upon the assumption that a response of 30% or less indicates no benefit.  The actual type I error is 0.048 
and the exact binomial test will require 10 or more responders in 20 patients evaluable for the primary 
endpoint to reject the null hypothesis of 0.3. Anticipating up to 10% patients not evaluable for the primary 
endpoint, a total of 22 participants will be enrolled.  
Study enrollment is anticipated to occur over 36 months at a rate of approximately 7 patients per year 
12.2.1 Analysis Populations 
The evaluable patients for the clinical endpoints will be eligible participants who received at least 1 dose 
of protocol treatment, unless otherwise specified in Section 11.1 under the specific/particular endpoint. 
The evaluable patients for the exploratory endpoints will be eligible participants who received at least 1 
dose of protocol treatment and has at least 1 correlative blood specimen collected on the study.  
12.3 Study Stopping Rules 
The overall study will be paused if any of the following occurs: 
o  ≥2 of the first six participants develop any grade 4 toxicity (assessed as possibly, probably,  or 
definitely related to study drug) during cycle 1 of treatment, or  
o  ≥3 of the first 6 participants need to discontinue therapy with acalabrutinib during cycle 1 of 
treatment due to perceived lack of efficacy, or 
o Death with possible or higher attribution to acalabrutinib. 

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12.4 Statistical Analysis Plan  
For continuous variables, descriptive statistics will include the mean, standard deviation (or standard 
error), median, range, and interquartile range.  Frequencies and percentages will be displayed for 
categorical data.  Percentages by categories will be based on the number of participants with no missing 
data (i.e. will add up to 100%). Kaplan-Meier survival curves will be displayed for time-to-event variables. 
Survival at specific timepoint will be estimated by the Kaplan-Meier product limit estimator along with 
the Greenwood estimator of standard error; 95% confidence interval will be constructed based on log-log 
transformation.  Median survival time will be estimated when available, along with 2-sided 95% 
confidence interval (CI) based on Brookmeyer and Crowley method. 
12.4.1 Analysis of Primary Endpoint 
The probability of having AIHA-ORR at 6 cycles will be measured and reported with 95% exact confidence 
interval (CI).  An exact binomial test against a null hypothesis of 30% rate will be performed at the 1-sided 
alpha of 0.05 to determine whether the AIHA-ORR rate at 6 cycles is disappointing or promising.  
12.4.2 Analysis of the Secondary Endpoints  
The probability of having AIHA-ORR at 3 or 12 cycles will be measured and reported with 95% exact 
confidence interval.  AIHA-specific RFS will be estimated using Kaplan-Meier methods along with 95% 
confidence interval. 
The CLL-ORR after 6 and12 cycles will be assessed and reported with 95% CI.  The Kaplan-Meier method 
will be used to estimate CLL-specific PFS and DOR, and the summary statistics (e.g., 12-month survival, 
median survival, 95% confidence intervals) will be provided.  DOR will be estimated only among 
responders (i.e. participants achieving CLL CR/PR at least once).   
The frequency of PRBC transfusion will be summarized by descriptive statistics. The difference between 
the average number of PRBC transfusion per month during protocol treatment vs. the average number of 
PRBC transfusion at baseline (in the past 6 months before protocol treatment, if available) will be assessed 
by paired t-test.  
Toxicity events will be tabulated and summarized using descriptive statistics such as count and 
percentages, by severity, attribution, and system organ class according to the CTCAE v5.0 (non-
hematologic) and by severity according to IWCLL 2018 (hematologic). 1 
12.4.3 Analysis of the Exploratory Endpoint(s)  
Flow cytometry will be used to assess T-cell repertoire and evaluate changes associated with 
acalabrutinib.  The distribution of T-cell subtypes distribution will be described by mean, standard 
deviation (SD), minimal, and maximal values.  Comparison of group variables will be as assessed using a 
nonparametric test of independence (e.g., Chi-square test or Fisher’s exact test).  
12.5 Handling of Missing Data 
Every attempt will be made to obtain data at the defined time points as described in the primary and 
secondary endpoints.  If the data are not sufficient to analyze specific endpoints, the participant’s data 
may be excluded entirely or partially, depending on the specific endpoints in question.  No missing data 
will be imputed.  Whenever possible, all available data will be included in the analysis.  A sample size for 
each analysis will be clearly stated along with the reason for exclusion, if any participant is excluded from 
the analysis due to missing data. 

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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  
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 

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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, 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 the most recent version of the 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. 
o 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 clinical state, other 
therapeutic interventions or concomitant drugs administered to the participant. 
o 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. 
o 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. 
o 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 
medications. 
o Unrelated - The event is clearly NOT related to the study treatment, and is clearly related to 
other factors such as the participant’s clinical state, other therapeutic interventions, or 
concomitant medications administered. 
14.2 Adverse Events of Special Interest (AESI) 
The following events are adverse events of special interest (AESIs) for participants exposed to 
acalabrutinib, and must be reported to the sponsor and manufacturer expeditiously, irrespective of 
regulatory seriousness criteria or causality: 
o Ventricular arrhythmias (e.g., ventricular extrasystoles, ventricular tachycardia, ventricular 
arrhythmia, ventricular fibrillation, etc.)] 
14.2.1 Overdose 
On a per dose basis, an overdose is defined as the following amount over the protocol-specified dose of 
acalabrutinib assigned to a given patient, regardless of any associated adverse events or sequelae. 
PO 
any amount over the protocol-specified dose 

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On a schedule or frequency basis, an overdose is defined as anything more frequent than the protocol 
required schedule or frequency.   
Complete data about drug administration, including any overdose, regardless of whether the overdose 
was accidental or intentional, should be reported. 
If the associated AE fulfills serious criteria, Investigators should report the event to the Sponsor within 24 
hours using the SAE Reporting Form.  The Sponsor should report any SAEs to the IRB and Regulatory 
Authorities per institutional and/or regulatory guidelines, and to Acerta-Pharma/AstraZeneca per 
contractual guidelines. 
All reports of Overdose should be forwarded to Acerta Pharma/AstraZeneca Data Entry Site (see email 
address below) within 30 days unless the report meets serious criteria.  If report meets serious criteria, it 
is to be reported to Acerta Pharma/AstraZeneca within 15 calendar days.  
14.2.2 Secondary Malignancies 
Adverse Events (AEs) for malignant tumors reported during a 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 tumor event should be assessed and reported as a Non-Serious AE. For example, if the 
tumor is included as medical history and progression occurs during the study, but the progression does 
not change treatment and/or prognosis of the malignant tumor, the AE may not fulfill the attributes for 
being assessed as Serious, although reporting of the progression of the malignant tumor as an AE is valid 
and should occur. Also, some types of malignant tumors, which do not spread remotely after a routine 
treatment that does not require hospitalization, may be assessed as Non-Serious; examples include Stage 
1 basal cell carcinoma and Stage 1A1 cervical cancer removed via cone biopsy. For studies in Early Stage 
and Late Stage Immuno-Oncology and Oncology Studies: The above instruction applies only when the 
malignant tumor event in question is a new malignant tumor (i.e., it is not the tumor 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 tumor under study). Malignant tumors 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 
tumor. 
14.3 Pregnancies 
14.3.1 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 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 (Section 14.5). 
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. 

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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 Acerta Pharma/AstraZeneca (Section 14.7) 
14.3.2 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.  
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, FDA, etc.) must also be 
reported in routine study data submissions. 
Adverse events will be assessed using the CTCAE v5.0 (non-hematologic) and IWCLL 2018 (hematologic). 
AEs recorded in the eCRF include: 
o For Cycle 1, highest grade of each AE type, plus any grade 3 or higher adverse event 
(regardless of whether or not it is the highest grade); 
o For Cycle 2+ through EOT, during each cycle/period, highest grade of each AE type 
o All SAEs/AESIs 
14.5 Expedited Reporting  
Table 14.5 indicates what events must be reported expeditiously. 
Table 14.5 Criteria for Expedited Reporting 
Time point 
What to report  
From signing of the consent to study completion 
 All UPs 
For the time period beginning at treatment 
through 90 days following cessation of treatment, 
or 30 days following cessation of treatment if the 
subject initiates new anticancer therapy, 
whichever is earlier 
 All SAEs regardless of relationship to protocol therapy  
 All UPs and AEs that meet the definition of a UP 
  AESIs (Section 14.4), overdose 
From Day 1 of protocol therapy up to 120 days 
post-last acalabrutinib dose 
 Pregnancies and lactation  
Post Safety Follow-Up to removal from study  
 All SAEs that are considered possibly, probably or 
definitely related to acalabrutinib.  
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. 

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14.5.1 Expedited reporting guidelines (COH only) 
14.5.1.1 
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. 
Email the following information to DCC@coh.org and the Study PI (adanilov@coh.org): Participant ID, date 
the event met criteria for reporting, whether the event meets the definition of serious, whether the event 
is an unanticipated problem, grade of event, attribution of event, whether the event is a known expected 
toxicity to study agent. 
14.5.1.2 
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. 
14.5.1.3 
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, and, for non-COH sites, a statement that the report should be submitted to their 
local IRB for review as an IND safety report if applicable per local IRB policy. 
Forward to participating sites all IND safety reports received from Acerta Pharma/AstraZeneca, indicating 
whether a consent form or protocol change is required within 30 days of notification to Study PI. 
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. Non-COH participating 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 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 also 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 “Acalabrutinib in AIHA SAE COH IRB #20311”.  
a. If available and applicable, sites may include the local IRB submission for this event in the 
submission.  

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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’s Institutional 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)] 
In addition, on behalf of the study PI, OIDRA will submit annually within 60 days (via COH OIDRA) 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 adverse drug experiences, and history of actions taken since the last report because of 
adverse drug experiences. 
14.7 Reporting to Acerta Pharma/AstraZeneca 
The Study PI (or designee) will: 
o Report the following to Acerta Pharma/AstraZeneca per the guidelines provided in Table 14.6.  
 
email: AEMailboxClinicalTrialTCS@astrazeneca.com  
o Assist Acerta Pharma/AstraZeneca in investigating any SAE and will provide any follow-up 
information reasonably requested by Acerta Pharma/AstraZeneca. 
Table 14.6 Timeframes for Reporting to Acerta Pharma/AstraZeneca 
Type of Report 
Reporting Timeframes 
Pregnancy 
Within 24 hours of being aware of the event 
All expedited SAE 
reports (includes AESIs) 
Within 24 hours of being aware of the event via a MedWatch 3500A form. 
 
Aggregate safety 
reports 
Forward Acerta Pharma/AstraZeneca quarterly (e.g. at time of COH PMT report). 
 
o Forward to Acerta Pharma/AstraZeneca copies of initial/annual/final FDA IND submissions. Email: 
AEMailboxClinicalTrialTCS@astrazeneca.com. 

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The Sponsor will submit appropriate reports to applicable local regulatory agencies and to ethics 
committees (ECs) as per local regulations. The Sponsor will notify Acerta Pharma/AstraZeneca in parallel 
with submission to the IRB and concerned Regulatory Authority for Suspected Unexpected Serious 
Adverse Reactions (SUSARs) and within fifteen (15) calendar days of awareness for other SAEs or Special 
Situation Reports using individual unblinded or blinded case reports (Institution’s Standard SAE Report 
Form, MedWatch, or CIOMS). New information will be submitted to Acerta Pharma/AstraZeneca within 
the same time frame as initial reports.  
Whenever possible, SAEs should be reported by diagnosis term not as a constellation of symptoms.   
Death due to disease progression should be recorded on the appropriate form in the electronic data 
capture (EDC) system.  If the primary cause of death is disease progression, the death due to disease 
progression should not be reported as an SAE.  If the primary cause of death is something other than 
disease progression, then the death should be reported as an SAE with the primary cause of death as the 
event AE term, as death is typically the outcome of the event, not the event itself.  The primary cause of 
death on the autopsy report should be the term reported.  Autopsy and postmortem reports must be 
forwarded to AstraZeneca, as outlined above.  If study drug is discontinued because of an SAE, this 
information must be included in the SAE report. 
15.0 ADHERENCE TO THE PROTOCOL & REPORTING OF PROTOCOL DEVIATIONS 
Deviations from the protocol should be avoided, except when necessary to eliminate an 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.  
15.1 Reporting by COH 
All protocol deviations and planned protocol deviations will be reported in accordance with the City of 
Hope Clinical Research Protocol Deviation policy. 
15.2 Reporting by 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. 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 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 
“[Acalabrutinib in AIHA] Deviation COH IRB #20311”. If 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). 

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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 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 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/UP/AEs 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/auditing 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/auditing for 
this study will be performed by the City of Hope Office of Clinical Trials Monitoring (OCTM), within the 
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 document specify the frequency of monitoring, monitoring procedures, the amount of subject 
data to be reviewed, and the distribution of monitoring 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 Data and Safety Monitoring Plan. This 
determination was made because this study involves a COH IND. 
16.6 City of Hope Data and Safety Monitoring Committee (DSMC) 
Data and safety 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. 

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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 NIH policies and procedures 
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 
(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 

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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. 
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. 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 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. 
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. 

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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 the study drug on embryogenesis and reproduction 
are unknown. 
17.6.2 Pediatric Population 
Pediatric participants (< 18 years of age) are excluded from this study because safety and effectiveness of 
protocol therapy has not yet been defined for the study population. Additional studies may be performed 
in the pediatric population once safety and effectiveness of protocol therapy is defined in the adult study 
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. 
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. 

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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 (COH IRB #16020) 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. 
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 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 

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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 and 
AstraZeneca, 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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Byrd JC, Wierda WG, Schuh A, et al. Acalabrutinib Monotherapy in Patients with Relapsed/Refractory 
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36. 
Awan FT, Schuh A, Brown JR, et al. Acalabrutinib Monotherapy in Patients with Ibrutinib Intolerance: Results 
from the Phase 1/2 ACE-CL-001 Clinical Study. Blood. 2016;128(22):638-638. 
37. 
Hillmen P, Schuh A, Eyre TA, et al. Acalabrutinib Monotherapy in Patients with Richter Transformation from 
the Phase 1/2 ACE-CL-001 Clinical Study. Blood. 2016;128(22):60-60. 
38. 
Ghia P, Pluta A, Wach M, et al. Acalabrutinib vs Rituximab Plus Idelalisib (IdR) or Bendamustine (BR) by 
Investigator Choice in Relapsed/Refractory (R/R) Chronic Lymphocytic Leukemia: Phase 3 ASCEND Study. Clinical 
Lymphoma, Myeloma & Leukemia. 2019;19:S280-S281. 
39. 
Sharman JP, Banerji V, Fogliatto LM, et al. ELEVATE TN: Phase 3 Study of Acalabrutinib Combined with 
Obinutuzumab (O) or Alone Vs O Plus Chlorambucil (Clb) in Patients (Pts) with Treatment-Naive Chronic Lymphocytic 
Leukemia (CLL). Blood. 2019;134(Supplement_1):31. 
40. 
Dierickx D, Beke E, Devos T, Delannoy A. The use of monoclonal antibodies in immune-mediated 
hematologic disorders. Med Clin North Am. 2012;96(3):583-619, xi. 
41. 
Long M, Beckwith K, Do P, et al. Ibrutinib treatment improves T cell number and function in CLL patients. 
The Journal of Clinical Investigation. 2017;127(8):3052-3064. 

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42. 
Barcellini W, Zaja F, Zaninoni A, et al. Low-dose rituximab in adult patients with idiopathic autoimmune 
hemolytic anemia: clinical efficacy and biologic studies. Blood. 2012;119(16):3691-3697. 
 
 

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APPENDIX A: PERFORMANCE STATUS SCALES 
Karnofsky 
Scale % 
Karnofsky 
Description 
ECOG* 
Scale 
ECOG 
Description 
100 
Normal, no complaints, no 
evidence of disease. 
0 
Fully active, able to carry on all 
pre-disease activities without 
restriction. 
90 
Able to carry on normal activity, 
minor symptoms or signs of 
disease. 
80 
Normal activity with effort, some 
signs or symptoms of disease. 
1 
Restricted in physically strenuous 
activity but ambulatory and able to 
carry out work of a light or 
sedentary nature e.g. light house 
work office work.  
70 
Cares for self, unable to carry on 
normal activity or to do active 
work. 
60 
Requires occasional assistance, but 
is able to care for most of own 
needs. 
2 
Ambulatory and capable of all self-
care but unable to carry out any 
work activities. Up and about more 
than 50% of waking hours  
50 
Requires considerable assistance 
and frequent medical care. 
40 
Disabled, requires special care and 
assistance. 
3 
Capable of only limited self-care, 
confined to bed or chair more than 
50% of waking hours  
30 
Severely disabled, hospitalization is 
indicated although death is not 
imminent. 
20 
Hospitalization necessary, very sick, 
active supportive treatment 
necessary. 
4 
Completely disabled. Cannot carry 
on any self-care. Totally confined 
to bed or chair  
10 
Moribund, fatal processes 
Dead 
 
5 
Dead 
*also known as Zubrod, SWOG or WHO scale 
 
 
 

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APPENDIX B: AIHA RESPONSE CRITERIA 
Treatment response will be determined per the investigators’ assessment, according to Barcellini et al.42 
AIHA Complete 
Response (CRAIHA): 
Hemoglobin >12 g/dL, 
AND no transfusion requirements. 
No laboratory evidence of ongoing hemolysis (haptoglobin, indirect bilirubin WNL, 
reticulocyte count <1.5 ULN) 
AIHA Partial Response 
(PRAIHA): 
Hemoglobin level ≥10 g/dL (without transfusions), 
OR hemoglobin increase of at least 2 g/dL above pretreatment level, 
Presence of laboratory evidence of ongoing hemolysis. 
 
 

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APPENDIX C: CLL/SLL RESPONSE CRITERIA 
Treatment response will be determined per the investigators’ assessment, according to Hallek et al1.  
Group Parameter 
CR 
PR 
PD 
SD 
A  
Lymph nodes  
None ≥1.5 cm  
Decrease ≥50% (from 
baseline)*  
Increase ≥50% from baseline or 
from response  
Change of −49% to +49%  
Liver and/or 
spleen size†  
Spleen size <13 
cm; liver size 
normal  
Decrease ≥50% (from 
baseline)  
Increase ≥50% from baseline or 
from response  
Change of −49% to +49%  
Constitutional 
symptoms  
None  
Any  
Any  
Any  
Circulating 
lymphocyte 
count  
Normal  
Decrease ≥50% from 
baseline  
Increase ≥50% over baseline  
Change of −49% to +49%  
B  
Platelet count  
≥100 × 109/L  
≥100 × 109/L or increase 
≥50% over baseline  
Decrease of ≥50% from 
baseline secondary to CLL  
Change of −49 to +49%  
Hemoglobin  
≥11.0 g/dL 
(untransfused 
and without 
erythropoietin)  
≥11 g/dL or increase 
≥50% over baseline  
Decrease of ≥2 g/dL from 
baseline secondary to CLL  
Increase <11.0 g/dL or 
<50% over baseline, or 
decrease <2 g/dL  
Marrow  
Normocellular, 
no CLL cells, no 
B-lymphoid 
nodules  
Presence of CLL cells, or 
of B-lymphoid nodules, 
or not done  
Increase of CLL cells by ≥50% 
on successive biopsies  
No change in marrow 
infiltrate  
*Sum of the products of 6 or fewer lymph nodes (as evaluated by CT scans and physical examination in clinical trials or by 
physical examination in general practice). 
†Spleen size is considered normal if <13 cm. There is not firmly established international consensus of the size of a normal liver; 
therefore, liver size should be evaluated by imaging and manual palpation in clinical trials and be recorded according to the 
definition used in a study protocol. 
CR, complete remission (all of the criteria have to be met); 
PR, partial remission (for a PR, at least 2 of the parameters of group A and 1 parameter of group B need to improve if previously 
abnormal; if only 1 parameter of both groups A and B is abnormal before therapy, only 1 needs to improve); 
PD, progressive disease (at least 1 of the criteria of group A or group B has to be met);  
SD, stable disease (all of the criteria have to be met; constitutional symptoms alone do not define PD). 
 
 

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APPENDIX D-1: ACALABRUTINIB MEDICATION DIARY INSTRUCTIONS 
Remember to bring this diary, all pill bottles, and any unused pills to each clinic visit. 
Call your study doctor or nurse immediately if you are having any new or worsening side effects. 
Study drug Instructions – When and How: 
o Take acalabrutinib twice a day by mouth 
o Take the pills with a large glass of water (~250ml) at approximately the same times each day  
o Swallow pills; do not chew them or crush them 
o Do not skip any doses unless your doctor tells you to. 
When to stop taking acalabrutinib 
o Do not stop taking acalabrutinib unless your doctor tells you to. 
What if I miss a scheduled dose? 
o If less than 3 hours have passed from the scheduled time, then take the missed dose as soon as you 
remember.   
o If more than 3 hours have passed from the scheduled time, then skip the missed dose. Wait for your 
next scheduled dose. Do not take extra medicine to make up the missed dose. 
What if I vomit after taking acalabrutinib? 
o If you vomit your pills, write this down in your pill diary.   
o Wait until the next scheduled dose; do not take extra medicine to make up the vomited dose.  
 
Additional Instructions: 
o Bring this diary, all pill bottles, and any unused pills to each clinic visit.  
o Keep your study drug in the original container until you take it. 
o Do NOT throw away empty pill bottles or unused pills. 
o Your dose may be adjusted based on your side effects 
 
Contact Information 
Study Doctor 
Phone: 
 
Name: 
Study Coordinator 
Phone: 
 
Name: 
Backup Study Coordinator  
Phone: 
 
Name: 
 

This document is confidential and for research purposes only. Do not copy, redistribute, disclose or use except as authorized.  
 
APPENDIX D-2: MEDICATION DIARY 
Study Name: A phase 2 trial of acalabrutinib for the treatment of relapsed/refractory autoimmune hemolytic anemia 
 
Day 
Date 
Time 
morning dose 
Dose/ # 
caplets 
taken 
Time  
evening 
dose 
Dose/ # 
caplets 
taken 
Time since 
last meal  
If dose missed, please provide reason: 
1 
 
 
 
 
 
 
 
2 
 
 
 
 
 
 
 
3 
 
 
 
 
 
 
 
4 
 
 
 
 
 
 
 
5 
 
 
 
 
 
 
 
6 
 
 
 
 
 
 
 
7 
 
 
 
 
 
 
 
8 
 
 
 
 
 
 
 
9 
 
 
 
 
 
 
 
10 
 
 
 
 
 
 
 
11 
 
 
 
 
 
 
 
12 
 
 
 
 
 
 
 
13 
 
 
 
 
 
 
 
14 
 
 
 
 
 
 
 
15 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Participant/Caregiver signature (please sign when submitting your diary): ____________________________________ Date ___/____/____ 
Subject ID#: 
Patient Initials (F, M, L): 
Institution:  
Cycle #: 
Cycle start date: 

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Study Name: A phase 2 trial of acalabrutinib for the treatment of relapsed/refractory autoimmune hemolytic anemia 
 
Day 
Date 
Time 
morning dose 
Dose/ # 
caplets 
taken 
Time  
evening 
dose 
Dose/ # 
caplets 
taken 
Time since 
last meal  
If dose missed, please provide reason: 
16 
 
 
 
 
 
 
 
17 
 
 
 
 
 
 
 
18 
 
 
 
 
 
 
 
19 
 
 
 
 
 
 
 
20 
 
 
 
 
 
 
 
21 
 
 
 
 
 
 
 
22 
 
 
 
 
 
 
 
23 
 
 
 
 
 
 
 
24 
 
 
 
 
 
 
 
25 
 
 
 
 
 
 
 
26 
 
 
 
 
 
 
 
27 
 
 
 
 
 
 
 
28 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Participant/Caregiver signature (please sign when submitting your diary): ____________________________________ Date ___/____/____ 
 
Subject ID#: 
Patient Initials (F, M, L): 
Institution:  
Cycle #: 
Cycle start date: 
Study personnel 
ONLY:  
# of Pill Bottles Returned: ______________ 
# of Pills Returned: ____________________  
Compare with drug diary entries made by participant/guardian.  If there is a 
discrepancy (in the # of bottles or the # of pills returned), please reconcile 
(initials & date):____________________________ 

This document is confidential and for research purposes only. Do not copy, redistribute, disclose or use except 
as authorized.  
 
APPENDIX E: REGISTRATION COVERSHEET  
COH IRB# 20311: A phase 2 trial of acalabrutinib for the treatment of relapsed/refractory 
autoimmune hemolytic anemia 
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 F: CORRELATIVE BLOOD COLLECTION FORM FOR MDACC ONLY 
Subject ID (issued by DCC):   
Participant Initials (F, M, L) (if applicable): 
Institution: 
 
To be used by non-COH sites for the following blood samples being sent to COH Danilov 
Laboratory: 
 
Sample # 
Collection 
Timepoint * 
Expected 
Volume 
Tube Type Used 
Collected 
Volume 
Time of Collection 
Date of 
Collection 
Indicate 
which sample 
was collected 
1.  
C1D1 
15-20 ml 
Green-top 
_____ mL 
____:____ AM/ PM 
____/____/____ 
 
2.  
C4D1 
15-20 ml 
Green-top 
_____ mL 
____:____ AM/ PM 
____/____/____ 
 
3.  
C7D1 
15-20 ml 
Green-top 
_____ mL 
____:____ AM/ PM 
____/____/____ 
 
4.  
C13D1 
15-20 ml 
Green-top 
_____ mL 
____:____ AM/ PM 
____/____/____ 
 
 
 
A copy of this form should accompany the sample shipments to COH Danilov Laboratory. Refer to the blood shipping 
guidelines for shipping instructions (Appendix G). 
 
CRA/Study Coordinator/ Nurse:   
Contact Number: 
CRA/Study Coordinator/ Nurse Signature:   
Date: 
 
 

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APPENDIX G: BLOOD SHIPPING GUIDELINES TO CITY OF HOPE 
These guidelines apply to MDACC site 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 Danilov lab (DL-danilovlab@coh.org) or designee. 
1. Blood samples in green-top tubes will be sent overnight at around 25oC in an appropriate 
container via FedEx. 
2. On the day of shipment, email Danilov lab (DL-danilovlab@coh.org) or designee the FedEx 
shipment tracking#. 
3. Ship samples with a copy of the correlative blood collection form (Appendix F) and a copy of the 
latest CBC results (with differential) and the date of the test to: 
 
The Danilov Laboratory  
Kaplan Clinical Research Bldg [(KCRB) Building 158], Room #1022 
City of Hope, 1500 East Duarte Rd, Duarte CA 91010 
DL-danilovlab@coh.org 
626-218-1959