Conditions: Human Immunodeficiency Virus (HIV)
Allocation: NON_RANDOMIZED | Intervention model: SINGLE_GROUP
Enrollment: 8
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the safety and tolerability of repeat doses of T-cell immunotherapy (SB-728mR-T) following cyclophosphamide conditioning.

CCR5 is a major co-receptor for HIV entry into T-cells. Disruption of CCR5 by zinc finger nuclease (SB-728mR), blocks HIV entry into the T-cells, therefore, protects the T-cells from HIV infection. Safety (primary outcome) and anti-viral effect (secondary outcome) of zinc finger nuclease-mediated CCR5 disrupted autologous T-cells (SB-728mR-T) will be evaluated in the study.

Detailed description:

Arms:
arm 1: None arm 2: None

Interventions: intervention 1: SB-728mR-T intervention 2: SB-728mR-T intervention 3: Cyclophosphamide
Intervention descriptions: intervention 1: -SB-728mR-T infusions of 2 equal doses 14 days apart (total of up to 40 billion ZFN modified T-cells) intervention 2: \- SB-728mR-T infusions of 3 equal doses 14 days apart (total of up to 40 billion ZFN modified T-cells) intervention 3: \- IV cyclophosphamide 1 g/m2 two days prior to the first SB-728mR-T infusion

Protocol document:
SAP_002.pdf: 
Confidential 
Sangamo Therapeutics, Inc. 
Statistical Analysis Plan 
Version Final, 15 Dec 2020 
 
Protocol Number: SB-728mR-1401                                           
A Phase 1/2, Open-label Study to Assess the Safety and Tolerability of Repeat 
Doses of Autologous T-Cells Genetically Modified at the CCR5 Gene by Zinc 
Finger Nucleases in HIV-Infected Subjects Following Cyclophosphamide 
Conditioning 
 
 
 
 
 
 
      




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Table of Contents 
LIST OF ABBREVIATIONS .................................................................................................................... 3 
1 
INTRODUCTION ............................................................................................................................. 4 
2 
STUDY OBJECTIVES ....................................................................................................................... 4 
2.1 
Primary Objective .................................................................................................................................. 4 
2.2 
Secondary Objectives ............................................................................................................................. 4 
3 
STUDY DESIGN ................................................................................................................................ 4 
3.1 
Dosing Schedule .................................................................................................................................... 5 
3.2 
Schedule of Procedures .......................................................................................................................... 5 
3.3 
Sample Size Consideration ..................................................................................................................... 5 
4 
STATISTICAL METHODS .............................................................................................................. 6 
4.1 
Analysis Conventions ............................................................................................................................. 6 
4.2 
Missing Data .......................................................................................................................................... 6 
4.3 
Analysis Populations .............................................................................................................................. 6 
4.4 
Subject Disposition ................................................................................................................................ 6 
4.5 
Demographic and Baseline Information ................................................................................................. 6 
4.5.1 
Demographic and Baseline Characteristics .................................................................................................. 6 
4.5.2 
Medical History ............................................................................................................................................ 7 
4.6 
Concomitant Medication and Current HIV Treatments ........................................................................... 7 
4.7 
Safety Evaluation ................................................................................................................................... 7 
4.7.1 
Treatment Exposure ..................................................................................................................................... 7 
4.7.2 
Adverse Events ............................................................................................................................................. 7 
4.7.3 
Clinical Laboratory Evaluations .................................................................................................................... 8 
4.7.4 
Vital Signs, Physical Examination and Electrocardiogram data .................................................................... 9 
5 
ALTERATIONS TO THE CLINICAL STUDY PROTOCOL ....................................................... 9 
6 
APPENDIX ........................................................................................................................................ 9 
Appendix 1: Tables, Listings, and Figures Specifications ...................................................................................... 9 
 
 
 
 
 
 
 


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List of Abbreviations 
 
AE 
 
Adverse Event 
AIDS 
 
Acquired Immunodeficiency Syndrome 
CCR5 
 
Chemokine (C-C motif) Receptor 5 
CD4 
 
Cluster of Differentiation 4 
CD8 
 
Cluster of Differentiation 8 
CRF 
 
Case Report Form 
CSR 
 
Clinical Study Report 
CTC 
 
Common Terminology Criteria 
CTX 
 
Cyclophosphamide 
eCRF 
 
Electronic Case Report Form 
HAART  
Highly Active Antiretroviral Therapy 
HIV 
 
Human Immunodeficiency Virus 
IV 
 
Intravenous 
MedDRA 
Medical Dictionary for Regulatory Activities 
PBMC  
Peripheral Blood Mononuclear Cell 
PT 
 
Preferred Term 
SAE 
 
Serious Adverse Event 
SAP 
 
Statistical Analysis Plan 
SB-728mR-T 
SB-728mR modified T-cells 
SOC 
 
System Organ Class 
TEAE 
 
Treatment-emergent Adverse Event 
WBC 
 
White Blood Cell Count 
 
 
 


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1 
Introduction 
This document describes the planned statistical analyses for Protocol SB-728mR-1401, A phase 1/2, 
open-Label Study to Assess the Safety and Tolerability of Repeat Doses of Autologous T-Cells Genetically 
Modified at the CCR5 Gene by Zinc Finger Nucleases in HIV-Infected Subjects Following 
Cyclophosphamide Conditioning. This document supplements the study protocol Amendment 2 which 
should be referred to for further details regarding the study objectives and design and is developed prior 
to database lock. This SAP provides additional details concerning the statistical analyses outlined in the 
protocol. Any deviations from this statistical analysis plan will be described in the Clinical Study Report.   
2 
Study Objectives 
2.1 
Primary Objective 
The primary objective of this study is to evaluate the safety and tolerability of repeat doses of SB-
728mR-T following CTX conditioning.  
2.2 
Secondary Objectives 
The secondary objectives of this study are to evaluate: 
• 
Effect of repeat doses of SB-728mR-T on engraftment following CTX conditioning 
• 
Long-term persistence of SB-728mR-T in peripheral blood as measured by pentamer PCR 
• 
Change in CD4+ T-cell counts in peripheral blood after repeat treatments with SB-728mR-T 
• 
Effect of SB-728mR-T on plasma HIV-1 RNA levels following HAART interruption 
• 
Change in HIV reservoirs as part of exploratory research  
3 
Study Design 
This is a Phase 1/2, open-label, multi-center study. Subjects who satisfy all inclusion/exclusion criteria 
are eligible to participate in this study. Subjects will be enrolled sequentially into two treatment cohorts, 
Cohort 1 and Cohort 2. The first 3 subjects will be enrolled and treated in Cohort 1. The next 3 subjects 
will be enrolled and treated in Cohort 2. Depending upon the outcome in Cohort 1 and Cohort 2, the 
remaining 6 subjects will be enrolled and treated in either Cohort 1 or Cohort 2. 
Cohorts 1 and 2 data will be collected as subject visits occur per the study protocol. The first time point 
at which a regimen decision for the final 6 subjects can be made is two weeks after the third infusion of 
the first and second patients in Cohort 2, and, if the decision is to use the Cohort 2 regimen, at least 2 
weeks after the first infusion of the third subject in Cohort 2, and after all safety issues that require a 
pause in enrollment to that point have been resolved. The staggering of patients in Cohort 1 will ensure 
that more data than this will be available for Cohort 1 subjects. 
General considerations to determine cohort selection for the last 6 subjects will be:  


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• 
Safety considerations: evaluation of severity and duration of AEs and SAEs and laboratory data 
in cohort 1 and cohort 2 subjects and resolution of any safety issues requiring a pause in 
enrollment 
• 
Efficacy considerations: primarily, evaluation of the change in CD4 and CD8 count, and level of 
engraftment of CCR5 modified T-cells as measured by pentamer duplication. These parameters 
peak 7 days after infusion. Secondarily, any viral load changes which have occurred during 
treatment interruptions in subjects from Cohort 1. 
 
Sangamo will perform the analyses and assessment at the time point described above. 
3.1 
Dosing Schedule 
Eligible subjects will be enrolled sequentially into two treatment cohorts: 
• 
Cohort 1:  Subjects will receive intravenous CTX 1.0 g/m2 on Day -2 followed by 2 infusions of 
SB-728mR-T on Day 0 and Week 2 
• 
Cohort 2: Subjects will receive intravenous CTX 1.0 g/m2 on Day -2 followed by 3 infusions of SB-
728mR-T on Day 0, Week 2, and Week 4 
 
Subjects will undergo an apheresis to collect PBMC for the production of SB-728mR-T cells. The 
manufactured SB-728mR-T cells will be divided into 2 to 3 doses (total dose: up to ~4.0 x 1010 cells) 
depending on cohort assignment. All subjects will receive a dose of CTX 1.0 g/m2 on Day -2, and the first 
and second doses of SB-728mR-T on Day 0 and Week 2, respectively. The third dose of SB-728mR-T will 
be administered on Week 4 for Cohort 2 subjects only. Treatment of at least the first 4 subjects will be 
staggered so that each subsequent subject will not be treated until at least 2 weeks after the preceding 
subject. Subjects who are aviremic and have CD4 cell counts ≥500 cells/µL will undergo a minimum 16 
weeks TI beginning 4 weeks after the last infusion of SB-728mR-T. TI may be extended beyond 16 weeks 
for subjects whose HIV RNA levels ≤ 10,000 copies/mL and CD4 count ≥ 500 cells/µL at the end of the 
16-week TI. Subjects will be followed for 12 months following the first SB-728mR-T infusion in the Study 
Period and an additional 24 months in the long-term follow-up (LTFU) period. 
3.2 
Schedule of Procedures 
A detailed schedule of events is provided in the protocol Appendix I.  
3.3 
Sample Size Consideration 
This is a phase 1/2 study in which up to 12 subjects will be treated to evaluate safety and tolerability of 
repeat infusions of SB-728mR-T following CTX conditioning. In order to have an evaluable sample size, 
subjects who prematurely discontinue the study prior to the conclusion of the TI may be replaced with 
another subject. 
There will be limited statistical power to evaluate safety, efficacy, and related biological endpoints. 
Therefore, analyses will be primarily descriptive and exploratory in nature. 


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4 
Statistical Methods 
4.1 
Analysis Conventions 
This section details general conventions to be used for the statistical analyses. 
• 
Separate summary will be provided for each cohort. 
• 
Summary statistics will consist of number and percent in each category for discreet variables, 
and sample size, mean, median, standard deviation and range for continuous variables. 
• 
All listings will be sorted by cohort and subject number. Within each subject, data points will be 
listed chronologically. 
• 
SAS Version 9.4 will be the statistical software for all statistical analyses, data summaries, 
listings, and graphs. 
4.2 
Missing Data 
When necessary for analysis, dates without a specific day of the month (e.g., JAN2020) will be assigned 
the 15th day of the month and dates without a specific day or month (e.g., 2020) will be assigned the 15th 
day of June. If the incomplete date is a start date and the above imputation inappropriately results in a 
date on or before the first infusion of SB-728mR-T, the incomplete date will be assigned to the day 
following the first infusion of SB-728mR-T. If an imputation results in an imputed start date after the 
stop date, the start date will be set to the day prior to the stop date. 
4.3 
Analysis Populations 
For the purpose of statistical analysis, the study has Safety population defined. 
The Safety Population include all subjects enrolled in study who receive any portion of the SB-728mR-T. 
4.4 
Subject Disposition 
Subject disposition will be summarized by cohort and for overall based on all enrolled subjects. The 
number of Enrolled Subjects, Number of Subjects Treated with at least 1 dose of SB-728mR-T, Number 
of Subjects Treated with 2 doses of SB-728mR-T, Number of Subjects Treated with 3 doses of SB-728mR-
T, the number and percent of subjects in safety population, the number and percent of subjects who 
complete study, who are early terminated from study and reason for early termination will be 
presented. 
4.5 
Demographic and Baseline Information 
4.5.1 Demographic and Baseline Characteristics 
Patient demographic and baseline characteristics will be summarized by treatment cohorts and all 
cohorts combined. Age at Informed Consent, Sex, Childbearing potential (for female subjects only), 
ethnicity, race, height (cm), weight (kg), Time from HIV Diagnosis or Suspected Infection (month), Time 
from First Antiretroviral Treatment (month) and CCR5 Delta 32 (heterozygous vs wild type) will be 
included. 


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Time from HIV Diagnosis or Suspected Infection (month) will be calculated as (date of first infusion of 
SB-728mR-T – date of HIV Diagnosis or Suspected Infection + 1) / 30.4375. Time from First Antiretroviral 
Treatment (month) will be calculated as (date of first infusion of SB-728mR-T – date of First 
Antiretroviral Treatment + 1) / 30.4375. In case of partial date, date will be imputed following the rule 
defined in section 4.2. 
4.5.2 Medical History 
Listing for Medical history will be provided. No summary table will be provided.  
4.6 
Concomitant Medication and Current HIV Treatments 
Concomitant medications and current HIV treatments are coded using WHODDE B2 format, March 1, 
2014 release. All concomitant medications reported on the concomitant medication eCRF and all current 
HIV treatments collected on Current HIV Treatment and Interruption Summary eCRF will be included in 
listing. No summary table will be provided. 
4.7 
Safety Evaluation 
The primary objective of this study is to evaluate the safety and tolerability of repeat doses of SB-
728mR-T following CTX conditioning. Safety assessment will occur on subjects who received SB-728mR-
T. Safety evaluation will be based on the Safety population. 
4.7.1 Treatment Exposure 
Subjects will receive 1.0 g/m2 of IV CTX 2 days prior to the first infusion of SB-728mR-T. Two days after 
receiving CTX, subjects will receive either two or three SB-728mR-T infusions (Cohorts 1 and 2 
respectively), each dose separated by 14 days. Dose administration information collected in eCRF for 
both CTX and SB-728mR-T will be included in listing. 
4.7.2 Adverse Events 
All adverse events will be collected during the study period. In LTFU, only the adverse events which are 
serious, unexpected and considered to be related to treatment of SB-728mR-T will be recorded in eCRF. 
A treatment-emergent adverse event (TEAE) is an adverse event with an onset on or after the first 
infusion of SB-728mR-T infusion, or an adverse event present at first infusion of SB-728mR-T but 
worsens. Only treatment-emergent adverse events will be summarized. All adverse events will be 
included in subject listings. 
All adverse events are coded using the Medical Dictionary for Regulatory Activities (MedDRA) version 
17.1. The incident of TEAEs will be summarized by MedDRA system organ class (SOC) and preferred term 
(PT). Severity will be categorized by toxicity grade according to the Division of AIDS Table for Grading the 
Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Version 1.0, December 2004, 
Clarification 1.0, August 2009 with the exception of the following: nausea or vomiting will be a Grade 3 
non-hematological AE if IV fluids are required for more than 24 hours. AEs not listed in the DAIDS Clinical 
Trial Toxicity Criteria with the exception of noninfective cystitis will be evaluated by using the criteria 
specified in protocol section 10.3. Noninfective cystitis will be graded according to the Common 
Terminology Criteria for Adverse Events (CTCAE) Version 4.03. The relationship of the AE to the 


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investigational drug will be determined by the principal investigator. Incidence of TEAEs will be provided 
for the following: 
• 
All TEAEs 
• 
TEAEs by Severity 
• 
TEAEs with grade ≥ 3 
• 
TEAEs related to Study Drug (SB-728mR-T) 
• 
TEAEs related to CTX 
• 
Serious TEAEs 
• 
TEAEs with action of study drug dose interrupted 
• 
TEAEs with action of study drug discontinued  
 
If a subject experience the same AE more than once with different severity, the event with the 
maximum grade will be tabulated in “by severity” tables. If a subject has different AEs of different 
severity under the same SOC, the subject is only counted in the worst severity under that SOC. If a 
subject experiences multiple AEs under the same preferred term (system organ class), the subject will 
be counted only once for that preferred term (system organ class). If a subject experiences multiple 
occurrences of the same AE with different relationship to study medication categories, the subject will 
be counted once under the related category under that SOC. 
The TEAE tables will be sorted in alphabetical order by SOCs and within each SOC, preferred terms are 
sorted in a descending order by frequency based on overall column. 
All AEs will be included in listings. All deaths will be listed with cause of death from death report eCRFs. 
The information from eCRF about reportable clinical condition and malignancy in LTFU will be also listed 
in listing. 
4.7.3 Clinical Laboratory Evaluations 
Clinical laboratory results (chemistry, hematology, immunology (CD4 and CD8 T-cell counts) and HIV-1 
RNA Viral Load), long-term persistence of SB-728mR-T in peripheral blood as measured by pentamer 
PCR will be evaluated throughout the study. Hepatitis B, Hepatitis C, and CCR5 SNP Cel-I assay will be 
collected at screening only. Serum Pregnancy will be test at screening and urine pregnancy tests will be 
collected at baseline and prior to SB-728mR-T infusions.  
Descriptive statistics for the actual value and change from baseline value will be summarized by visit for 
below selected lab parameters. 
• 
Hematology: WBC count with differential, Absolute Neutrophil Count (ANC), red blood cell (RBC) 
count, hematocrit, hemoglobin, platelets 
• 
Chemistry: Alanine Aminotransferase, Albumin, Alkaline Phosphatase, Aspartate 
Aminotransferase, Bicarbonate, Bilirubin, Calcium, Chloride, Creatinine, Phosphate, Potassium, 
Protein, Sodium, Urea Nitrogen 
• 
Immunology: CCR5 Modified CD4 Cells ( in 10^9/L, calculated as (pentamer/10^6 
PBMC)*4*(lymphocyte count + monocyte count)) , Pentamer Assay, CD3 (absolute count and 


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percentage), CD4 (absolute count and percentage), CD8 (absolute count and percentage), 
CD4/CD8 ratio. 
• 
Viral Load: HIV-1 RNA 
Baseline will use the value collected at baseline visit (one week prior to CTX administration per 
protocol), if that value is missing, the last value prior to date of CTX dosing will be used. If in the same 
visit, the lab test result is collected in both central lab and local lab, the central lab result will be used for 
summary.  
A line plot by cohort will be generated to show the change of median CD4 (based on absolute count), 
CD8 (based on absolute count), CCR5 modified CD4 T Cells and HIV-1 RNA values over visits. For each 
subject, a line plot will be generated to show the HIV-1 RNA level change over time. For HIV-1 RNA level, 
y axis will be in log-scale. 
Laboratory values will be converted to a set of standard units prior to analysis. If the result contains “<”, 
the result will be imputed to half of the boundary value (e.g. if the original result is “<20”, it will be 
imputed to 10 in analysis). For HIV-1 RNA, the original unit is “copies/mL”, it will be converted to “log 
copies/mL” when summary the statistics. If no HIV-1 RNA is detected, it will be summarized as 0. 
All laboratory parameters will be included in subject listings, with abnormal values flagged. 
4.7.4 Vital Signs, Physical Examination and Electrocardiogram data 
Vital Signs (excluding height and weight at the Baseline visit), Physical Exam and Electrocardiogram data 
will be collected at the site in the source documentation only. No table and listing will be generated. 
5 
Alterations to the Clinical Study Protocol 
The following change is made from statistical section of protocol: 
• 
Analysis population is changed from “Intent-to-treat” to Safety population, as the definition 
is based on number of subjects who received any infusion. 
6 
Appendix 
Appendix 1: Tables, Listings, and Figures Specifications 
Table, listing, and figure shells to support the clinical study report will be specified in an additional 
document. 
 
 
 

Prot_001.pdf: 
Sangamo BioSciences, Inc. 
Phase 1/2 Protocol SB-728mR-1401 
Confidential 
 
Page 1 of 66                                                                                   Version: October 10, 2014 
Clinical Study Protocol 
 
A Phase 1/2, Open-Label Study to Assess the Safety and 
Tolerability of Repeat Doses of Autologous T-Cells 
Genetically Modified at the CCR5 Gene by Zinc Finger  
Nucleases in HIV-Infected Subjects Following 
Cyclophosphamide Conditioning 
  
Protocol Number: 
SB-728mR-1401 
BB-IND: 
16082 
Sponsor: 
Sangamo BioSciences, Inc. 
Point Richmond Tech Center II 
501 Canal Blvd., Suite A100 
Richmond, CA  94804 
Phone:  (510) 970-6000 
Fax:  (510) 970-6009 
Medical Monitor: 
 
Winson Tang, M.D.  
Phone:  (510) 970-7800 
Fax:  (510) 970-6009 
Original Version: 
Amendment 1: 
Amendment 2: 
 
June 25, 2014 
August 6, 2014 
 
October 10, 2014 
 
 
 
 
 
Confidentiality Statement 
This document contains confidential information. It is intended solely for the use of the principal 
investigator, co-investigators, staff, appropriate institutional review boards or ethical committees, and 
other required regulatory bodies.


Sangamo BioSciences, Inc.  
Phase 1/2 Protocol SB-728mR-1401                                                                                                             Confidential 
Page 2 of 66                                                                                   Version: October 10, 2014 
 
Sangamo BioSciences, Inc. 
 
 
   Clinical Approval Signature Page 
 
 
 
 
 
Protocol Number: 
SB-728mR-1401 
 
 
 
 
 
Protocol Title:  
A Phase 1/2 Open-Label Study to Assess the Safety and Tolerability of 
Repeat Doses of Autologous T-Cells Genetically Modified at the 
CCR5 Gene by Zinc Finger Nucleases in HIV-Infected Subjects 
Following Cyclophosphamide Conditioning 
 
 
 
 
Amendment 2: 
October 10, 2014 
 
 
 
 
 
 
___________________________________ 
________________ 
Winson Tang, M.D   
 
 
 
 
 
 
Date 
Vice President, Clinical Research 
 
 
 
 
 
 
___________________________________ 
________________ 
Dale Ando, M.D.  
Date 
Vice President Therapeutic Development and CMO 
 
 
 


Sangamo BioSciences, Inc.  
Phase 1/2 Protocol SB-728mR-1401                                                                                                             Confidential 
Page 3 of 66                                                                                   Version: October 10, 2014 
Protocol SB-728mR-1401 Synopsis 
Title 
A Phase 1/2 Open-Label Study to Assess the Safety and Tolerability of 
Repeat Doses of Autologous T-Cells Genetically Modified at the CCR5 
Gene by Zinc Finger Nucleases in HIV-Infected Subjects Following 
Cyclophosphamide (CTX) Conditioning 
Sponsor 
Sangamo BioSciences, Inc. 
Investigational 
Products 
SB-728mR-T (autologous T-cells modified at the CCR5 gene by ZFNs via 
messenger ribonucleic acid (mRNA) electroporation) 
Objectives 
Primary:  
To evaluate the safety and tolerability of repeat doses of SB-728mR-T 
following CTX conditioning. 
Secondary: 
1. Evaluate the effect of repeat doses of SB-728mR-T on engraftment 
following CTX conditioning 
2. Evaluate long-term persistence of SB-728mR-T in peripheral blood as 
measured by pentamer PCR 
3. Evaluate change in CD4+ T-cell counts in peripheral blood after repeat 
treatments with SB-728mR-T  
4. Evaluate the effect of SB-728mR-T on plasma HIV-1 RNA levels 
following HAART interruption 
5. Evaluate the change in HIV reservoirs as part of exploratory research 
Study Population Up to 12 aviremic HIV-infected subjects on HAART may be enrolled and 
treated in two dose cohorts.  
Main Inclusion 
Criteria 
1. HIV diagnosed men and women ≥ 18 years of age on HAART with 
undetectable viral loads for the preceding 2 months and peripheral blood 
CD4+ T-cell counts ≥500 cells/µL at screening. 
2. Aviremic subjects who initiated antiretroviral therapy within (≤) 1 year 
of HIV diagnosis or suspected infection  
3. Aviremic subjects on HAART with low innate immune system 
activation as determined by percentage of activated CD14+/CD16+ 
monocytes ≤ 60%. 
Study Design 
Phase 1/2, open-label, multi-center study. 
Treatment Plan 
Up to 12 subjects will be enrolled and treated in two dose cohorts: 
Cohort 1: Subjects will receive intravenous CTX 1.0 g/m2 on  Day -2 
followed by 2 infusions of SB-728mR-T on Day 0 and Week 2 
Cohort 2: Subjects will receive intravenous CTX 1.0 g/m2 on Day -2 
followed by 3 infusions of SB-728mR-T on Day 0, Week 2, and 
Week 4 
Enrollment of Cohort 1 and Cohort 2 will be sequential. The first 3 subjects 
will be enrolled and treated in Cohort 1. The next 3 subjects will be enrolled 
and treated in Cohort 2. Depending upon the outcome in Cohort 1 and 
Cohort 2, the remaining 6 subjects will be enrolled and treated in either 
Cohort 1 or Cohort 2. 


Sangamo BioSciences, Inc.  
Phase 1/2 Protocol SB-728mR-1401                                                                                                             Confidential 
Page 4 of 66                                                                                   Version: October 10, 2014 
Treatment of at least the first 4 subjects will be staggered so that each 
subsequent subject will not be treated until at least 2 weeks after the 
preceding subject.  
Enrolled subjects will undergo a 10L leukapheresis to collect peripheral 
blood mononuclear cells for the manufacturing of SB-728mR-T. The final 
product will be split into 2 or 3 doses and frozen until infusion. 
Two days after receiving CTX, subjects will receive either two or three SB-
728mR-T infusions (Cohorts 1 and 2 respectively), each dose separated by 
14 days. CTX will not be administered to a subject until the subject’s SB-
728mR-T product lot is released and the number of cells manufactured 
meets the minimum dose requirement. 
Subjects with aviremia and CD4 cell counts ≥500 cells/µL will have their 
anti-retroviral treatment stopped 4 weeks after the last dose of SB-728mR-
T. HAART will be discontinued for a period of at least 16 weeks.  
During the 16-week treatment interruption (TI), HAART will be reinstituted 
in subjects whose CD4 cell counts drop to <500 cells/µL and/or whose 
HIV-RNA increases to >100,000 copies/mL on three consecutive 
measurements tested every 2 weeks. 
At the end of the 16-week treatment interruption:  
 HAART will be reinstituted in subjects with HIV RNA levels 
>10,000 copies/mL and/or CD4 <500 cells/µL.  
 Subjects with HIV RNA levels ≤10,000 copies/mL and CD4 count ≥ 
500 cells/µL may elect to remain off HAART and undergo extended 
TI (subjects with HIV RNA levels below limit of detection will 
remain off HAART).  
During extended TI, HIV-1 RNA and CD4 counts will be measured 
monthly. HAART will be reinstituted in subjects when one or both of the 
following criteria are met: 
 HIV RNA levels > 10,000 copies/mL, confirmed by two additional 
consecutive monthly  measurements 
 CD4 count < 500 cells/µL, confirmed by an additional consecutive 
monthly measurement  
Study Duration 
The duration of study participation will be approximately 40 months.  
Study Period: Approximately 16 months, including 4 months for screening, 
leukapheresis, and SB-728mR-T production, and 12 months follow-up 
following the first SB-728mR-T treatment. 
Long-term Follow-up (LTFU) Period: An additional 24 months following 
the Study Period for long-term safety.  
Sample Size and 
Analyses 
This is a phase 1/2 study in which up to twelve evaluable subjects in two 
cohorts will be treated to evaluate safety and tolerability of repeat infusions 
of SB-728mR-T following CTX conditioning. 
There will be limited statistical power to evaluate safety, efficacy, and 
related biological endpoints. Therefore, analyses will be primarily 
descriptive and exploratory in nature. 


Sangamo BioSciences, Inc.  
Phase 1/2 Protocol SB-728mR-1401                                                                                                             Confidential 
Page 5 of 66                                                                                   Version: October 10, 2014 
TABLE OF CONTENTS 
1.     INTRODUCTION............................................................................................................... 10 
1.1 
CLINICAL EXPERIENCE WITH SB-728MR-T .......................................................... 10 
1.2  
CLINICAL EXPERIENCE WITH THE FIRST GENERATION SB-728-T ........................... 10 
1.3 
CYCLOPHOSPHAMIDE TO ENHANCE SB-728MR-T ENGRAFTMENT ......................... 11 
1.4 
HAART TREATMENT INTERRUPTION ................................................................... 12 
1.5 
RATIONALE FOR PROPOSED SB-728MR-T DOSE SCHEDULE ................................ 12 
1.6 
RISK BENEFIT ANALYSIS .................................................................................... 13 
1.7 
STUDY HYPOTHESIS .......................................................................................... 13 
2. 
STUDY OBJECTIVES ................................................................................................... 13 
2.1 
PRIMARY OBJECTIVE ......................................................................................... 13 
2.2 
SECONDARY OBJECTIVES .................................................................................. 14 
3. 
STUDY DESIGN ............................................................................................................. 14 
3.1 
OVERVIEW ........................................................................................................ 14 
3.2 
NUMBER OF SUBJECTS ...................................................................................... 15 
3.3 
STUDY DURATION .............................................................................................. 15 
3.4 
VISIT SCHEDULE ............................................................................................... 15 
3.5 
STUDY PROCEDURES ........................................................................................ 15 
4. 
SUBJECT SELECTION ................................................................................................ 15 
4.1 
INCLUSION CRITERIA .......................................................................................... 15 
4.2 
EXCLUSION CRITERIA ........................................................................................ 16 
5.  
INFORMED CONSENT ................................................................................................ 18 
6. 
STUDY METHODOLOGY ........................................................................................... 18 
6.1 
SCREENING VISIT PROCEDURES ......................................................................... 18 
6.2 
SUBJECT ENROLLMENT PROCEDURES ................................................................ 19 
6.3 
PRE- LEUKAPHERESIS AND LEUKAPHERESIS ........................................................ 19 
6.3.1 Pre-Leukapheresis: ......................................................................................... 19 
6.3.2 Leukapheresis: ............................................................................................... 19 
6.4 
BASELINE ASSESSMENTS ................................................................................... 19 
6.4.1  
Baseline for Research Blood Collection: ....................................................... 19 
6.4.2 Baseline: ....................................................................................................... 19 
6.5 
STUDY TREATMENT AND FOLLOW-UP .................................................................. 20 
6.5.1 Cyclophosphamide Administration (Day -2) ..................................................... 20 
6.5.2 SB-728mR-T Infusions: Day 0 and Week 2 (+/- 1 day); and Week 4 (Cohort 2 only) 
(+/- 1 day) ................................................................................................................ 21 
6.5.3 Day 1 / Day 15, and Day 29 (Cohort 2 only) (one day post SB-728mR-T infusions)
 
21 
6.5.4 Weekly Visits Post SB-728mR-T Infusion (+/- 2 day)........................................ 22 
6.5.5 16-Week HAART Treatment Interruption ........................................................ 22 
6.5.6 Month 7, Month 9 and Month 12 (+/- 1 week)................................................... 23 
6.5.7 Long-term Follow-up (LTFU): Month 18 and Month 24 (+/- 1 month) and Month 36 
(=/- 3 months) .......................................................................................................... 24 


Sangamo BioSciences, Inc.  
Phase 1/2 Protocol SB-728mR-1401                                                                                                             Confidential 
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7.  
INSTRUCTIONS FOR EVALUATIONS .................................................................... 25 
8.  
INVESTIGATIONAL PRODUCT AND OTHER STUDY MEDICATIONS .......... 25 
8.1 
SB-728MR-T.................................................................................................... 25 
8.1.1  Inventory, Storage, and Handling of the Drug Product ...................................... 26 
8.1.2 SB-728mR-T Administration .......................................................................... 27 
8.1.3 Precautions .................................................................................................... 27 
8.1.4 Dose Modifications ........................................................................................ 27 
8.2 
CYCLOPHOSPHAMIDE ......................................................................................... 28 
8.3 
HAART ............................................................................................................ 28 
8.3.1 Discontinuation of HAART ............................................................................ 28 
8.3.2 Reinstitution of HAART ................................................................................. 28 
8.4 
CONCOMITANT MEDICATION ............................................................................... 29 
9.  
SAFETY AND POTENTIAL RISKS ........................................................................... 29 
9.1 
SB-728MR-T.................................................................................................... 29 
9.1.1 Emergence of CXCR4 HIV ............................................................................. 29 
9.1.2 Carcinogenicity ............................................................................................. 30 
9.1.3 Immunogenicity ............................................................................................. 30 
9.2 
CYCLOPHOSPHAMIDE ......................................................................................... 30 
9.3 
HAART TREATMENT INTERRUPTION (TI) ............................................................. 31 
10. 
ADVERSE EVENTS ...................................................................................................... 32 
10.1 
DEFINITIONS OF AN ADVERSE EVENT .................................................................. 32 
10.2 
ADVERSE EVENT REPORTING PERIOD ................................................................. 33 
10.3 
RECORDING OF AN ADVERSE EVENT ................................................................... 33 
11. 
SERIOUS ADVERSE EVENT ...................................................................................... 34 
11.1 
DEFINITIONS OF A SERIOUS ADVERSE EVENT ...................................................... 34 
11.2 
SERIOUS ADVERSE EVENT REPORTING PERIOD ................................................... 35 
11.3 
RECORDING OF A SERIOUS ADVERSE EVENT ....................................................... 35 
12 
CLINICAL CONDITION AND SERIOUS ADVERSE EVENT DURING LONG-
TERM FOLLOW-UP ..................................................................................................... 35 
12.1 
CLINICAL CONDITION ......................................................................................... 35 
12.2 
REPORTING SERIOUS ADVERSE EVENTS IN LTFU ................................................ 36 
13. 
SUBJECT WITHDRAWAL AND STOPPING RULES............................................. 36 
13.1 
SUBJECT WITHDRAWAL AND DISCONTINUATION FROM STUDY ............................... 36 
13.2 
STOPPING RULES .............................................................................................. 36 
13.2.1 
Stopping Rules for Treatment Interruption .................................................... 36 
13.2.2 
Stopping Rules for Study ............................................................................ 37 
14. 
STATISTICAL ANALYSIS AND DATA ANALYSIS ............................................... 37 
14.1 
SAMPLE SIZE .................................................................................................... 38 
14.2 
STATISTICAL METHODS/DATA ANALYSIS .............................................................. 38 
14.3 
INTENT-TO-TREAT POPULATION .......................................................................... 38 


Sangamo BioSciences, Inc.  
Phase 1/2 Protocol SB-728mR-1401                                                                                                             Confidential 
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14.4 
DEMOGRAPHICS ................................................................................................ 38 
14.5 
ENDPOINTS AND ANALYSIS ................................................................................. 38 
14.5.1 
Primary Endpoint ....................................................................................... 38 
14.5.2 
Secondary Endpoints .................................................................................. 38 
15. 
INVESTIGATOR OBLIGATIONS .............................................................................. 38 
15.1 
INFORMED CONSENT ......................................................................................... 39 
15.2 
INSTITUTIONAL REVIEW BOARD AND BIOSAFETY COMMITTEE ................................ 39 
15.2.1. 
Protocol Amendments ................................................................................. 39 
15.2.2. 
Other Reporting Obligations ........................................................................ 39 
15.3 
SUBJECT PRIVACY ............................................................................................. 39 
15.4 
REPORTING OBLIGATIONS .................................................................................. 40 
16. 
ADMINISTRATIVE CONSIDERATIONS ................................................................. 40 
16.1 
STUDY DOCUMENTATION ................................................................................... 40 
16.2 
RECORD RETENTION ......................................................................................... 40 
16.3 
CASE REPORT FORMS ....................................................................................... 40 
16.4 
TERMINATION OF THE STUDY .............................................................................. 41 
16.5 
STUDY MONITORING .......................................................................................... 41 
16.6 
PUBLICATION STATEMENT .................................................................................. 42 
16.7 
STUDY FUNDING................................................................................................ 42 
REFERENCES ............................................................................................................................ 43 
APPENDIX I:  SCHEDULE OF EVENTS – COHORT 1 ...................................................... 45 
APPENDIX I:  SCHEDULE OF EVENTS – COHORT 2 ...................................................... 46 
APPENDIX II: DIVISION OF AIDS TABLE FOR GRADING THE SEVERITY OF 
ADULT AND PEDIATRIC ADVERSE EVENTS ...................................................... 47 
 
 
 
 
 
 
 
 
 
 


Sangamo BioSciences, Inc.  
Phase 1/2 Protocol SB-728mR-1401                                                                                                             Confidential 
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Schema of the Study Visits   
 
6-8 wks
A
p
h
e
r
e
s
i
s
P
r
o
d
u
c
t
i
o
n
Study Period
BL
D-2 D0  D1  1   2   3  4    5   6  7  8 10  12  14  16  18  20 22  24   7     9    12
18    24   36  
Week 
Month
CTX
SB-728mR-T #1
Treatment Interruption
Long Term 
Follow-up
BL  
BR
SB-728mR-T #2
SB-728mR-T #3
D15 D29
Screen
Black font indicates both Cohort 1 and Cohort 2 
Blue font indicates Cohort 1: IV CTX 1.0 g/m2 followed by two SB-728mR-T infusions 14 days apart 
Orange font indicates Cohort 2: IV CTX 1.0 g/m2 followed by three SB-728mR-T infusions 14 days apart 


Sangamo BioSciences, Inc.  
Phase 1/2 Protocol SB-728mR-1401                                                                                                             Confidential 
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ABBREVIATIONS 
AE 
 
adverse event/experience 
AIDS  
acquired immunodeficiency syndrome 
ALP 
 
alkaline phosphatase 
ALT 
 
alanine aminotransferase (SGPT) 
ANC  
absolute neutrophil count 
 
 
AST 
 
aspartate aminotransferase (SGOT) 
CBC  
complete blood count 
CCR2  
chemokine (C-C motif) receptor 2 
CCR5  
chemokine (C-C motif) receptor 5 
CD4 
 
cluster of differentiation 4 
C of A  
Certificate of Analysis 
CRF 
 
case report form 
CTX  
cyclophosphamide 
CXCR4 
chemokine (C-X-C motif) receptor 4 
DMSO  
dimethyl sulfoxide  
DNA  
deoxyribonucleic acid 
FDA  
Food and Drug Administration 
HAART 
highly active antiretroviral therapy 
HBsAg 
hepatitis B surface antigen 
HCV  
hepatitis C virus 
HIV 
 
human immunodeficiency virus 
IFN 
 
interferon 
IV 
 
intravenous 
IRB 
 
institutional review board 
mRNA  
messenger ribonucleic acid 
LTFU  
long-term follow-up 
NNRTI  
non-nucleoside reverse transcriptase inhibitors  
NRTI  
nucleoside reverse transcriptase inhibitors 
NIH 
 
National Institutes of Health 
PBMC  
peripheral blood mononuclear cell 
PCR 
 
polymerase chain reaction 
PI 
 
Principal Investigator 
RNA  
ribonucleic acid 
SAE 
 
serious adverse event 
SB-728-T 
SB-728 modified T-cells 
SB-728mR-T SB-728mR modified T-cells  
TI 
 
Treatment Interruption 
VL 
 
viral load 
ZFN 
 
zinc finger nucleases 


Sangamo BioSciences, Inc.  
Phase 1/2 Protocol SB-728mR-1401                                                                                                             Confidential 
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1.     INTRODUCTION 
The advent of potent anti-retroviral agents has changed HIV infection from a nearly universal 
fatal disease to a chronic viral infection. However, in response to selection pressures associated 
with the use of antiretrovirals, the virus is developing resistance to many of these drugs. Thus, 
there is a need for new therapeutic approaches that can eradicate HIV such as T-cell 
immunotherapy. The objectives of T cell immunotherapy are to augment HIV-specific T-cells 
and to reverse or decrease the progressive destruction of CD4+ T-cells that leads to clinical 
AIDS. However, these CD4+ T-cells remain susceptible to infection with HIV. Sangamo 
BioSciences, Inc. (Sangamo) has developed a process to modify autologous T-cells ex vivo at the 
CCR5 gene by zinc finger nucleases (ZFNs). Since CCR5 is an important co-receptor for HIV 
entry, it is hypothesized that disruption of CCR5 in T-cells with zinc finger nucleases will offer a 
survival advantage to these cells.  
The first generation of Sangamo’s autologous T cell agent, called SB-728-T, used a replication 
deficient recombinant Ad5/F35 adenoviral vector ancillary product to deliver the CCR5 
modifying ZFNs to autologous T cells. SB-728-T has been evaluated in four separate clinical 
studies to date, three of which were conducted under Sangamo’s BB-IND 14129. 
The new investigational product SB-728mR-T is a second generation refinement of SB-728-T, a 
CCR5 gene modified autologous T cell product. The rationale for developing this second 
generation product is multifaceted. The availability of an improved gene delivery system of 
mRNA electroporation that can effectively modify the CCR5 gene with high efficiency, with no 
need for adenoviral gene transfer and thus avoiding the potential for associated immunogenicity, 
is of key importance. The prevalence of preexisting antibodies to adenovirus has been reported to 
be more than 50%. Indeed, the prevalence of adenoviral antibodies detected in the conduct of the 
SB-728-T program in the HIV subjects has been 40%. In addition, expression of the ZFNs 
encoded by the mRNA is transient, and there is minimal toxicity to the T cells during 
manufacturing.   
SB-728mR-T consists of enriched autologous T-cells that have been transduced ex vivo with SB-
728mR-T resulting in disruption of the CCR5 gene. SB-728mR is an mRNA encoding the CCR5 
specific ZFNs (SBS8196z and SBS8267) which through electroporation delivers these nucleases 
to transduced cells. The two ZFNs of the SB-728mR bind to a specific DNA sequences encoding 
the first transmembrane domain of the CCR5 gene, just upstream from the naturally occurring 
CCR5 delta 32 mutation. Binding of the CCR5-specific ZFNs to CCR5 gene induces a double 
stranded break which is repaired by the cell leading to random sequence insertions or deletions in 
up to 30% of cells transduced with SB-728mR. These insertions and deletions disrupt CCR5 
protein expression.  
Additional information can be found in the Clinical Investigator’s Brochure for SB-728mR-T. 
1.1 
Clinical Experience with SB-728mR-T 
This is the first study in which SB-728mR-T will be administered to humans. Side effects for 
SB-728mR-T in man are unknown but are expected to be the same or similar to the first 
generation autologous T cell agent, SB-728-T. 
1.2  
Clinical Experience with the First Generation SB-728-T  
Single doses of SB-728-T have been administered to 70 HIV subjects in four Phase 1/2 clinical 
studies, one of which was sponsored by UPenn and the remaining three by Sangamo. In general, 
the infusions of SB-728-T have been safe and well tolerated with the most common AEs being 


Sangamo BioSciences, Inc.  
Phase 1/2 Protocol SB-728mR-1401                                                                                                             Confidential 
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complaints consistent with a leukocyte transfusion reaction such as fever, chills, headaches, 
myalgia, and arthralgia. These symptoms were mild to moderate in severity, short lived, 
reversible, and readily managed with fluids and acetaminophen. Garlic-like body odor was 
reported in the majority of subjects and is related to the metabolism of DMSO used as a 
cryopreservative for the T-cells. There has been only one related SAE reported to date and that 
occurred in the University of Pennsylvania study (Tebas et al. 2014).  The subject developed 
fever, chills, joint and back pain within 12 hours of infusion.  
The cumulative experience with SB-728-T administered to 70 HIV subjects over 4 years 
suggests that infusion of SB-728-T was associated with increases in total lymphocyte and CD4 
count. Circulating CCR5 modified cells peaks around 2 weeks post T-cell infusion, and declined 
thereafter with an estimated mean half-life of 48 weeks. The CCR5 modified cells traffic to the 
lymphoid tissues of the rectal mucosa. The CCR5 modified cells are long lived and persist in the 
circulation, the longest time period tested to date being 42 months. A total of 35 subjects across 4 
studies initiated an Analytical Treatment Interruption (TI). Of these, 24 subjects completed either 
the 12- or 16-week TI. Eight subjects are still currently undergoing the 16-week TI. Nine of the 
24 subjects (38%) have >1-log drop in HIV-RNA from peak levels. Three subjects have had at 
least one VL that was below the level of detection. One subject has had viral control without 
HAART with HIV-RNA levels below the limit of detection (occasional blips) for a period of 31 
weeks.   
1.3 
Cyclophosphamide to Enhance SB-728mR-T Engraftment 
CTX is a nitrogen mustard alkylating agent that attaches an alkyl group to the guanine base of 
DNA. It has beneficial immunomodulatory effects that may be exploited for adaptive 
immunotherapy. Several mechanisms have been suggested including; 1) T-cell growth factors 
such as type 1 IFN, 2) dendritic cell expansion and activation with antigen driven T cell 
proliferation, 3) improved homing to lymphoid organs, 4) homeostatic proliferation and 5) 
elimination of regulatory T-cells.  
Lymphodepletive treatment to enhance engraftment of adoptively transferred T-cells has been 
pioneered in the treatment of cancer. The T cell populations used in these studies consisted of 
antigen specific or chimeric T cell receptor-transduced autologous cells. Recently, clinical 
success was reported with the use of CTX lymphodepletion prior to the adoptive transfer of 
tumor infiltrating lymphocytes and chimeric antigen receptor CD19 (CART19) transduced 
autologous T-cells (Dudley et al., 2005; Dudley and Rosenberg, 2003; Porter et al., 2011). The 
data suggest that nonmyeloablative lymphodepletion prior to adoptive transfer of T-cells results 
in greatly enhanced in vivo expansion. Furthermore, the expanded cells retain their immunologic 
function.      
In an ongoing Sangamo sponsored clinical trial (SB-728-1101), escalating doses of CTX were 
administered to 18 HIV subjects in five dose cohorts: 0.2 g (n=3), 0.5 g/m2 (n=6), 1.0 g/m2 
(n=3), 2.0 g/m2 (n=3), and 1.5 g/m2 (n=3) prior to SB-728-T infusion. Data in the first 4 cohorts 
to date suggests that SB-728-T infusions were safe and well tolerated. However, increasing doses 
of CTX were associated with a number of toxicities. These included nausea and vomiting, 
alopecia, and neutropenia. In addition, the severity of the AEs increased with more Grade 3 and 
4 AEs in Cohort 4 (2 g/m2) with all of the AEs attributed to CTX. There were five Grade 3 
(severe) AEs [neutropenia (2), alopecia (2) and nausea (1)] and one Grade 4 AE (neutropenia) in 
Cohort 4. By comparison, there were only two Grade 3 AEs (MRSA cellulitis/abscess of left arm 


Sangamo BioSciences, Inc.  
Phase 1/2 Protocol SB-728mR-1401                                                                                                             Confidential 
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and superficial left cephalic vein thrombosis) in Cohort 1 and one Grade 3 AE (decrease serum 
phosphorus) in Cohort 2 and all of them were unrelated to CTX or SB-728-T. One subject in 
Cohort 4 developed two dose limiting toxicities, Grade 3 nausea and Grade 4 neutropenia.  
Subjects in Cohorts 1-5 received between 0.8 to 3.6 x1010 of SB-728-T cells. There were dose 
related increases in total CD4 and CCR5-modified CD4 T cells with increasing doses of CTX 
between 200 mg and 1 g/m2. However, dose escalation to 1.5 and 2.0 g/m2 of CTX resulted in 
declines in total CD4 and CCR5-modified CD4 T cells to levels that were similar to that seen 
with 0.5 g/m2 dose cohort. Sixteen of the 18 subjects underwent a 16-week TI beginning 6 weeks 
after SB-728-T administration. There was an approximate 1-log decrease in HIV-RNA in one 
subject in the 0.2 g and 0.5 g/m2 dose cohorts and an approximate 3-log decrease in one subject 
in the 1.0 g/m2 dose cohort. The TIs are still ongoing for two subjects each in Cohorts 3 (1.0 
g/m2) and 4 (2.0 g/m2) and for all 3 subjects in Cohort 5 (1.5 g/m2).  
 
Due to the enhanced engraftment and safety profile in the 1.0 g/m2 CTX group as compared to 
the other four cohorts, a CTX dose of 1.0 g/m2 has been selected for this study.  
Additional information on the safety of CTX is discussed in Section 9.2. 
 
1.4 
HAART Treatment Interruption 
HAART TI was initially advocated to enhance antiviral immune response in acute HIV infection 
(Paton, 2008) and in the setting of virologic failure and multidrug resistance (Lawrence et al., 
2003). However, studies conducted to date have failed to demonstrate a clinical benefit in either 
setting. In subjects with successfully treated chronic HIV infection, TI is associated with inferior 
clinical outcomes (Oxenius et al, 2002). However, TI has been successfully deployed as an 
analytical method to assess the effectiveness of different immunologic/immune-modulatory 
interventions, especially during vaccine trials. The kinetics of viral rebound are well 
characterized, typically occurring within 2 to 4 weeks following discontinuation of drug, and 
viral replication is routinely re-suppressed with resumption of therapy. Data from UPenn study 
suggests that TI can be safely performed in the currently proposed study (Section 9.3). 
A variety of in-vitro studies may be used to assess HIV-1 specific immune responses following 
the infusion of CCR5 disrupted CD4 cells. However, the correlation of in vitro testing to immune 
protection in vivo is largely unknown (van Lunzen et al, 2007). By comparison, plasma HIV 
RNA level is an excellent biomarker for assessing the antiviral activity of a test agent in patients 
with chronic HIV infection. Therefore, sustained suppression of plasma HIV-1 RNA after the 
discontinuation of HAART and or the protection of CD4 cell loss associated with ongoing viral 
replication would be the most stringent test of an immunologic intervention such as SB-728mR-
T. 
In the current study, only subjects with aviremia and CD4 cell counts ≥500 cells/µL at the 
initiation of the TI will have their HAART interrupted. In addition, subjects will be monitored 
closely during the TI period. A set of criteria to reinstitute HAART based on CD4 count and VL 
data during TI, at the end of the TI, and during extended TI is described in Section 8.3.  
Subjects may have HAART reinstituted at any time at the discretion of the subject and/or PI.  
1.5 
Rationale for Proposed SB-728mR-T Dose Schedule 
We postulate that the anti-viral effect of SB-728-T may depend upon the number of bi-allelic 
modified T-cells in which both CCR5 alleles have been disrupted. There was a strong correlation 


Sangamo BioSciences, Inc.  
Phase 1/2 Protocol SB-728mR-1401                                                                                                             Confidential 
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between declines in VL with the estimated number of bi-allelic modified cells during the 
treatment interruption. This suggests that strategies to increase the engraftment of modified cells 
may be beneficial. One potential strategy to increase T-cell engraftment is through repeated 
administration of SB-728mR-T. Studies in a murine tumor model by Kircher et al. suggest that a 
fractionated administration schedule improves bio-distribution of CD8 T cells. Unfortunately, the 
experimental design (magnetic resonance imaging) did not allow for quantization of engraftment 
in that study. Clinical studies to date have been inconclusive (Kircher 2003). Repeat infusion (at 
least 6 weeks after the first dose) of T cells expressing a CD19 chimeric antigen receptor coupled 
to both the CD28 and ζ-endodomains increased engraftment after the second dose in one subject 
but not in two other subjects (Savoldo 2011).  In a study with CD8 T cells transduced with a 
chimeric receptor gene (CD4/CD3-ζ), Walker et al. showed that six infusions (each infusion 
separated by 56 days) did not increase engraftment (Walker 2000). However, when CD4/CD3-ζ 
modified CD4 and CD8 T cells were administered simultaneously (3 infusions, each separated 
by 14 days), engraftment increased slightly. However, the increased survival of the modified 
cells may be due to HIV-specific CD4 T cell help. Therefore, the optimal schedule of dosing 
(fractionated schedule versus single dose) remains to be determined. The current change in 
manufacturing from an adenoviral vector to mRNA electroporation will allow for repeat dosing 
of SB-728mR-T. The expectation is that with repeat dosing, we will increase engraftment, 
potentially to levels that will control HIV.  
1.6 
Risk Benefit Analysis 
SB-728-T infusions in the four studies conducted to date have been well tolerated with 
chills/rigors, nausea and low grade fevers the most common AEs. The highest dose that has been 
administered to an individual subject was 3.6 x 1010 cells. Similarly, CTX has been safely 
administered to HIV patients in study SB-728-1101. Data from this dose escalation study suggest 
that a non-myeloablative dose 1.0 g/m2 provides for maximal engraftment with the least toxicity. 
The AEs at this dose were readily managed by routine medical interventions such as antiemetics 
and adequate hydration. Collectively, these data suggest that the potential benefit of expanding 
HIV-1 resistant CCR5 modified T-cells may be greater than the potential adverse effects of low 
dose CTX. 
1.7 
Study Hypothesis 
The objectives of T-cell immunotherapy in people infected with HIV are to augment HIV-
specific T-cells and to reverse or decrease the progressive destruction of T-cells that leads to 
clinical AIDS. SB-728-T has been safely administered to over 70 HIV-infected subjects in four 
clinical trials conducted to date. The level of engraftment has varied from negligible to ~10% of 
the T-cells in the vascular compartment. Preliminary analyses of VL during TI in these studies 
suggest that an anti-HIV effect may correlate with the level of SB-728-T engraftment. 
Concurrently, non-myeloablative lymphodepletion with CTX has been demonstrated to enhance 
engraftment of adoptively transferred T-cells through a variety of mechanisms. The current study 
is being undertaken to increase SB-728mR-T engraftment through the administration of repeat 
doses of SB-728mR-T following CTX conditioning. 
  
2. 
STUDY OBJECTIVES 
2.1 
Primary Objective 
The primary objective of this study is to evaluate the safety and tolerability of repeat doses of 
SB-728mR-T following CTX conditioning. 


Sangamo BioSciences, Inc.  
Phase 1/2 Protocol SB-728mR-1401                                                                                                             Confidential 
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2.2 
Secondary Objectives 
The secondary objectives of this study are to evaluate: 
1. Effect of repeat doses of SB-728mR-T on engraftment following CTX conditioning 
2. Long-term persistence of SB-728mR-T in peripheral blood as measured by pentamer 
PCR 
3. Change in CD4+ T-cell counts in peripheral blood after repeat treatments with SB-
728mR-T 
4. Effect of SB-728mR-T on plasma HIV-1 RNA levels following HAART interruption 
5. Change in HIV reservoirs as part of exploratory research 
 
3. 
STUDY DESIGN 
3.1 
Overview 
This is a Phase 1/2, open-label, multi-center study. Subjects who satisfy all inclusion/exclusion 
criteria (Section 4) are eligible to participate in this study. Subjects will be enrolled sequentially 
into two treatment cohorts, Cohort 1 and Cohort 2. The first 3 subjects will be enrolled and 
treated in Cohort 1. The next 3 subjects will be enrolled and treated in Cohort 2. Depending upon 
the outcome in Cohort 1 and Cohort 2, the remaining 6 subjects will be enrolled and treated in 
either Cohort 1 or Cohort 2.    
Cohorts 1 and 2 data will be collected as subject visits occur per the study protocol. The first 
time point at which a regimen decision for the final 6 subjects can be made is two weeks after the 
third infusion of the first and second patients in Cohort 2, and, if the decision is to use the Cohort 
2 regimen, at least 2 weeks after the first infusion of the third subject in Cohort 2, and after all 
safety issues that require a pause in enrollment to that point have been resolved.   The staggering 
of patients in Cohort 1 will ensure that more data than this will be available for Cohort 1 
subjects.  
General considerations to determine cohort selection for the last 6 subjects will be: 
 Safety considerations: evaluation of severity and duration of AEs and SAEs and 
laboratory data in cohort 1 and cohort 2 subjects and resolution of any safety 
issues requiring a pause in enrollment 
 Efficacy considerations:  primarily, evaluation of the change in CD4 and CD8 
count, and level of engraftment of CCR5 modified T-cells as measured by 
pentamer duplication.  These parameters peak 7 days after infusion.  Secondarily, 
any viral load changes which have occurred during treatment interruptions in 
subjects from Cohort 1.   
Sangamo will perform the analyses and assessment at the time point described above.  
Subjects will undergo an apheresis to collect PBMC for the production of SB-728mR-T cells. 
The manufactured SB-728mR-T cells will be divided into 2 to 3 doses (total dose: up to ~4.0 x 
1010 cells) depending on cohort assignment. All subjects will receive a dose of CTX 1.0 g/m2 on 
Day -2, and the first and second doses of SB-728mR-T on Day 0 and Week 2, respectively.  The 
third dose of SB-728mR-T will be administered on Week 4 for Cohort 2 subjects only. 
Treatment of at least the first 4 subjects will be staggered so that each subsequent subject will not 
be treated until at least 2 weeks after the preceding subject. Subjects who are aviremic and have 
CD4 cell counts ≥500 cells/µL will undergo a minimum 16 week TI beginning 4 weeks after the 


Sangamo BioSciences, Inc.  
Phase 1/2 Protocol SB-728mR-1401                                                                                                             Confidential 
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last infusion of SB-728mR-T. TI may be extended beyond 16 weeks for subjects whose HIV 
RNA levels ≤ 10,000 copies/mL and CD4 count ≥ 500 cells/µL at the end of the 16-week TI. 
Subjects will be followed for 12 months following the first SB-728mR-T infusion in the Study 
Period and an additional 24 months in the long-term follow-up (LTFU) period.   
Additional research blood collection and/or an optional leukapheresis may be performed during 
the study upon sponsor request. 
3.2 
Number of Subjects 
Up to 12 aviremic HIV-infected subjects on HAART will be enrolled and treated in 2 dose 
cohorts.  
3.3 
Study Duration 
The duration of study participation will be approximately 40 months, including 16 months for 
the Study Period (approximately 4 months for screening, leukapheresis, and SB-728mR-T 
production, and 12 months following the first SB-728mR-T infusion) and an additional 24 
months of LTFU.  
3.4 
Visit Schedule 
Subjects will complete all screening procedures and enrolled subjects will undergo a 10 L 
leukapheresis to collect peripheral blood mononuclear cells for the manufacturing of SB-728mR-
T (approximately 2 months). Subjects will then receive 1.0 g/m2 of IV CTX 2 days prior to the 
first infusion of SB-728mR-T. The first SB-728mR-T infusion will occur on Day 0. Subsequent 
SB-728mR-T infusions will be given 14 days apart. Subjects will be seen one day after each SB-
728mR-T infusion and weekly on Weeks 1 through 6 (Cohort 1) and Week 8 (Cohort 2). 
Subjects will then begin a minimum 16-week TI beginning 4 weeks after the last SB-728mR-T 
infusion (Week 6 for Cohort 1 and Week 8 for Cohort 2). During the TI, subjects will be 
evaluated every 2 weeks for the first 8 weeks and monthly for the following 8 weeks. After 
completion of the 16-week TI (Section 9.3), subjects may extend the TI if they meet the 
protocol-specified requirements for TI extension. During extended TI, HIV-1 RNA and CD4 
counts will be tested monthly. All subjects will be seen at Month 7, Month 9, Month 12, Month 
18, Month 24, and Month 36. 
Upon the sponsor’s request, additional blood collection and /or an optional leukapheresis may be 
performed during the study. 
3.5 
Study Procedures 
Subjects will have periodic blood tests to assess safety labs, plasma HIV-1 RNA levels and 
CD4+ T-cell counts; physical exams; AE assessment; and review of medications (Appendix I).  
 
4. 
SUBJECT SELECTION 
4.1 
Inclusion Criteria 
1. 
Written informed consent signed and dated by study subject.   
2. 
Male or female, 18 years of age or older. 
3. 
Documented HIV diagnosis.  
4. 
Adequate venous access and no other contraindications for leukapheresis. 
5. 
Absolute neutrophil count (ANC) ≥ 2500/mm3.  
6. 
Hemoglobin level  13 g/dL (males); ≥ 12 g/dL (females). 
7. 
Platelet count ≥ 200,000/mm3.  


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Phase 1/2 Protocol SB-728mR-1401                                                                                                             Confidential 
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8. 
Serum creatinine ≤ 1.5 mg/dL. 
9. 
AST and ALT  2.5 times the upper limit of normal.  
10. Must be willing to comply with study-mandated evaluations; including only 
changing antiretroviral regimen when indicated by the study doctor during the 
study period.  
11. Female of childbearing potential must have a negative serum pregnancy test at 
screening and negative urine pregnancy test at the baseline visit prior to infusion. 
A female subject is considered to be of childbearing potential if she is 
postmenarcheal, has an intact uterus and at least 1 ovary, and is less than 2 years 
postmenopausal.   
12. Have no polymorphisms in the CCR5 ZFN target region as determined by Cel 1 
SNP assay.  
13. Aviremic subjects who initiated antiretroviral therapy within (≤) 1 year of HIV 
diagnosis or suspected infection. The general classes of antiviral agents that a 
subject must be taking in order to be enrolled into the study include: non-
nucleoside reverse transcriptase inhibitors (NNRTI); nucleoside reverse 
transcriptase inhibitors (NRTI); protease inhibitors; integrase inhibitors; and 
fusion inhibitors. HAART regimens must be in accordance with the Department 
of Health and Human Services (DHHS) document, “Guidelines for the Use of 
Antiretroviral Agents in HIV-1-Infected Adults and Adolescents”. Should a 
newly-approved product become available that is not captured in the current 
guideline, clinicians and sponsor will determine subject eligibility. 
14. Aviremic subjects on HAART with low innate immune system activation as 
determined by percentage of activated CD14+/CD16+ monocytes ≤ 60%. 
15. Have had undetectable VLs for at least 2 months prior to screening. Subjects who 
had intermittent isolated episodes of detectable low-level viremia <500 copies 
RNA/mL; blips) will remain eligible. 
16. HIV-1 RNA below the limit of detection  
17. CD4+ T-cell count ≥500 cells/µL.  
18. Willing to discontinue current antiretroviral therapy during the TI. 
4.2 
Exclusion Criteria 
1. 
Acute or chronic hepatitis B or hepatitis C infection.  
2. 
Active or recent (in prior 6 months) AIDS defining complication. 
3. 
CXCR4 tropic or dual tropic HIV virus. 
4. 
Any cancer or malignancy within the past 5 years, with the exception of 
successfully treated basal cell or squamous cell carcinoma of the skin or low 
grade (0 or 1) anal or cervical dysplasia. 
5. 
Current diagnosis of NYHA grade 3 or 4 CHF, uncontrolled angina or 
uncontrolled arrhythmias. 
6. 
History or any features on physical examination indicative of a bleeding diathesis. 
7. 
Previous treatment with any HIV experimental vaccine within 6 months prior to 
screening, or any previous gene therapy using an integrating vector. 


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Phase 1/2 Protocol SB-728mR-1401                                                                                                             Confidential 
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NOTE: Subjects treated with placebo in an HIV vaccine or gene therapy study 
will not be excluded if documentation that they received placebo or sham gene 
therapy is provided. 
8. 
Use of chronic corticosteroids, hydroxyurea, or immunomodulating agents (e.g., 
interleukin-2, interferon-alpha or gamma, granulocyte colony stimulating factors, 
etc.) within 30 days prior to screening. 
NOTE: Use of inhaled or topical steroids is not exclusionary.  
9. 
Breast-feeding, pregnant or unwilling to use acceptable methods of birth control 
for 6 months following the last infusion of SB-728mR-T cells. 
NOTE: The following are acceptable methods of birth control: 
a. Condoms (male or female) with or without a spermicidal agent  
b. Intrauterine device (IUD)  
c. Diaphragm or cervical cap with spermicide 
d. Hormonal-based contraception 
Subjects who become pregnant after SB-728mR-T infusion must inform the 
investigator of their pregnancy and agree to provide follow-up information at 
time of delivery. 
10. Use of Aspirin, dipyridamole, warfarin or any other medication that is likely to 
affect platelet function or other aspects of blood coagulation during the 2 week 
period prior to leukapheresis.  
11. Active drug or alcohol use or dependence that, in the opinion of the investigator, 
would interfere with adherence to study requirements. 
12. Serious illness requiring systemic treatment and/or hospitalization within 30 days 
prior to study entry. 
13. Elevations of baseline serum bilirubin and amylase ≥3 times the upper limit of 
normal.  
NOTE: Asymptomatic elevations due to HAART medications are not 
exclusionary, when, in the opinion of the investigator, the abnormalities are not 
attributable to intrinsic hepatic disease.   
14. Recent vaccination or intercurrent illness (within 5 weeks prior to SB-728mR-T 
infusion). 
NOTE: it is recommended that subjects should have completed their routine 
vaccinations (hepatitis A or B, pneumococcus, influenza and tetanus diphtheria 
booster) at least 30 days prior to screening for the study. 
15. Have an allergy or hypersensitivity to study product excipients (human serum 
albumin, DMSO and Dextran 40). 
16. Currently participating in another clinical trial or participation in such a trial 
within 30 days prior to screening visit.  
17. Subjects who are currently taking maraviroc or have received maraviroc within 6 
months prior to screening. 
18. Any other condition that, in the opinion of the clinical investigator or sponsor, 
might compromise any aspect of this trial. 


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Phase 1/2 Protocol SB-728mR-1401                                                                                                             Confidential 
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5.  
INFORMED CONSENT 
Prior to entering the study, the investigator or designated personnel will explain to each subject 
the nature of the study, its purpose, the procedures, the expected duration, alternative therapies 
available, and the benefits and risks involved in study participation.  Subjects will be given an 
information and consent document, will have the opportunity to ask questions, and will be 
informed of their right to withdraw from the study at any time without prejudice. After this 
explanation and before any study-specific procedures have been performed, the subject must 
voluntarily sign and date the informed consent document. 
The subject will receive a copy of the signed and dated written informed consent form and any 
other written information required to be provided to the subject. Subjects will be re-consented at 
the time of any informed consent amendment, as applicable, and will be provided a copy of the 
consent form. 
 
6. 
STUDY METHODOLOGY 
Prior to initiation of this study, the study site must have the protocol and subject informed 
consent form approved by the IRB. Subjects must be willing to participate in all study 
procedures in this protocol. The following sections describe all study procedures. See Section 7 
for details of evaluations. Additional detailed instructions will be provided in the Study 
Reference Manual.   
A table of all study procedures is presented in the Schedule of Events (Appendix I).  
6.1 
Screening Visit Procedures 
The objective of the screening visit is to identify subjects who meet the stated inclusion and 
exclusion criteria and who are willing and able to participate in the study. The following 
screening information and procedures must be completed and results reviewed for eligibility. 
The following will be performed at the screening visit: 
1. Obtain a signed and dated subject informed consent form and authorization document 
to use and disclose medical information prior to performing any study-specific 
procedures 
2. Assign a subject number 
3. Review the inclusion and exclusion criteria 
4. A complete medical history including demographic information; access and review 
of concomitant medications. If the subject is not normally seen at the study center, it 
may be necessary to obtain medical records to confirm study eligibility.  
5. Complete Physical Exam, including vital signs  
6. 12-lead ECG 
7. Hepatitis B surface antigen (HBsAG) and hepatitis C antibody (HCV)  
8. Serum pregnancy test (female of childbearing potential) 
9. Urinalysis for presence of glucose, protein, bilirubin, blood, pH, and specific gravity 
10. CBC  
11. Serum chemistry: electrolytes (Na, K, CO2, Cl), creatinine, BUN, glucose, uric acid, 
total bilirubin, ALP, ALT (or SGPT), AST (or SGOT), LDH, albumin, calcium, and 
total protein, phosphorus.  


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Phase 1/2 Protocol SB-728mR-1401                                                                                                             Confidential 
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12. CD4+ T-cell counts  
13. HIV-1 RNA  
14. CCR5 SNP Cel-I assay (not required if prior results available) 
15. HIV-1 Co-receptor Tropism 
16. Innate immune system activation evaluation (not required if prior results available) 
17. Research blood 
6.2 
Subject Enrollment Procedures 
Prior to the first leukapheresis, the study site must verify that the subject meets all inclusion and 
none of the exclusion criteria. A subject is considered enrolled after they meet all the entry 
criteria and have undergone the first leukapheresis.   
6.3 
Pre- Leukapheresis and Leukapheresis  
Subjects who meet all the eligibility criteria will be scheduled for leukapheresis. Sangamo 
BioSciences should be contacted by the study center prior to scheduling leukapheresis and 
Sangamo will ensure availability of manufacturing facility.   
6.3.1 Pre-Leukapheresis: 
The following blood tests must be drawn approximately 1 week prior to the leukapheresis 
procedure and results sent to the Apheresis unit and Sangamo.   
1. CBC 
2. Electrolytes (Na, K, C02, Cl) 
3. Calcium 
4. Liver function tests (albumin, total protein, alkaline phosphatase, AST, ALT,  total 
bilirubin) 
6.3.2 Leukapheresis: 
From a single 10L volume leukapheresis, at least 10 x 109 white blood cells will be harvested to 
manufacture SB-728mR-T. The leukapheresis procedure will be conducted according to the 
facilities guideline. The cells from the leukapheresis product will be genetically modified and 
expanded using anti-CD3/CD28 beads. The cell product is expected to be ready for release to the 
study center approximately 6-8 weeks later. If the product from the first leukapheresis does not 
meet cell release criteria or there are insufficient cells for the intended dose, a second 
leukapheresis may be scheduled. The second leukapheresis will be at least three weeks after the 
first leukapheresis. AEs documented during leukapheresis will be entered onto the CRFs. 
6.4 
Baseline Assessments 
6.4.1  Baseline for Research Blood Collection: 
The following blood tests will be drawn between the leukapheresis procedure and CTX 
administration:   
1. CBC 
2. CD4+ T-cell count 
3. Research blood 
6.4.2 Baseline: 


Sangamo BioSciences, Inc.  
Phase 1/2 Protocol SB-728mR-1401                                                                                                             Confidential 
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Baseline assessments will be performed approximately one week prior to CTX administration, 
and the subject should be evaluated. The following tests are performed at the baseline visit: 
1. Assessment of AEs 
2. Review concomitant medications 
3. Urine pregnancy test (for females of child bearing potential only) 
4. Chemistry 
5. CBC 
6. Urinalysis 
7. CD4+ T-cell count 
8. HIV-1 RNA  
9. Height and Weight  
10. Research blood (may be performed on the day of CTX infusion and prior to CTX 
infusion) 
The following may be performed up to 4 weeks prior to the first SB-728mR-T infusion 
11. Pentamer 
12. SB-728mR immunogenicity 
6.5 
Study Treatment and Follow-up 
After baseline tests are reviewed, the study center and Sangamo BioSciences will schedule SB-
728mR-T dosing. Refer to the Study Reference Manual for details. All subjects will be followed 
for a total of 36 months after the first SB-728mR-T infusion according to the schedule in 
Appendix I. 
6.5.1 Cyclophosphamide Administration (Day -2) 
CTX should be administered 2 days prior to SB-728mR-T infusion. All subjects will remain at 
the study site after CTX administration until vital signs are satisfactory and stable. Subject may 
be released from the study site at investigator’s discretion. Subjects will be monitored, as needed, 
post CTX administration.  
1. AE assessment 
2. Assessment of concomitant medications 
3. Vital signs: temperature, pulse, and blood pressure (pre and post CTX 
administration) 
Pre-CTX administration: 
4. Chemistry 
5. CBC 
6. Urinalysis 
7. CD4+ T-cell count 
8. Volume status of subject will be assessed to ensure subject is euvolemic 
9. Euvolemic subjects will be infused IV with 1L of IV fluids over approximately 1-2 
hours. 


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Phase 1/2 Protocol SB-728mR-1401                                                                                                             Confidential 
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10. Antiemetic administration: Subjects may be prescribed with an antiemetic (IV, oral 
or suppository) before, during, and after CTX infusion to prevent and treat nausea 
and vomiting. Recommended antiemetic regimen: Palonosetron (Aloxi) 0.25 mg IV 
and Aprepitant (Emend) 125 mg by mouth (PO) 60 minutes before CTX. Other 
antiemetics may be given at the discretion of the investigator and with sponsor 
consultation if possible. 
CTX Administration: 
1. CTX 1.0 g/m2 administration 
Post-CTX Administration: 
2. 1L of IV fluids infused over approximately 1-2 hrs after CTX administration  
3. Subjects should consume at least 4L of fluids over the 24 hrs after receiving CTX.  
4. Recommended antiemetic regimen: Aprepitant (Emend) 80 mg PO daily (QD) for the 
following 6 days. Other antiemetics may be given at the discretion of the investigator 
and with sponsor consultation if possible. 
Post CTX administration, if neutrophil count drops to ≤ 750/mm3, administration of 
Filgrastim is recommended. Filgrastim can be discontinued when neutrophil count is ≥ 
1000/mm3 (Section 8.2). 
6.5.2 SB-728mR-T Infusions: Day 0 and Week 2 (+/- 1 day); and Week 4 (Cohort 2 only) 
(+/- 1 day) 
SB-728mR-T should be infused 2 days after completion of the CTX administration (Section 
8.1). All subjects will remain at the study site for approximately 2 hours after SB-728mR-T 
infusion and vital signs are satisfactory and stable.  
1. AE assessment 
2. Assessment of concomitant medications 
3. Vital signs: temperature, pulse, and blood pressure (pre and post SB-728mR-T 
infusion, and as needed) 
Pre-SB-728mR-T Infusion: 
4. Chemistry (Day 0) 
5. CBC 
6. Urine pregnancy test (for females of child bearing potential only) 
7. Urinalysis (Day 0) and (Week 4: Cohort 2) 
8. CD4+ T-cell count 
9. HIV-1 RNA (Weeks 2 and 4) 
10. Pentamer (Week 2) and (Week 4: Cohort 2) 
11. Research blood (Day 0 and Week 2) 
SB-728mR-T Infusions Day 0 and Week 2 (Cohort 1); Day 0, Week 2 and Week 4 (Cohort 2): 
12. SB-728mR-T infusion 
Each SB-728mR-T infusion will occur 14 days apart. 
6.5.3 Day 1 / Day 15, and Day 29 (Cohort 2 only) (one day post SB-728mR-T infusions) 


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Phase 1/2 Protocol SB-728mR-1401                                                                                                             Confidential 
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1. AE assessment  
2. CBC  
3. Urinalysis (Day 1) 
4. CD4+ T-cell count 
5. Pentamer  
6. Research blood (Day 1 only) 
6.5.4 Weekly Visits Post SB-728mR-T Infusion (+/- 2 day) 
Cohort 1: Week 1, Week 3, Week 4, and Week 5  
Cohort 2: Week 1, Week 3, Week 5, Week 6, and Week 7 
1. AE assessment 
2. Review of concomitant medications  
3. Chemistry (Weeks 1 and 3) and (Week 5: Cohort 2 only) 
4. CBC 
5. Urinalysis (Week 1) and (Week 4: Cohort 1 only) 
6. CD4+ T-cell count  
7. HIV-1 RNA  
8. Pentamer  
6.5.5 16-Week HAART Treatment Interruption  
Cohort 1 (Week 6-Week 22): Weeks 6, 8, 10, 12, 14, 18, and 22 
Cohort 2 (Week 8-Week 24): 8, 10, 12, 14, 16, 20, and 24  
All subjects with aviremia and CD4 cell counts ≥500 cells/µL will undergo a minimum 16-week 
TI. Subjects will be seen every other week (+/- 3 days) for the first 8 weeks and then every 
month (+/- 1 week) for the remaining 8 weeks of the TI. (Section 8.3) 
Subjects will discontinue HAART under the supervision of the principal investigator. NNRTIs 
such as Rescriptor, Sustiva, Intelence, and Viramune have been reported to have a longer half 
life than NRTIs. Therefore, to avoid suboptimal drug exposure which may promote drug 
resistance, subjects on a NNRTI containing regimen should discontinue the NNRTI seven days 
before stopping their other antiretrovirals (Taylor et al., 2007). The time of medication 
interruption is noted in medication records and CRFs. The TI begins for an individual subject on 
the day that all antiretrovirals agents have been discontinued.  
The following procedures will be performed at each visit during the TI: 
1. Begin TI (discontinue all HAART) (Week 6: Cohort 1) (Week 8: Cohort 2) 
2. AE assessment 
3. Assessment of concomitant medications 
4. Vital signs (temperature, pulse, blood pressure, and weight) (Weeks 6 and 22: Cohort 
1) (Week 8 and 24: Cohort 2) 
5. Chemistry (Weeks 8, 12, 22: Cohort 1), (Weeks 8, 12 24: Cohort 2) 
6. CBC  
7. CD4+ T-cell (during the initial 16 week TI, test will be repeated every 2 weeks for 3 
consecutive measurements for values <500 cells/µL) 


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Phase 1/2 Protocol SB-728mR-1401                                                                                                             Confidential 
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8. HIV-1 RNA (during the initial 16 week TI, test will be repeated every 2 weeks for 3 
consecutive measurements for values >100,000 copies/mL) 
9. HIV-1 coreceptor tropism and resistance testing will be performed once if HIV RNA 
exceeds 1,000 copies/mL 
10. Pentamer  
11. SB-728mR-T immunogenicity (Week 12 only) 
12. Research blood (Weeks 6, 12, and 22: Cohort 1) and (Weeks 8, 14, and 24: Cohort 2) 
At the end of the 16-week TI at Week 22 (Cohort 1) and Week 24 (Cohort 2): 
 HAART will be reinstituted in subjects with HIV RNA levels >10,000 copies/mL and/or 
CD4 <500 cells/µL.    
 Subjects with HIV RNA levels ≤ 10,000 copies/mL and CD4 count ≥ 500 cells/µL may 
elect to remain off HAART and undergo extended TI beyond 16-weeks (subjects with a 
VL that is below the limit of detection will remain off HAART). (Section 8.3) 
During extended TI, HIV-1 RNA and CD4 counts will be measured monthly. HAART will be 
reinstituted when one or both of the following criteria are met: 
 HIV RNA levels > 10,000 copies/mL, confirmed by two additional consecutive monthly 
measurements (for a total of 3 measurements) 
 CD4 count < 500 cells/µL, confirmed by an additional consecutive monthly measurement 
(for a total of 2 measurements) 
Subjects will not be put back on HAART until all results are available.  
Subjects may have HAART reinstituted at any time at the discretion of the subject and/or PI. 
6.5.6 Month 7, Month 9 and Month 12 (+/- 1 week) 
1. AE assessment 
2. Assessment of concomitant medications 
3. Complete Physical Exam, including vital signs (Month 12 only) 
4. Chemistry  
5. CBC 
6. Urinalysis (Months 7 and 12 only) 
7. CD4+ T-cell count 
(For subjects in extended TI, test will be repeated monthly. HAART will be 
reinstituted if CD4 count <500 cells/µL for a total of 2 consecutive measurements) 
8. HIV-1 RNA 
(For subjects in extended TI, test will be repeated monthly. HAART will be 
reinstituted if HIV-1 RNA levels > 10,000 copies/mL for a total of 3 consecutive 
measurements) 
9. Pentamer  
10. SB-728mR-T immunogenicity (Months 7 and 12 only) 
11. Research blood  


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Phase 1/2 Protocol SB-728mR-1401                                                                                                             Confidential 
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6.5.7 Long-term Follow-up (LTFU): Month 18 and Month 24 (+/- 1 month) and Month 36 
(=/- 3 months) 
1. Complete Physical Exam, including vital signs (Months 24 and 36 only) 
2. Clinical condition assessment 
3. Assessment of concomitant medications (Months 24 and 36 only) 
4. Chemistry  
5. CBC  
6. CD4 T-cell count 
(For subjects in extended TI, test will be repeated monthly. HAART will be 
reinstituted if CD4 count <500 cells/µL for a total of 2 consecutive measurements) 
7. HIV-1 RNA 
(For subjects in extended TI, test will be repeated monthly. HAART will be 
reinstituted if HIV-1 RNA levels > 10,000 copies/mL for a total of 3 consecutive 
measurements) 
8. Pentamer 
There are no disallowed medications (experimental or licensed) for subjects in the long-term 
follow-up portion of the study. 
 
The following additional study procedures may be performed upon request of sponsor:  
1. Additional Research Blood collection of 80 mL one or two times. The second blood 
collection of 80 mL will be performed only when insufficient cells are obtained from 
the first collection. If any subject agrees to undergo optional leukapheresis in the 
study, this research blood collection of 80 mL will not be performed.  
a. Blood collection for CBC with differential and CD4+ T-cell counts 
b. 80 mL blood collection 
2. Optional leukapheresis  
Subject who agrees to an optional leukapheresis will undergo the following additional 
study procedures:  
 Pre-Leukapheresis Visit: ≤ 7 days prior to the leukapheresis procedure, the 
following blood tests will be performed and results sent to the apheresis facility 
and Sangamo: 
a. CBC 
b. Electrolytes (Na, K, C02, Cl) 
c. Calcium 
d. Liver function tests (albumin, total protein, alkaline phosphatase, AST, 
ALT,  total bilirubin) 
e. CD4+ T-cell counts (The test will be performed only if the leukapheresis 
center cannot collect this blood sample) 
 Leukapheresis Procedure Visit: The following will be performed:  


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Phase 1/2 Protocol SB-728mR-1401                                                                                                             Confidential 
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a. CBC and CD4+ T-cell counts (prior to the leukapheresis). If the 
leukapheresis center cannot collect the blood sample, this blood collection 
should be done at the pre-leukapheresis visit.  
b. a 10L volume leukapheresis procedure will be conducted according to the 
apheresis facility guidelines.  
 
7.  
INSTRUCTIONS FOR EVALUATIONS 
 Complete Physical Exam: a complete physical examination must include at a minimum 
an examination of the skin, head, mouth, and neck; auscultation of the chest; cardiac 
exam; abdomen; examination of the lower extremities for edema; and a breast exam for 
females. The complete physical exam will also include vital signs (temperature, pulse, 
blood pressure) (weight and height at Screen and Baseline Visits). 
 CBC: Hemoglobin, hematocrit, platelet count, red cell count, and white cell count with 
differential count and absolute neutrophil count.  
 Chemistry: Bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), 
alkaline phosphatase (ALP), sodium, potassium, chloride, bicarbonate, urea nitrogen, 
creatinine, total protein, albumin, calcium, and phosphorous.  
 Hepatitis B: subjects must have documentation of a negative HBsAg test at screening.   
 Hepatitis C: subjects must have documentation of a negative HCV antibody test at 
screening. If the HCV antibody is positive, the subject may return for a HCV RNA 
test.  If the HCV RNA test is negative, the subject may undergo leukapheresis.  
 HIV-1 Co-receptor Tropism and Resistance Testing: the HIV-1 co-receptor tropism assay 
measures whether a patient has CCR5, CXCR4 or dual tropic virus.  The tropism assay 
looks at the surface receptors on HIV to determine the dominant co-receptor. Resistance 
testing will be performed using a highly accurate HIV drug resistance test that provides 
the complete picture of resistance and combines actual phenotype and genotype drug 
resistance data. The report will include drug resistance information for all of the approved 
NRTIs, NNRTIs, protease inhibitors, and integrase inhibitors. 
 
 
8.  
INVESTIGATIONAL PRODUCT AND OTHER STUDY MEDICATIONS 
8.1 
SB-728mR-T 
SB-728mR-T is autologous T-cells modified at the CCR5 gene by ZFNs that are delivered by 
mRNA electroporation. Autologous T lymphocytes are transduced ex vivo with SB-728mR. The 
final T-cell product, SB-728mR-T, is generated using 2 major elements: 1) SB-728mR 
electroporation used for gene delivery of CCR5 specific zinc finger nucleases and  2) CCR5 
modified autologous T-cells (SB-728mR-T) that have undergone ex vivo T-cell activation, ex 
vivo genetic modification by the SB-728mR, expansion and formulation.  The composition of the 
final T-Cell product is:  
Composition of SB-728mR-T 
Component 
Unit Formula  
SB-728 Treated T-cells 
0.5-1.25 x 108/mL 


Sangamo BioSciences, Inc.  
Phase 1/2 Protocol SB-728mR-1401                                                                                                             Confidential 
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PlasmaLyte A 
31.25% 
Dextran 40 and 5% Dextrose 
10% 
25% Human Serum Albumin 
20% 
Dimethyl Sulfoxide (DMSO) 
7.5% 
Dextrose 5%/.45% NaCl 
31.25% 
 
The final drug product is tested for identity, cell count, purity, viability, potency, mycoplasma, 
endotoxin, and sterility. Cells that have not met specifications or will not be infused will be 
destroyed by the manufacturer according to their procedures. A copy of the Certificate of 
Analysis (C of A) will accompany each infusion bag.   
8.1.1  Inventory, Storage, and Handling of the Drug Product 
SB-728mR-T is cryopreserved in a 250 mL cryocyte infusion bag at ≤ -130◦C.  The infusion bags 
will contain approximately 50 mL of T-cells (actual volume dependent on number of cells) and 
have a label affixed containing the following information: protocol number, subject study 
number, lot number and “FOR AUTOLOGOUS USE ONLY”. Each bag of cryopreserved 
genetically modified T-cells will contain approximately 0.5 x 1010 cells at a concentration of 
approximately 1 x 108 cells/mL of infusible cryomedia.   
The CCR5 ZFN-modified T-cells are not released from the manufacturer until the release criteria 
are met. Release tests are performed in process, on the pre-harvest cells, and on the final 
cryopreserved product. QC testing will be performed by contract manufacturer, Sangamo 
BioSciences, Inc. and commercial testing laboratories, prior to administration of cells to the 
subject. Quality control test results and documentation will be reviewed by external Quality 
Assurance personnel. The final release test for cell viability by Trypan Blue will be performed 
approximately 72 hours before the scheduled thaw and infusion. The final product will be split 
into 2 or 3 doses and will be stored frozen at the manufacturing facility until ready to be shipped 
to the clinical study center. The T-cell product and the C of A will be shipped frozen either via 
courier or overnight to the clinical study center prior to the scheduled infusion(s). The T-cell 
product should remain frozen at the clinical study center until successful placement of the IV 
infusion line into the subject. 
The T-cell product is considered biohazard material therefore if any CCR5 ZFN-modified T-cells 
are not infused, the infusion bag and tubing will be disposed of according to the study center’s 
procedures for safe handling of biological material. 
Accessibility to labeled T-cell product should only be to those individuals authorized by the 
investigator to dispense this study drug. 
The study center is required to maintain complete records of all study products received. 
Inventory will include the description of labeled product received during the course of this study, 
as well as a record of the labeled product that is dispensed. At the conclusion or termination of 
this study, return or destruction of all drug supplies must be coordinated with Sangamo 
BioSciences. Refer to the Study Reference Manual for additional details. 
The investigator agrees not to supply labeled product to any person other than study personnel 
and subjects in this study. 


Sangamo BioSciences, Inc.  
Phase 1/2 Protocol SB-728mR-1401                                                                                                             Confidential 
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8.1.2 SB-728mR-T Administration 
Side effects following SB-728mR-T cell infusions may include transient fever, chills, and/or 
nausea. It is recommended that the subject be pre-medicated with acetaminophen 650 mg by 
mouth and diphenhydramine hydrochloride (Benadryl) 25-50 mg by mouth or IV, prior to the 
infusion of SB-728mR-T. These medications may be repeated every 3-4 hours as needed. A 
course of non-steroidal anti-inflammatory medication may be prescribed if the subject continues 
to have fever not relieved by acetaminophen. It is recommended that subjects not receive 
systemic corticosteroids such as hydrocortisone, prednisone, prednisolone (Solu-Medrol) or 
dexamethasone (Decadron) at any time, except in the case of a life-threatening emergency, since 
this may have an adverse effect on T-cells. If corticosteroids are required for an acute infusion 
reaction, an initial dose of hydrocortisone 100 mg is recommended. 
SB-728mR-T will be shipped to the study site prior to the scheduled infusions. The first SB-
728mR-T dose should be infused 2 days after completion of the CTX administration. The study 
product should be thawed just prior to the scheduled infusion. Prior to the infusions, two 
individuals will independently verify all information in the presence of the subject to confirm 
that the information is correctly matched to the subject. The cell product should be infused 
within 15 minutes after it is thawed and before the solution becomes warm in the IV bag to 
ensure viability of infused cells.  Detailed instructions for the thaw and infusion of cells are in 
the Study Reference Manual. 
8.1.3 Precautions 
SB-728mR-T is an investigational product, and there is a possible risk of anaphylaxis. 
Emergency medical equipment will be available during the infusion in case the subject has an 
allergic response, or severe hypotensive crisis, or any other reaction to the infusion. Vital signs 
(temperature, pulse, blood pressure) will be taken before and after infusion, and as needed, then 
according to the study center procedures for a minimum of two hours. The subject will be asked 
to remain in the study unit until the study staff considers it safe for him/her to leave. 
In the unlikely event that the subject develops sepsis or systemic bacteremia following SB-
728mR-T infusion, appropriate cultures and medical management should be initiated. If possible 
contamination of the SB-728mR-T product is suspected, the product can be retested for sterility 
using archived samples that are stored at the manufacturing facility. 
As the transmission of HIV and other blood-borne pathogens can occur through contact with 
contaminated needles, blood and blood products, appropriate blood and secretion precautions 
should be employed by all personnel in the drawing of blood and shipping and handling of 
specimens for this study, as currently recommended by the Centers for Disease Control and 
Prevention and the National Institutes of Health. 
All dangerous goods materials, including diagnostic specimens and infectious substances, must 
be transported according to the instructions detailed in the International Air Transport 
Association (IATA) Dangerous Goods Regulations. 
8.1.4 Dose Modifications 
 The total dose of SB-728-mR-T will depend on the number of cells manufactured for each 
subject. No dose modifications are possible.   


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Phase 1/2 Protocol SB-728mR-1401                                                                                                             Confidential 
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8.2 
Cyclophosphamide 
CTX is a sterile white powder containing CTX monohydrate. It is available in vials of 500 mg, 
1.0 g and 2.0 g vials for single use only. The vials should be stored at 25◦C. CTX 1.0 g/m2 should 
be administered 2 days prior to SB-728mR-T infusion. CTX will not be administered to a subject 
until the subject’s SB-728mR-T product lot is released and the number of cells manufactured 
meets the minimum dose requirement. 
Subjects may be pre-medicated with acetaminophen 650 mg by mouth and diphenhydramine 
hydrochloride (Benadryl) 25-50 mg by mouth or IV, prior to the infusion of CTX. These 
medications may be repeated every 3-4 hours as needed.  
Antiemetics 
Recommended antiemetics such as Aloxi 0.25 mg IV and Emend 125 mg PO should be given 60 
minutes before CTX followed by Emend 80 mg PO once a day for the following 6 days. Other 
antiemetic regimens may be given at the discretion of the investigator and with sponsor 
consultation, if possible.  Subjects may be prescribed with an antiemetic (IV, oral or suppository) 
if nausea and vomiting develops during CTX administration.  
Filgrastim 
After CTX administration, if neutrophil count drops to ≤ 750/mm3, administration of Filgrastim 
is recommended. Filgrastim can be discontinued when neutrophil count is ≥ 1000/mm3. 
The adverse effects of CTX that occur at a frequency of >10% are discussed in Section 9.2. 
Please refer to the FDA approved manufacturer’s package insert and the Study Reference 
Manual for additional information. 
8.3 
HAART 
8.3.1 Discontinuation of HAART  
Subjects with aviremia and CD4 cell counts ≥500 cells/µL 4 weeks after the last SB-728mR-T 
infusion will discontinue HAART under the supervision of the principal investigator during the 
TI. NNRTIs such as Rescriptor, Sustiva, Intelence, and Viramune have been reported to have a 
longer half life than NRTIs. Therefore, to avoid suboptimal drug exposure which may promote 
drug resistance, subjects on an NNRTI containing regimen should discontinue the NNRTI seven 
days before stopping their other antiretrovirals (Taylor et al., 2007). The time of medication 
interruption is noted in medication records and CRFs. 
8.3.2 Reinstitution of HAART 
During the 16-week TI, tests for HIV-RNA and CD4 count will be repeated in 14 days for values 
>100,000 copies/mL and <500 cells/µL, respectively. HAART therapy will be reinstituted if the 
subject experiences a sustained VL increase to >100,000 copies/mL (on 3 consecutive 
measurements tested every 2 weeks) and/or a sustained drop in the CD4 count <500 cells/µL (on 
3 consecutive measurements tested every 2 weeks). The drug regimen that the subject will 
receive will be determined by the Principal Investigator in consultation with the subject’s 
primary HIV physician. To guide the selection of therapy, the tropism and sensitivity of the virus 
to antivirals will be determined by HIV-1 coreceptor and resistance testing, respectively. If the 
VL or CD4 drop is not sustained, the subject will be advised not to reinstate HAART until after 
the TI to allow for evaluation of the subject’s VL. 


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Phase 1/2 Protocol SB-728mR-1401                                                                                                             Confidential 
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At the end of the 16-week TI at Week 22 (Cohort 1) and Week 24 (Cohort 2): 
 HAART will be reinstituted in subjects with HIV RNA levels >10,000 copies/mL, 
and /or CD4 <500 cells/µL.  
 Subjects with HIV RNA levels ≤10,000 copies/mL and CD4 count ≥ 500 cells/µL 
may elect to remain off HAART and undergo extended TI beyond 16 weeks (subjects 
with HIV RNA levels below the limit of detection will remain off HAART).   
During extended TI, HIV-1 RNA and CD4 counts will be measured monthly. HAART will be 
reinstituted in subjects when one or both of the following criteria are met: 
 HIV RNA levels > 10,000 copies/mL, confirmed by two additional consecutive 
monthly measurements 
 CD4 count < 500 cells/µL, confirmed by an additional consecutive monthly 
measurement 
Subjects will not be put back on HAART until all results are available.  
Subjects may have HAART reinstituted at any time at the discretion of the subject and/or PI. 
8.4 
Concomitant Medication 
The investigator will record all concomitant medications including those given in treatment of 
AEs on the concomitant medication page in the subject’s case report form. Any medication taken 
by the subject from screening throughout the course of the study, including over-the-counter 
medicinal products, dietary supplements, and herbal medications, should be recorded on this 
form. 
Aspirin, dipyridamole, Plavix, warfarin, or any other medications likely to affect platelet 
function or other aspects of blood coagulation are prohibited during the 2-week period prior to 
leukapheresis.  
Oral corticosteroids, hydroxyurea, and immunomodulating agents are prohibited until 
completion of the Study Period. A brief course (< 1 week) of oral corticosteroids is allowed on 
study. 
Routine vaccines are prohibited for six months following infusion of cells, unless medically 
indicated. 
 
9.  
SAFETY AND POTENTIAL RISKS 
9.1 
SB-728mR-T 
This is the first study in which SB-728mR-T will be administered to humans. Side effects for 
SB-728mR-T in man are unknown, they may or may not be the same or similar to SB-728-T. 
SB-728-T at doses ranging from 5 to 40 billion cells has been safely administered to 
approximately 70 HIV-infected subjects in four clinical trials to date. One SB-728-T-related 
SAE (infusion reaction) occurred on the UPenn study. The longest duration of follow-up has 
been over 3 years in the first subject infused.  No new clinical conditions or SAEs related to SB-
728-T have been reported in the subjects participating in long-term follow-up.  
9.1.1 Emergence of CXCR4 HIV 
There is a theoretical possibility that CXCR4 viral variants may emerge following inhibition of 
CCR5. CXCR4 variants are more common in late stage HIV infection. Even if the CCR5 


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Phase 1/2 Protocol SB-728mR-1401                                                                                                             Confidential 
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depleted cells results in relative selection of low levels of CXCR4 variants, the antiretroviral 
treatment regimen will be able to maintain viral suppression therefore it is not expected that this 
will be a problem of clinical significance. Subjects in this study will be tested for presence of 
dual tropic or CXCR4 tropic virus prior to entering into the study and any subjects with evidence 
of dual or CXCR4 tropism will be excluded. During the TI, a sample will be sent for the HIV-1 
coreceptor assay to asses for CXCR4 or dual tropism when the VL increases to > 1,000 
copies/mL. Subjects with a CXCR4 or dual tropic virus will be restarted on HAART. 
9.1.2 Carcinogenicity 
There is a risk that people who receive gene transfer may develop new tumors derived from their 
genetically modified cells. This risk is primarily associated with viral gene transfer vectors that 
integrate into the cellular DNA where it may dysregulate genes controlling proliferation. The risk 
with mRNA electroporation is extremely low. Extensive preclinical safety studies have been 
carried out and support the safety of CCR5 specific ZFNs, are briefly summarized here and are 
recently published in Nature Biotechnology (Perez et al, 2008). Deep sequencing studies at 
genome sites chosen by their ability to bind to the SB-728mR ZFNs with up to 2 base 
mismatches have shown that the CCR5 specific ZFNs effect cleavage only at the target CCR5 
gene and at approximately one tenth the CCR5 rate at the highly homologous site of the CCR2 
gene.  Extremely low levels of modification are also seen in the intron of a third gene, ABLIM-2 
at an extremely low frequency of <1 in 18,000 genes. This data confirms the specificity of CCR5 
specific ZFNs to the CCR5 gene. No specific effects on cell growth have been observed, 
indicating that in vitro CCR5 specific ZFN modification does not appear to affect cell biology 
and replication.  Overall increases in double stranded DNA breaks as visualized by fluorescence 
microscopy has shown a transient increase just after ZFN treatment, which is self limiting, 
occurs at the time and level of expected CCR5 specific ZFN activity and is below the level 
induced by etoposide, which blocks topoisomerase II leading to DNA breaks during cell 
division. No T cell transformation has been detected in a soft agar transformation assay, or in 
multiple animal biotoxicity studies in which each animal received greater than the equivalent of a 
human dose, and over all animals a log equivalent of a human dose was evaluated. Taking this 
data together, there is currently no indication that CCR5 specific ZFN modified T-cells is unsafe 
and may cause T-cell tumors.  
9.1.3 Immunogenicity 
The immunogenicity of SB-728mR-T infusion is unknown. SB-728mR is short lived in the 
transduced cells.  Immunogenicity tests for CCR5 specific ZFNs in subjects who received SB-
728-T have been performed.  Preliminary data show that no immunogenicity against CCR5 
specific ZFNs was observed at 3 months post SB-728-T infusion.  
 
 9.2 
Cyclophosphamide 
CTX is associated with a variety of side effects. The adverse effects that occur at a frequency of 
>10% includes alopecia, infertility, nausea and vomiting, hemorrhagic cystitis and bone marrow 
suppression. Antiemetics will be given prophylactically and as needed for nausea and vomiting. 
Leukopenia is more common than thrombocytopenia and anemia with the onset 7 days after 
administration and a nadir at 10 to 14 days followed by recovery at 21 days. After CTX 
administration, if neutrophil count drops to ≤ 750/mm3, administration of Filgrastim is 
recommended. Filgrastim can be discontinued when neutrophil count is ≥ 1000/mm3. Subjects 
will be monitored, as needed, post CTX administration. 


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Phase 1/2 Protocol SB-728mR-1401                                                                                                             Confidential 
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Hemorrhagic cystitis is a potential untoward effect of CTX therapy with the metabolite acrolein 
implicated as the major urothelial toxin. The incidence of hemorrhagic cystitis was reported to be 
6% among subjects who received CTX (1.0-1.2 g/m2) for ovarian cancer. At these low doses, the 
American Society of Clinical Oncology recommends administering fluids to induce a diuresis. 
Hemorrhagic cystitis has not been reported in the Sangamo study in which similar preventative 
measures were taken. In this study, subjects will be hydrated with 1 liter of IV fluids prior to 
CTX administration and with another liter prior to discharge from the study center. Subjects are 
instructed to drink 4L of fluids over the next 24 hrs to insure adequate diuresis.  
CTX is a carcinogen and has been associated with malignancies. The risk depends upon the dose 
administered, other co-administered chemotherapy, use of radiotherapy, treatment intensity and 
duration of therapy. Cumulative doses totaling 10 g or less has been shown to be associated with 
an incidence of malignancy that is similar to that of the normal untreated population (Baker et 
al., 1987). Therefore, the low dose (1.0 g/m2) that will be administered in this study is unlikely to 
be carcinogenic. 
9.3 
HAART Treatment Interruption (TI) 
The efficacy and safety of HAART interruption for HIV patients has been reviewed by Patton 
(Patton, 2008). Data indicates that there is no clinical benefit to patients with acute HIV infection 
or those with virologic failure due to multidrug resistance. Indeed, TI may be harmful in patients 
with chronic successfully treated infections. Therefore, TI is currently only recommended in the 
context of clinical trials. 
The safety of TI has been demonstrated in the SB-728-T studies conducted by UPenn and 
Sangamo. Subjects underwent varying lengths of TI (12 and 16 weeks) during these studies. 
HAART was interrupted beginning 4, 6, and 8 weeks after SB-728-T infusion. Subjects were 
closely monitored throughout the TI and HIV-1 coreceptor tropism and resistance testing were 
performed during TI. After reinstitution of HAART, subjects became aviremic in a short period 
of time.  No subject has had a change in HIV tropism during the studies.  
 
Several precautions have been instituted in this protocol to insure subject safety. Subjects will be 
monitored closely during the TI period with study visits every 2 weeks for the first 8 weeks and 
monthly for the remaining 8 weeks. If the HIV RNA increases to >100,000 copies/mL and/or the 
CD4 count drops to <500 cells/µL, the tests will be repeated every 2 weeks for a total of 3 
consecutive measurements. HAART will be reinstituted in subjects whose CD4 cell counts drop 
to <500 cells/µL and/or whose HIV-RNA increases to >100,000 on three consecutive 
measurements. During extended TI, HIV-1 RNA and CD4 counts will be measured monthly and 
additional monitoring will be performed as needed for safety.  CD4 T-cell count will be repeated 
monthly for a total of 2 consecutive measurements if CD4 count <500 cells/µL and HIV-1 RNA 
will be repeated monthly for a total of 3 consecutive measurements if HIV-1 RNA levels > 
10,000 copies/mL. In addition, all subjects infected with a CXCR4 virus will resume HAART. 
The effectiveness of these stopping rules is demonstrated by the reinstitution of HAART in 
subjects in the studies cited above. 
It is possible that some subjects could experience symptoms compatible with retroviral rebound 
syndrome, or rarely, other clinical events that occur before use of HAART (e.g. immune 
thrombocytopenia). The kinetics of viral rebound are well characterized, typically occurring 
within 2 to 4 weeks following discontinuation of drug, and viral replication is routinely re-
suppressed with resumption of therapy. 


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Phase 1/2 Protocol SB-728mR-1401                                                                                                             Confidential 
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The psychological risks associated with TI appear to be minimal. In a survey reported at the 
2002 International AIDS Conference in Barcelona, study investigators quizzed enrollees about 
their experience in the Spanish Swiss Intermittent Treatment Trial, and found that the majority 
"viewed their experience positively." Only two stated they would not participate in a similar TI 
trial, compared to 72 that said they definitely would and 25 who answered that they would 
consider it. In terms of any problems taking HAART after interruptions, 73 reported that that it 
was no different, 10 said it felt easier while 17 found it more difficult. Furthermore, fewer side 
effects were reported upon restarting HAART than when therapy was first initiated (Le Braz et 
al., 2002). 
10. 
ADVERSE EVENTS 
10.1 
Definitions of an Adverse Event 
An AE is any untoward medical occurrence associated with the use of a drug in humans, whether 
or not considered drug related. The term “adverse event” could include any of the following 
events which develop or increase in severity during the course of the study. Examples include: 
 Any sign, symptom, or physical examination finding that worsens in nature, severity, or 
frequency compared to baseline. Whether thought to be related or unrelated to the 
condition under study 
 Any clinically significant laboratory abnormality or laboratory abnormality that requires 
medication or hospitalization 
 All reactions from study drug, including those occurring as a result of an overdose, abuse, 
withdrawal phenomena, sensitivity, or toxicity to study drug 
 Concurrent illness 
 Injury or accident 
A pre-existing condition is one that is present prior to or at the start of the study and is to be 
reported as part of the subject’s medical history.  It should be reported as an AE only if the 
frequency, intensity, or the character of the condition worsens during study treatment. 
The term AE also applies to laboratory findings or results of other diagnostic procedures that are 
considered to be clinically relevant (e.g., that required unscheduled diagnostic procedures or 
treatment measures, or resulted in withdrawal from the study). 
Suspected Adverse Reaction is any AE for which there is a reasonable possibility that the drug 
caused the AE. “Reasonable possibility” means there is evidence to suggest a causal relationship 
between the drug and the AE. Suspected adverse reaction implies a lesser degree of certainty 
about causality than adverse reaction, which means any AE caused by a drug. 
Unexpected AE or Unexpected Suspected Adverse Reaction:  An AE or suspected adverse 
reaction is considered “unexpected” if it is not listed in the investigator brochure or is not listed 
at the specificity or severity that has been observed; or, if an investigator brochure is not required 
or available, is not consistent with the risk information described in the general investigational 
plan or elsewhere in the current application, as amended.  For example, under this definition, 
hepatic necrosis would be unexpected (by virtue of greater severity) if the investigator brochure 
referred only to elevated hepatic enzymes or hepatitis.  Similarly, cerebral thromboembolism and 
cerebral vasculitis would be unexpected (by virtue of greater specificity) if the investigator 
brochure listed only cerebral vascular accidents.  “Unexpected,” as used in this definition, also 
refers to AEs or suspected adverse reactions that are mentioned in the investigator brochure as 


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Phase 1/2 Protocol SB-728mR-1401                                                                                                             Confidential 
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occurring with a class of drugs or as anticipated from the pharmacological properties of the drug, 
but are not specifically mentioned as occurring with the particular drug under investigation. 
10.2 
Adverse Event Reporting Period 
During the Study Period, subjects will be queried and events will be assessed at each clinic visit.  
Subjects will be reminded to immediately report any SAE to the investigator.  Any study 
procedure related AEs that occur from enrollment to initiation of treatment will also be recorded.  
Refer to Section 12 for reporting clinical conditions during LTFU.   
10.3 
Recording of an Adverse Event 
The principal investigator is responsible for evaluating all AEs, obtaining supporting documents, 
and determining that documentation of the event is adequate. He/she is responsible for 
determining the severity and relationship to the investigational drug.  The principal investigator 
may delegate these duties to sub-investigators and must assure that these sub-investigators are 
qualified to perform these duties under the supervision of the principal investigator. 
All AEs will be recorded in the subject's case report form (CRF).  The detailed description of the 
event will include appropriately graded severity of the AE and its relationship to the study drug. 
Severity will be categorized by toxicity grade according to the Division of AIDS Table for 
Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), 
Version 1.0, December 2004, Clarification 1.0, August 2009 with the exception of the following: 
nausea or vomiting will be a Grade 3 non-hematological AE if IV fluids are required for more 
than 24 hours. 
 
AEs not listed in the DAIDS Clinical Trial Toxicity Criteria with the exception of noninfective 
cystitis will be evaluated by using the following criteria:  
 Grade 1, Mild: Symptoms causing no or minimal interference with usual social & 
functional activities  
 Grade 2, Moderate:  Symptoms causing greater than minimal interference with usual 
social & functional activities  
 Grade 3, Severe:  Symptoms causing inability to perform usual social & functional 
activities 
 Grade 4, Potentially Life-threatening: Symptoms causing inability to perform basic self-
care functions OR medical or operative intervention indicated to prevent permanent 
impairment, persistent disability, or death  
 Grade 5: For any AE where the outcome is death. 
Noninfective cystitis will be graded according to the Common Terminology Criteria for Adverse 
Events (CTCAE) Version 4.03 with the following criteria:  
 Grade 1: Microscopic hematuria; minimal increase in frequency, urgency, dysuria, or 
nocturia; new onset of incontinence   
 Grade 2:  Moderate hematuria; moderate increase in frequency, urgency, dysuria, 
nocturia or incontinence; urinary catheter placement or bladder irrigation indicated; 
limiting instrumental activities of daily living (ADL) 
 Grade 3:  Gross hematuria; transfusion, IV medications or hospitalization indicated; 
elective endoscopic, radiologic or operative intervention indicated  


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Phase 1/2 Protocol SB-728mR-1401                                                                                                             Confidential 
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 Grade 4: Life-threatening consequences; urgent radiologic or operative intervention 
indicated 
 Grade 5: Death 
The relationship of the AE to the investigational drug will be determined by the principal 
investigator and will be categorized as:  
Not Related: Any AE that does not meet the definition of a suspected AE reaction. 
 
All grade 3 and 4 clinical laboratory results that represent an increase in severity from baseline 
will be reported as AEs if it is not associated with a diagnosis already reported on the case report 
form.  A grade 1 or 2 clinical laboratory abnormality should be reported as an AE only if it is 
considered clinically significant by the investigator. 
In the event of death, the cause of death should be recorded as the AE and reported as an SAE.  
“Death” is not the AE; “death” is an outcome.  If an autopsy is performed, a copy of the autopsy 
report should be obtained if possible. 
 
11. 
SERIOUS ADVERSE EVENT 
11.1 
Definitions of a Serious Adverse Event 
Any AE or suspected adverse reaction is considered “serious” ” if, in the view of either the 
investigator or sponsor, it results in any of the following outcomes: 
 Death 
 A life-threatening AE 
 Inpatient hospitalization or prolongation of existing hospitalization 
 A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions 
 A congenital anomaly/birth defect in the offspring of an exposed patient 
 
An AE or suspected adverse reaction is considered “life-threatening” if, in the view of either the 
investigator, or sponsor, its occurrence places the patient or subject at immediate risk of death. It 
does not include an AE or suspected adverse reaction that, had it occurred in a more severe form, 
might have caused death). 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, they 
may jeopardize the patient or subject and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias 
or convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse. 
With regard to results obtained from tests in laboratory animals or in vitro testing, whether or not 
conducted by the sponsor, a SAE includes any event suggesting significant risk to human 
subjects. 
 


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Phase 1/2 Protocol SB-728mR-1401                                                                                                             Confidential 
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11.2 
Serious Adverse Event Reporting Period 
SAEs, whether or not unexpected or considered to be associated with the use of the labeled 
product, must be communicated to Sangamo BioSciences upon discovery of the event, either by 
telephone or fax within 24 hours. 
Medical Monitor: 
Winson Tang, M.D. 
Phone Number: 
Office : (510) 970-7800 
 
Mobile: (310) 497-7038  
Fax Number: 
(510) 970-6009 
The investigator is responsible for promptly notifying the Institutional Review Board (IRB) in 
accordance with local regulations, of all SAEs. The National Institutes of Health (NIH) requires 
that all investigators participating in gene transfer research report all serious AEs immediately to 
the FDA, NIH, and Institutional Biosafety Committee. Sangamo BioSciences will assume the 
responsibility for reporting SAEs to the FDA. 
All “serious” events must be followed with appropriate medical management until resolved or 
stabilized.   
Refer to Section 12 for reporting of SAEs during LTFU. 
 
11.3 
Recording of a Serious Adverse Event  
SAEs reported by telephone must be recorded on a written SAE Report Form, provided by 
Sangamo BioSciences.  The SAE report form must be faxed to Sangamo BioSciences within 24 
hours. 
The medical monitor will then advise the investigator regarding the nature of any further 
information or documentation that is required.  Follow-up reports must be submitted in a timely 
fashion as additional information becomes available.  
12 
CLINICAL CONDITION AND SERIOUS ADVERSE EVENT DURING LONG-
TERM FOLLOW-UP 
12.1 
Clinical Condition 
During the LTFU period, the following clinical conditions should be reported to the Sponsor and 
recorded on the subject Case Report Form: 
 Any new condition that may be considered to be related to treatment with SB-728mR-T  
 The emergence of a new malignancy, neurologic, rheumatologic/autoimmune or 
hematologic disorder regardless of severity or relationship to treatment with SB-728mR-
T. 
 Exacerbation of a pre-existing neurologic, rheumatologic or other autoimmune disorder 
regardless of relationship to treatment with SB-728mR-T 
Malignancies will be submitted to Sangamo within 7 days of learning of the diagnosis and will 
include the date of diagnosis and type of malignancy, stage at diagnosis, presence of metastasis, 
surgical procedures and therapy.  
Severity of reportable clinical conditions will be categorized by using the following criteria:  
 Grade 1, Mild: Symptoms causing no or minimal interference with usual social & 
functional activities 


Sangamo BioSciences, Inc.  
Phase 1/2 Protocol SB-728mR-1401                                                                                                             Confidential 
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 Grade 2, Moderate:  Symptoms causing greater than minimal interference with usual 
social & functional activities  
 Grade 3, Severe:  Symptoms causing inability to perform usual social & functional 
activities 
 Grade 4, Potentially Life-threatening: Symptoms causing inability to perform basic self-
care functions OR medical or operative intervention indicated to prevent permanent 
impairment, persistent disability, or death  
 Grade 5: For any AE where the outcome is death. 
12.2 
Reporting Serious Adverse Events in LTFU 
SAEs will be reported to the Sponsor (Section 11.2) upon discovery of the event, either by 
telephone or fax within 24 hours and recorded (Section 11.3) in the Case Report Form only if 
the event is serious, unexpected, and considered to be related to treatment of SB-728mR-T.  
Refer to Section 11.1 for SAE definitions. 
 
13. 
SUBJECT WITHDRAWAL AND STOPPING RULES   
13.1 
Subject Withdrawal and Discontinuation from Study  
Subjects should be discontinued from study for any of the following reasons: 
 
Request by the subject to withdraw. 
 
Request of the sponsor or primary care provider if he or she thinks the study is no 
longer in the best interest of the subject. 
 
Pregnancy prior to SB-728mR-T infusion. 
 
Subject judged by the investigator to be at significant risk of failing to comply with 
the provisions of the protocol as to cause harm to self or seriously interfere with the 
validity of the study results. 
 
At the discretion of the IRB, Office for Human Research (OHR), Food and Drug 
Administration (FDA), investigator, or Sangamo. 
Subjects will be strongly encouraged to continue with follow-up safety evaluations if they 
withdraw consent. If a subject discontinues from the study a conference between the investigator 
and medical monitor may take place to ensure that all subjects will comply with the follow-up 
safety evaluations of the protocol. Subjects will be assessed for treatment-related AEs and 
disease status. 
13.2 
Stopping Rules  
13.2.1 Stopping Rules for Treatment Interruption 
The TI will be stopped if the subject experiences a sustained VL increase to >100,000 copies/mL 
(at least 3 consecutive measurements tested every 2 weeks) and/or a sustained drop (at least 3 
consecutive measurements tested every 2 weeks) in the CD4 count <500 cells/µL during the 
initial 16 weeks of TI. HAART will be reinstituted in these subjects. The drug regimen that the 
subject will receive will be determined by the Principal Investigator in consultation with the 
subject’s primary HIV physician. To guide the selection of therapy, the tropism and sensitivity of 
the virus to antivirals will be determined.  
At the end of the 16-week TI: 


Sangamo BioSciences, Inc.  
Phase 1/2 Protocol SB-728mR-1401                                                                                                             Confidential 
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 HAART will be reinstituted in subjects with HIV RNA levels >10,000 copies/mL, and 
/or CD4 <500 cells/µL. 
 Subjects with HIV RNA levels ≤10,000 copies/mL and CD4 count ≥ 500 cells/µL may 
elect to remain off HAART and undergo extended TI beyond 16 weeks (subjects with 
HIV RNA levels below the limit of detection will remain off HAART).   
 
HAART will be reinstituted in subjects, whose TI is extended beyond 16 weeks, when one or 
both of the following criteria are met: 
 HIV RNA levels >10,000 copies/mL, confirmed by two additional consecutive monthly 
measurements.  
 CD4 count <500 cells/µL, confirmed by an additional consecutive monthly measurement.  
 
Subjects may have HAART reinstituted at any time at the discretion of the subject and/or PI. 
13.2.2 Stopping Rules for Study  
Safety data including AEs, clinical laboratory results (chemistry, hematology, CD4 T-cell counts 
and VL) will be evaluated throughout the study 
The study will be paused if there are excessive or unexpected toxicities associated with the 
protocol. Specifically, the study will be paused and reevaluated if it is determined: 
 
That one subject has a ≥ Grade 3 toxicity (with the exception of alopecia) as determined 
by the DAIDS Clinical Trial Toxicity Criteria of December 2004, Clarification 1.0, 
August 2009 and judged to be related to the study treatment.   
 
A subject experiences an absolute lymphocyte count greater than 10,000/uL, until the 
evaluation of the nature of the lymphocyte increase is determined. If it is found not to be 
related to the study treatment, then the study will resume. 
 
Confirmed CXCR4 or CXCR4 and CCR5 dual tropic virus: if at least two subjects 
develop a VL that can be assessed for tropism (>1,000 copies/mL) and they are both 
either CXCR4 or dual tropic. 
The study will be stopped if: 
 
The Investigator, Sponsor, independent safety monitor or regulatory body decides for any 
reason that subject safety may be compromised by continuing the study.   
 
The Sponsor decides to discontinue the development of the intervention to be used in this 
study. 
 
An analysis of clonal outgrowth of T-cells determines that it is a result of SB-728mR-T 
mediated oncogenesis. 
 
Sustained (confirmed) virologic failure without an alternative explanation: If any subject 
develops an increase in HIV-1 RNA of > 5000 copies/mL when not undergoing TI, the 
test will be repeated once a week for an additional 2 weeks. If the VL remains > 5000 
copies/mL for at least 3 weeks, and has no alternative explanation (such as non-
compliance) other than the study treatment, the study will be stopped. 
 
14. 
STATISTICAL ANALYSIS AND DATA ANALYSIS 
This is an exploratory study and thus, there will be limited statistical power to evaluate efficacy 
and related biological endpoints. Therefore, analyses will be primarily descriptive and 


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Phase 1/2 Protocol SB-728mR-1401                                                                                                             Confidential 
Page 38 of 66                                                                                   Version: October 10, 2014 
exploratory in nature.  
14.1 
Sample Size 
This is a phase 1/2 study in which up to 12 subjects will be treated to evaluate safety and 
tolerability of repeat infusions of SB-728mR-T following CTX conditioning. In order to have an 
evaluable sample size, subjects who prematurely discontinue the study prior to the conclusion of 
the TI may be replaced with another subject.  
 
14.2 
Statistical Methods/Data Analysis 
All tables, listings, and data summaries will be performed in SAS version 9.2 or later. 
14.3 
Intent-to-Treat Population 
All subjects enrolled in this study who receive any portion of the SB-728mR-T infusion will be 
included in the intent-to-treat population. 
14.4 
Demographics 
Demographic and baseline characteristics will be summarized by treatment cohorts.   
14.5 
Endpoints and Analysis 
Safety and efficacy analyses will be descriptive and exploratory in nature because of the small 
sample size. Continuous variables will be summarized by means, standard deviations, medians 
and ranges by cohort. Categorical variables will be summarized with counts and percentages per 
category by cohort.  
14.5.1 Primary Endpoint 
Safety assessment will occur on all subjects who received SB-728mR-T. All reported AEs will 
be coded to a standard set of terms using the Medical Dictionary for Regulatory Activities 
(MedDRA) AE dictionary. The frequency of each event will be summarized by severity and by 
relatedness to the study treatment. 
Terminations, premature withdrawals, AEs, concomitant medications, and laboratory data will be 
tabulated. Laboratory data will be summarized for each time-point that specimens are collected. 
Change-from-baseline values may be calculated for selected laboratory parameters. Shift-tables 
(change-from-baseline relative to the normal range) may be constructed for selected laboratory 
parameters. 
14.5.2 Secondary Endpoints 
These exploratory endpoints may help to define the primary endpoints for future studies: 
1. Effect repeat doses of SB-728mR-T on engraftment following CTX conditioning 
2. Long-term persistence of SB-728mR-T in peripheral blood as measured by pentamer 
PCR 
3. Change in total number of CD4+ T-cell counts in peripheral blood after repeat treatments 
with SB-728mR-T 
4. Effect of SB-728mR-T on plasma HIV-1 RNA levels following HAART interruption 
5. Change in HIV reservoirs as part of exploratory research 
 
15. 
INVESTIGATOR OBLIGATIONS 
The investigator will ensure that the study is conducted in compliance with the protocol, the 
Declaration of Helsinki and according to ICH Guidelines for Good Clinical Practice (E6) and all 


Sangamo BioSciences, Inc.  
Phase 1/2 Protocol SB-728mR-1401                                                                                                             Confidential 
Page 39 of 66                                                                                   Version: October 10, 2014 
regulatory and institutional requirements, including those for subject privacy, informed consent, 
Institutional Review Board or Ethics Committee approval and record retention. 
15.1 
Informed Consent 
According to 21 CFR Part 50.20, no investigator may involve a human being as a subject in 
research covered by these regulations unless the investigator has obtained the legally effective 
informed consent of the subject or the subject’s legally authorized representative. An investigator 
shall seek such consent only under circumstances that provide the prospective subject sufficient 
opportunity to consider whether or not to participate and that minimize the possibility of 
coercion or undue influence. The information that is given to the subject or the representative 
shall be in language understandable to the subject or the representative. 
Sangamo will provide the investigator with a template for the consent form.  State and local laws 
and/or institutional requirements may require the disclosure of additional information in the 
informed consent. The proposed consent form must be submitted to Sangamo prior to submission 
to the IRB or IEC to ensure that it meets Sangamo standards for consent forms. 
The IRB or IEC must approve the consent form. A copy of the approved form must be submitted 
to Sangamo.  
Prior to the initiation of any procedures relating to the study, informed consent shall be 
documented by the use of a written consent form approved by the IRB and signed and dated by 
the subject at the time of consent. A copy of the signed informed consent will be given to the 
person signing the form. The investigator must keep each subject’s signed consent form on file 
for inspection by a regulatory authority at any time. 
15.2 
Institutional Review Board and BioSafety Committee 
This protocol, informed consent document, and relevant substantive data are to be submitted to 
the appropriate Institutional Review Board (IRB) and BioSafety Committee (BSC) for review 
and approval before the initiation of the study. Amendments to the protocol will also be 
submitted to the IRB and BSC (as appropriate) prior to implementation of the change. A letter 
documenting the IRB/BSC’s approval must be received by the Sponsor prior to initiation of the 
study.  
15.2.1. Protocol Amendments 
Any changes to this protocol will be initiated by Sangamo in writing as a protocol amendment. 
The amendment must be submitted to the IRB together with a revised informed consent form, if 
applicable. Written documentation of IRB approval must be received before the amendment may 
take effect. 
15.2.2. Other Reporting Obligations 
The Principal Investigator is also responsible for informing their IRB of the progress of the study 
and for obtaining annual IRB renewal. The IRB must be informed at the time of completion of 
the study. The Principal Investigator should provide their IRB (if required by the institution) with 
a summary of the results of the study. 
15.3 
Subject Privacy 
Subject medical information obtained for the purposes of this trial is confidential, and disclosure 
to third parties, other than those noted below, is prohibited. Upon the subject’s request and 
written permission, medical information may be given to his/her personal physician or other 


Sangamo BioSciences, Inc.  
Phase 1/2 Protocol SB-728mR-1401                                                                                                             Confidential 
Page 40 of 66                                                                                   Version: October 10, 2014 
appropriate medical personnel responsible for the subject’s welfare. Data generated for this study 
must be available for inspection on request to representatives of the FDA, other national or local 
health authorities, Sangamo, and the associated IRB/IEC. 
Release of research results or data that reveal subject names or other identifiers, such as 
photographs, audio or videotapes, must be carried out in accordance with Department of Health 
and Human Services Standards for Privacy of Individual Health information, 45 CFR 164.508. 
Written authorization must be obtained from the subject and IRB/IEC prior to the release of such 
information. Identifiable subject data may not be used for purposes of promoting the study drug. 
15.4 
Reporting Obligations 
Sangamo BioSciences, Inc., the sponsor of this IND, is required to report to the FDA annually on 
the status of the trial. Status reports must be filed by the Principal Investigator with their IRB on 
an annual basis. 
 
16. 
ADMINISTRATIVE CONSIDERATIONS 
16.1 
Study Documentation 
The Investigator and study staff are responsible for maintaining a comprehensive and centralized 
filing system containing all study-related documentation. These files must be suitable for 
inspection by the Sponsor or the FDA at any time and should consist of the following elements: 
a) 
Subject files containing the completed medical records, supporting source 
documentation, electronic case report forms and the IRB approved Informed 
Consent signed by subjects. 
b) 
Study files containing all version of the IRB approved protocol with all 
amendments, IRB approved informed consent forms, copies of all pre-study 
documentation, Form FDA 1572 and all correspondence to and from the IRB and 
the Sponsor. 
c) 
The investigator should maintain a list of appropriately qualified persons who are 
delegated to perform significant study-related studies. In addition, the investigator 
should maintain a signature sheet to document signatures and initials of all 
persons authorized to make entries and/or corrections on the source documents 
and electronic case report forms. 
16.2 
Record Retention 
According to 21 CFR 312.62(c), the investigator shall retain records required to be maintained 
under this part for a period of 2 years following the date a marketing application is approved for 
the drug for the indication for which it is being investigated. If no application is to be filed or if 
the application is not approved for such indication, the investigator shall retain these records 
until 2 years after the investigation is discontinued and the FDA is notified. These documents 
should be retained for a longer period, however, if required by the applicable regulatory 
requirements or by an agreement with Sangamo BioSciences. It is the responsibility of Sangamo 
BioSciences to inform the investigator as to when these documents no longer need to be retained. 
16.3 
Case Report Forms 
The investigator is responsible for the quality of the data recorded on the case report form. The 
data recorded should be a complete and accurate account of the subject’s record collected during 
the study. 


Sangamo BioSciences, Inc.  
Phase 1/2 Protocol SB-728mR-1401                                                                                                             Confidential 
Page 41 of 66                                                                                   Version: October 10, 2014 
Clinical data will be recorded on case report forms (CRFs) provided by Sangamo. All forms 
must be legible and complete. The investigator must review all entries for completeness and 
correctness. When changes or corrections are made on any case report form, an audit trail will be 
generated to record date and time when a change is made, who made the change, and reason for 
the change as needed. The original entry should not be obscured. 
The investigator agrees to complete and sign case report forms in a timely fashion, after 
completion of each subject, and make them available to the Sangamo study monitor for full 
inspection. In addition, all data queries should be resolved promptly. 
16.4 
Termination of the Study 
Sangamo retains the right to terminate the study and remove all the study materials from the 
study site at any time. Specific instances that may precipitate such termination are as follows: 
 
Completion of the study at an investigational site 
 
Investigator withdrawal from participation in study 
 
Termination of this study by Sangamo 
16.5 
Study Monitoring  
Sangamo BioSciences, as sponsor of this study, is responsible to regulatory authorities for 
ensuring the proper conduct of the study as regards protocol adherence and validity of the data 
recorded on the case report forms presented to the regulatory authorities.  Sangamo BioSciences 
has therefore assigned a clinical monitor and a medical monitor to this study. Their duties are to 
aid the investigator and, at the same time, Sangamo BioSciences in the maintenance of complete, 
legible, well-organized, and easily retrievable data. In addition, a Sangamo BioSciences study 
monitor will ensure an understanding of the protocol, reporting responsibilities, and the validity 
of the data.   
Individual study sites will be monitored by a Sangamo representative at appropriate intervals to 
assure satisfactory consenting process, data recording, and protocol adherence. In order to 
perform their roles well, the Sangamo BioSciences monitors must be given direct access to 
primary subject data (source documents) that support data entered onto the case report forms. 
The investigator and staff are expected to cooperate and provide all relevant study 
documentation in detail at each site visit on request for review. Each study center will also be 
routinely monitored by telephone to keep abreast of subject status and to answer questions. 
Regulatory authorities, the IRB, and/or the sponsor’s clinical quality assurance group may 
request access to all source documents, case report forms, and other study documentation for on-
site audit, or inspection. Direct access to these documents must be guaranteed by the 
investigator, who must provide support at all times for these activities. 
The investigator or designated person should agree, as a minimum requirement, to record the 
following information in the subject notes: 
 Protocol identification number, brief description or title of study 
 Date and statement that subject has given written informed consent 
 All study follow-up visit dates 
 AEs as described in Sections 10.0 and 11.0 of this protocol 
Entries in the subject notes must contain the signature or initials of the person making the entries. 


Sangamo BioSciences, Inc.  
Phase 1/2 Protocol SB-728mR-1401                                                                                                             Confidential 
Page 42 of 66                                                                                   Version: October 10, 2014 
The clinical study monitor will perform source data verification at each monitoring visit. 
16.6 
Publication Statement 
The results of this clinical trial may be used by Sangamo in registration documents for regulatory 
authorities in the U.S. or abroad, or for public dissemination in the form of papers, abstracts, 
posters, or other informational materials to be presented at scientific meetings, or published in 
professional journals, or as a part of an academic thesis by an investigator. 
All proposed publications, papers, abstracts, or other written materials related to the study, or an 
outline of any proposed oral presentations, shall be submitted to Sangamo for approval at least 
45 days prior to (1) submission of such written materials for publication or (2) any proposed oral 
disclosure to a third party. Sangamo shall have the right to review and comment on such written 
material or outline, and to confirm the accuracy of the data described therein by comparison with 
that collected during the course of this study. In the event that Sangamo determines that an 
enabling description of patentable subject matter is contained in such written material or outline, 
it shall notify the clinical site(s) within 1 month after receipt by Sangamo and Sangamo will have 
an additional 90 days for review. 
In the event of publication using multi-center data, the number of subjects enrolled by each 
investigator will usually determine the order of participation, unless otherwise agreed upon by 
the investigators and Sangamo. 
16.7 
Study Funding 
The costs necessary to perform the study will be agreed to by the investigator and/or the 
management of the study facility and will be documented in a separate financial agreement. All 
financial agreements will be signed by the investigator and Sangamo BioSciences. 
 


Sangamo BioSciences, Inc.  
Phase 1/2 Protocol SB-728mR-1401                                                                                                             Confidential 
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REFERENCES 
Baker GL, Kahl LE, et al.: Malignancy following treatment of rheumatoid arthritis with 
cyclophosphamide. Long-term case-control follow-up study. Am J Med 83: 1-9, 1987. 
Dudley ME, Wunderlich JR, et al: Adoptive cell transfer therapy following non-myeloablative 
but lymphodepleting chemotherapy for the treatment of patients with refractory metastatic 
melanoma. J Clin Onc 23:2346-57, 2005.  
Dudley ME, Rosenberg SA: Adoptive cell-transfer for the treatment of patients with cancer. Nat 
Rev Cancer, 3:666-75, 2003. 
Kircher MF et al. High Resolution Three-Dimensional Imaging of Antigen-Specific Cytotoxic T-
Lymphocyte Trafficking to Tumors. Cancer Research 63(20): 6838-6846 (2003). 
Lawrence J, Mayers DL, et al.: Structured treatment interruption in patients with multidrug 
resistant human immunodeficiency virus. New Engl J Med 349:837-46, 2003. 
LeBraz MLB, Fagard CF, et al.: Physical and psychological impacts of structured treatment 
interruptions. Poster presentation: The XIV International AIDS Conference: Abstract no. 
ThPpB2134. 
Oxenius A, Price DA, et al.: Stimulation of HIV-specific cellular immunity by structured 
treatment interruption fails to enhance viral control in chronic HIV infection. Proc Natl Acad Sci 
USA 99:13747-52, 2002. 
Panel on Antiretroviral Guidelines for Adults and Adolscents. Guidelines for the use of 
antiretroviral agents in HIV-1-infected adults and adolenscents. Department of Health and 
Human Services. Available at http://aidsinfor.nih.gov/Content/Files/AdultandAdolescentGL.pdf. 
Patton, NI: Treatment Interruption strategies: how great are the risks? Curr Opin Infect Dis 
21:25-30, 2008. 
Perez et al.: Establishment of HIV-1 resistance in CD4+ T cells by genome editing using zinc-
finger nucleases.  Nature Biotechnology 26, 808 - 816 (2008)  
Porter DL, Levine BL, et al.: Chimeric antigen receptor-modified T cells in chronic lymphoid 
leukemia. New Engl J Med 365:725-33, 2011. 
Rapoport AP, Levine BL, et al.: Molecular remission of CML after autotransplantation followed 
by adoptive transfer of costimulated autologous T cells. Bone Marrow Transplant. 33:53-60, 
2004. 
Rapoport AP, Stadtmauer EA, et al.: Restoration of immunity in lymphopenic individuals with 
cancer by vaccination and adoptive T-cell transfer. Nat Med 11: 1230-1237, 2005. 
Rapoport AP, Aqui NA, et al.: Combination immunotherapy using adoptive T-cell transfer and 
tumor antigen vaccination based on hTERT and survivin following ASCT for myeloma. Blood 
117: 788-97, 2011. 
Savoldo, B et al. CD28 Costimulation Improves Expansion and Persistence of Chimeric Antigen 
Receptor-modified T Cells in Lymphoma Patients. Journal of Clin Invest 121(5): 1822-6 (2011) 
Taylor S, Boffito M, et al.: Stopping antiretroviral therapy. AIDS 21:1673-82, 2007. 


Sangamo BioSciences, Inc.  
Phase 1/2 Protocol SB-728mR-1401                                                                                                             Confidential 
Page 44 of 66                                                                                   Version: October 10, 2014 
Tebas et al.: Gene Editing of CCR5 in Autologous CD4 T Cells of Persons Infected with HIV. 
New Engl J Med 370: 901-10, 2014. 
van Lunzen J, Glaunsinger T, et al.: Transfer of autologous gene-modified T cells in HIV-
infected patients with advanced immunodeficiency and drug-resistant virus. Molecular Therapy 
15:1024-33, 2007. 
Walker RE et al. Long-term In Vivo Survival of Receptor-modified Syngeneic T Cells in 
Patients with Human Immunodeficiency Virus Infection. Blood 96(2): 467-74 (2000). 
 


Sangamo BioSciences, Inc. 
Phase 1/2 Protocol SB-728mR-1401  
Confidential 
 
Page 45 of 66                                                                                   Version: October 10, 2014 
APPENDIX I:  SCHEDULE OF EVENTS – COHORT 1 
 
Study Period 
LTFU 
Procedure 
Screen 
 
Pre-Leukapheresis 
(1 wk prior to 
leukapheresis)
Leukapheresisa 
Baseline for Research 
Blood 
(between Leuk & CTX) 
Baseline 
(~1 wk prior to CTX) 
Day  
-2  
 
CTX 
Day 0 
 
SB-
728mR-T 
Infusion#
1  
Day 
1 
 
1 
day 
post 
infu
sion 
Wk 1 
(+/- 2d) 
 
Wk 2 
(+/- 1d) 
 
SB-
728mR-T 
Infusion 
#2  
  
Day
15 
 
1 
day 
post 
infu
sion 
Wk 3 
(+/- 2d)  
Wk 4 
 (+/- 2d) 
 
Wk 5 
(+/- 2d) 
 
Wk 6 
------ 
Start TI 
(+/- 3d) 
  
Wk 8 
(+/- 3d) 
 
 
 
 
Wk 10 
(+/- 3d) 
  
Wk 12 
(+/- 3d) 
 
 
Wk 14 
(+/- 3d) 
 
 
Wk 18 
(+/- 7d) 
 
 Wk 22 
------ 
Evaluate TI 
(+/- 7d) 
 
M7, M9,  
M12 
(+/- 7d) 
 
M18  
and M24 
(+/- 1m) 
and  
M36 
 (=/- 3m) 
 
Inclusion Exclusion / Informed  
Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Exam 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
M12 only 
X 
M24 and 
M36 only 
Vital Signsb 
X 
 
 
 
X 
X 
X 
 
 
X 
 
 
 
 
X  
 
 
 
 
 
X  
X 
M12 only 
X 
M24 and 
M36 only 
12-lead ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Leukapheresis 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CTX Administration 
 
 
 
 
 
Xc 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SB-728mR-T infusion 
 
 
 
 
 
 
Xd 
 
 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse eventse 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xe 
Concomitant medications 
X 
 
 
 
 
X 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
M24 and 
M36 only 
Hepatitis B and C 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Testf  
X 
 
 
 
X 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chemistry 
X 
Xg  
 
 
X 
X 
X 
 
X 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
X 
X 
X 
CBC 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
 
 
 
X 
X 
X 
X 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
X   
M7 and 
M12 only 
 
CD4+ T-cell counts 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X h  
X h  
X h  
X h  
X h  
X h  
X h  
X 
X 
HIV-1 RNA (Viral Load) 
X 
 
 
 
X 
 
 
 
X 
X 
 
X 
X 
X 
X i  
X i  
X i  
X i  
X i  
X i  
X i  
X 
X 
CCR5 SNP CEL-1 assay 
Xj 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pentamer 
 
 
 
 
Xk 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SB-728mR-T Immunogenicity 
 
 
 
 
Xk 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
M 7 & 12 
only 
 
HIV-1 Tropism and/or Resistance 
test 
Xj 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xm 
Research Blood 
X 
 
 
X 
Xl 
 
X 
X 
 
X 
 
 
 
 
X  
 
 
X 
 
 
X 
X 
 
Upon request of sponsor: Additional 80 mL research blood collection, CBC with differential, and CD4+ T-cell Count:  One to 2 times during the study. If subject agrees to participate in the optional leukapheresis procedure, this additional blood collection will not be performed. 
 
a If second leukapheresis is required, it must be > 3 weeks after the first leukapheresis.  
b Screen, Wk 6, Wk 22, and M12 (temp, pulse, BP and weight); Baseline (ht and wt);  CTX, Day 0 and Wk 2 (temp, pulse,  BP)  
c Administer CTX 2 days prior to the first SB-728mR-T infusion.Refer to Protocol Sections 6.5.1 and 8.2 and the Study Reference Manual for further details 
d Refer to Protocol Sections 6.5.2 and 8.1 and the Study Reference Manual for further details  
e Refer to Protocol Section 12 for reporting of Clinical Conditions and SAEs in LTFU 
f Serum pregnancy test at Screen and urine pregnancy tests at Baseline and prior to SB-728mR-T infusions on Day 0 and Wk 2   
g Electrolytes (Na, K, C02, Cl), calcium, liver function tests (albumin, total protein, alkaline phosphatase, AST, ALT, total bilirubin) 
h CD4 test will be repeated every 2 weeks for 3 consecutive measurements for values <500 cells/µL 
i HIV-1 RNA test will be repeated every  2 weeks for 3 consecutive measurements for values >100,000 
copies/mL  
j Perform if not previously tested 
k May be performed up to 4 weeks prior to the first SB-728mR-T infusion (Day 0).  
lResearch blood may be drawn on day of and prior to CTX infusion. 
mHIV-1 Coreceptor Tropism and Resistance testing will be performed once if HIV RNA exceeds 1,000 


Sangamo BioSciences, Inc. 
Phase 1/2 Protocol SB-728mR-1401  
Confidential 
 
Page 46 of 66                                                                                   Version: October 10, 2014 
APPENDIX I:  SCHEDULE OF EVENTS – COHORT 2 
 
 
 
 
Study Period 
LTFU 
Procedure 
Screen 
 
Pre-Leukapheresis 
(1 wk prior to leukapheresis) 
Leukapheresisa 
Baseline for Research Blood 
(between Leuk & CTX) 
Baseline 
(~1 wk prior to CTX) 
Day  
-2 
 
CTX 
Day 0 
 
SB-
728mR-T 
Infusion 
#1  
 
Day 
1 
 
1 
day 
post 
infu
sion 
 
Wk 1 
(+/- 
2d) 
 
Wk 2 
(+/- 1d) 
 
SB-
728mR-
T 
Infusion 
#2  
 
 
Day 
15 
 
1 
day 
post 
infu
sion 
Wk 
3 
(+/- 
2d)  
Wk 4 
(+/- 1d) 
 
SB-
728mR-T 
Infusion 
#3 
 
 
Day 
29 
 
1 
day 
post 
infu
sion 
 
Wk 5 
(+/- 
2d) 
 
Wk 6 
(+/- 
3d) 
  
Wk 7 
(+/- 
2d) 
 
Wk 8 
------ 
Start TI 
(+/- 
3d) 
 
 
 
 
Wk 10 
(+/- 3d) 
  
Wk 12 
(+/- 3d) 
 
 
Wk 14 
(+/- 3d) 
 
 
Wk 16 
(+/- 3) 
Wk 20 
(+/- 7d) 
 
 
Wk 24 
------ 
Evaluate 
TI 
(+/- 7d) 
 
M7, M9,   
M12 
(+/- 7d) 
 
M18  
and M24 
(+/- 1m) 
and  
M36 
 (=/- 3m) 
 
Inclusion Exclusion / 
Informed  Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Exam 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
M12 only 
X 
M24 and 
M36 only 
Vital Signsb 
X 
 
 
 
X 
X 
X 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
X 
M12 only 
X 
M24 and 
M36 only 
12-lead ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Leukapheresis 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CTX Administration 
 
 
 
 
 
Xc 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SB-728mR-T infusion 
 
 
 
 
 
 
Xd 
 
 
Xd 
 
 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse eventse 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xe 
Concomitant 
medications 
X 
 
 
 
 
X 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
M24 and 
M36 only 
Hepatitis B and C 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Testf 
X 
 
 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chemistry 
X 
Xg 
 
 
X 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
 
 
X 
X 
X 
CBC 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
 
 
 
X 
X 
X 
X 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
M7 and 
M12 only 
 
CD4+ T-cell counts 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xh 
Xh 
Xh 
Xh 
Xh 
Xh 
Xh 
X 
X 
HIV-1 RNA (Viral 
Load) 
X 
 
 
 
X 
 
 
 
X 
X 
 
X 
X 
 
X 
X 
X 
Xi 
Xi 
Xi 
Xi 
Xi 
Xi 
Xi 
X 
X 
CCR5 SNP CEL-1 assay 
Xj 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pentamer 
 
 
 
 
Xk 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SB-728mR-T 
Immunogenicity 
 
 
 
 
Xk 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
M 7 & 12 
only 
 
HIV-1 Tropism and/or 
Resistance test 
Xj 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xm 
Research Blood 
X 
 
 
X 
Xl 
 
X 
X 
 
X 
 
 
 
 
 
 
 
X  
 
 
X 
 
 
X 
X 
 
Upon request of sponsor: Additional 80 mL research blood collection, CBC with differential, and CD4+ T-cell Count:  One to 2 times during the study. If subject agrees to participate in the optional leukapheresis procedure, this additional blood collection will not be performed. 
 
a If second leukapheresis is required, it must be > 3 weeks after the first leukapheresis.  
b Screen, Wk 8, Wk 24, and M12 (temp, pulse, BP and weight); Baseline (ht and wt);  CTX, Day 0 , Wk 2 and Wk 4 (temp, pulse,  BP)  
c Administered CTX 2 days prior to the first SB-728mR-T infusion. Refer to Protocol Sections 6.5.1 and 8.2 and the Study Reference Manual for further details  
d Refer to Protocol Sections 6.5.2 and 8.1 and the Study Reference Manual for further details  
e Refer to Protocol Section 12 for reporting of Clinical Conditions and SAEs in LTFU 
fSerum pregnancy test at Screen and urine pregnancy tests at Baseline and prior to SB-728mR-T infusions on Day 0, Wk 2, and Wk 4 
g Electrolytes (Na, K, C02, Cl), calcium, liver function tests (albumin, total protein, alkaline phosphatase, AST, ALT, total bilirubin) 
h CD4 test will be repeated every 2 weeks for 3 consecutive measurements for values <500 cells/µL 
iHIV-1 RNA test will be repeated every  2 weeks for 3 consecutive measurements for values >100,000 
copies/mL  
j Perform if not previously tested 
k May be performed up to 4 weeks prior to the first SB-728mR-T infusion (Day 0).  
l Research blood may be drawn on day of and prior to CTX infusion. 
mHIV-1 Coreceptor Tropism and Resistance testing will be performed once if HIV RNA exceeds 1,000 


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APPENDIX II: DIVISION OF AIDS TABLE FOR GRADING THE SEVERITY OF 
ADULT AND PEDIATRIC ADVERSE EVENTS 
 
Version 1.0, December, 2004; clarification August 2009 
 
The Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events 
(“DAIDS AE Grading Table”) is a descriptive terminology which can be utilized for Adverse 
Event (AE) reporting. A grading (severity) scale is provided for each AE term. 
 
This clarification of the DAIDS Table for Grading the Severity of Adult and Pediatric AE’s 
provides additional explanation of the DAIDS AE Grading Table and clarifies some of the 
parameters.  
 
I. 
INSTRUCTIONS AND CLARIFICATIONS 
 
Grading Adult and Pediatric AEs 
The DAIDS AE Grading Table includes parameters for grading both Adult and Pediatric AEs.  
When a single set of parameters is not appropriate for grading specific types of AEs for both 
Adult and Pediatric populations, separate sets of parameters for Adult and/or Pediatric 
populations (with specified respective age ranges) are given in the Table.  If there is no 
distinction in the Table between Adult and Pediatric values for a type of AE, then the single set 
of parameters listed is to be used for grading the severity of both Adult and Pediatric events of 
that type.   
Note: In the classification of adverse events, the term “severe” is not the same as 
“serious.” Severity is an indication of the intensity of a specific event (as in mild, 
moderate, or severe chest pain).  The term “serious” relates to a participant/event 
outcome or action criteria, usually associated with events that pose a threat to a 
participant’s life or functioning.  
 
Addenda 1-3 Grading Tables for Microbicide Studies 
For protocols involving topical application of products to the female genital tract, male genital 
area or rectum, strong consideration should be given to using Appendices I-III as the primary 
grading scales for these areas. The protocol would need to specifically state that one or more of 
the Appendices would be primary (and thus take precedence over the main Grading Table) for 
items that are listed in both the Appendix and the main Grading Table. 
Addendum 1 - Female Genital Grading Table for Use in Microbicide Studies - PDF 
Addendum 2 - Male Genital Grading Table for Use in Microbicide Studies - PDF  
Addendum 3 - Rectal Grading Table for Use in Microbicide Studies - PDF  
 
Grade 5 
For any AE where the outcome is death, the severity of the AE is classified as Grade 5.  
 
Estimating Severity Grade for Parameters Not Identified in the Table 
In order to grade a clinical AE that is not identified in the DAIDS AE grading table, use the 
category “Estimating Severity Grade” located on Page 3. 
 


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Determining Severity Grade for Parameters “Between Grades” 
If the severity of a clinical AE could fall under either one of two grades (e.g., the severity of an 
AE could be either Grade 2 or Grade 3), select the higher of the two grades for the AE. If a 
laboratory value that is graded as a multiple of the ULN or LLN falls between two grades, select 
the higher of the two grades for the AE. For example, Grade 1 is 2.5 x ULN and Grade 2 is 2.6 x 
ULN for a parameter. If the lab value is 2.53 x ULN (which is between the two grades), the 
severity of this AE would be Grade 2, the higher of the two grades. 
 
Values Below Grade 1 
Any laboratory value that is between either the LLN or ULN and Grade 1 should not be graded. 
 
Determining Severity Grade when Local Laboratory Normal Values Overlap with Grade 1 
Ranges  
In these situations, the severity grading is based on the ranges in the DAIDS AE Grading Table, 
even when there is a reference to the local lab LLN. 
 
For example: Phosphate, Serum, Low, Adult and Pediatric > 14 years Grade 1 range is 2.50 
mg/dL - < LLN. A particular laboratory’s normal range for Phosphate is 2.1 – 3.8 mg/dL. A 
participant’s actual lab value is 2.5.   In this case, the value of 2.5 exceeds the LLN for the local 
lab, but will be graded as Grade 1 per DAIDS AE Grading Table. 
 
II. 
DEFINITIONS OF TERMS USED IN THE TABLE: 
 
Basic Self-care Functions 
Adult 
Activities such as bathing, dressing, toileting, 
transfer/movement, continence, and feeding. 
Young Children 
Activities that are age and culturally appropriate (e.g., feeding 
self with culturally appropriate eating implement). 
LLN 
Lower limit of normal 
 
Medical Intervention 
Use of pharmacologic or biologic agent(s) for treatment of an 
AE. 
NA 
Not Applicable 
Operative Intervention 
Surgical OR other invasive mechanical procedures. 
ULN 
Upper limit of normal 
Usual Social & Functional 
Activities 
Adult 
Adaptive tasks and desirable activities, such as going to work, 
shopping, cooking, use of transportation, pursuing a hobby, etc. 
Young Children 
Activities that are age and culturally appropriate (e.g., social 
interactions, play activities, learning tasks, etc.). 
 
 


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PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-THREATENING 
ESTIMATING SEVERITY GRADE 
Clinical adverse event 
NOT identified 
elsewhere in this 
DAIDS AE Grading 
Table  
Symptoms causing no 
or minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
greater than minimal 
interference with usual 
social & functional 
activities 
Symptoms causing 
inability to perform usual 
social & functional 
activities 
Symptoms causing 
inability to perform basic 
self-care functions OR 
Medical or operative 
intervention indicated to 
prevent permanent 
impairment, persistent 
disability, or death  
SYSTEMIC 
Acute systemic 
allergic reaction  
Localized urticaria 
(wheals) with no 
medical intervention 
indicated 
Localized urticaria with 
medical intervention 
indicated OR Mild 
angioedema with no 
medical intervention 
indicated 
Generalized urticaria 
OR Angioedema with 
medical intervention 
indicated OR 
Symptomatic mild 
bronchospasm 
Acute anaphylaxis OR 
Life-threatening 
bronchospasm OR 
laryngeal edema 
Chills 
Symptoms causing no 
or minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
greater than minimal 
interference with usual 
social & functional 
activities  
Symptoms causing 
inability to perform usual 
social & functional 
activities 
NA 
Fatigue 
Malaise 
Symptoms causing no 
or minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
greater than minimal 
interference with usual 
social & functional 
activities 
Symptoms causing 
inability to perform usual 
social & functional 
activities 
Incapacitating fatigue/ 
malaise symptoms 
causing inability to 
perform basic self-care 
functions 
Fever (nonaxillary) 
37.7 – 38.6C 
38.7 – 39.3C 
39.4 – 40.5C 
> 40.5C  
Pain (indicate body 
site) 
DO NOT use for pain 
due to injection (See 
Injection Site 
Reactions: Injection 
site pain) 
See also Headache, 
Arthralgia, and 
Myalgia 
Pain causing no or 
minimal interference 
with usual social & 
functional activities 
Pain causing greater 
than minimal 
interference with usual 
social & functional 
activities 
Pain causing inability to 
perform usual social & 
functional activities 
Disabling pain causing 
inability to perform basic 
self-care functions OR 
Hospitalization (other 
than emergency room 
visit) indicated 
 
Basic Self-care Functions – Adult: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding. 
Basic Self-care Functions – Young Children: Activities that are age and culturally appropriate (e.g., feeding self with culturally 
appropriate eating implement). 
Usual Social & Functional Activities – Adult: Adaptive tasks and desirable activities, such as going to work, shopping, 
cooking, use of transportation, pursuing a hobby, etc. 
Usual Social & Functional Activities – Young Children: Activities that are age and culturally appropriate (e.g., social 
interactions, play activities, learning tasks, etc.). 
 


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PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-THREATENING 
Unintentional weight 
loss 
NA 
5 – 9% loss in body 
weight from baseline 
10 – 19% loss in body 
weight from baseline 
 20% loss in body 
weight from baseline OR  
Aggressive intervention 
indicated [e.g., tube 
feeding or total 
parenteral nutrition 
(TPN)] 
INFECTION 
Infection (any other 
than HIV infection) 
Localized, no 
systemic antimicrobial 
treatment indicated 
AND Symptoms 
causing no or minimal 
interference with 
usual social & 
functional activities 
Systemic antimicrobial 
treatment indicated 
OR Symptoms 
causing greater than 
minimal interference 
with usual social & 
functional activities 
Systemic antimicrobial 
treatment indicated 
AND Symptoms causing 
inability to perform usual 
social & functional 
activities OR Operative 
intervention (other than 
simple incision and 
drainage) indicated 
Life-threatening 
consequences (e.g., 
septic shock) 
INJECTION SITE REACTIONS 
Injection site pain 
(pain without touching) 
Or 
Tenderness (pain 
when area is touched)  
Pain/tenderness 
causing no or minimal 
limitation of use of 
limb 
Pain/tenderness 
limiting use of limb OR 
Pain/tenderness 
causing greater than 
minimal interference 
with usual social & 
functional activities 
 
Pain/tenderness 
causing inability to 
perform usual social & 
functional activities 
 
Pain/tenderness causing 
inability to perform basic 
self-care function OR 
Hospitalization (other 
than emergency room 
visit) indicated for 
management of 
pain/tenderness 
Injection site reaction (localized) 
Adult > 15 years 
 
Erythema OR 
Induration 
of 5x5 cm – 9x9 cm 
(or 25 cm2 – 81cm2) 
Erythema OR 
Induration OR Edema  
> 9 cm any diameter 
(or > 81 cm2) 
Ulceration OR 
Secondary infection OR 
Phlebitis OR Sterile 
abscess OR Drainage 
Necrosis (involving 
dermis and deeper 
tissue) 
 
Pediatric  15 years 
Erythema OR 
Induration OR Edema 
present but  2.5 cm 
diameter 
Erythema OR 
Induration OR Edema 
> 2.5 cm diameter but 
< 50% surface area of 
the extremity segment 
(e.g., upper arm/thigh) 
Erythema OR Induration 
OR Edema involving  
 50% surface area of 
the extremity segment 
(e.g., upper arm/thigh) 
OR Ulceration OR 
Secondary infection OR 
Phlebitis OR Sterile 
abscess OR Drainage 
Necrosis (involving 
dermis and deeper 
tissue) 
Basic Self-care Functions – Adult: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding. 
Basic Self-care Functions – Young Children: Activities that are age and culturally appropriate (e.g., feeding self with culturally 
appropriate eating implement). 
Usual Social & Functional Activities – Adult: Adaptive tasks and desirable activities, such as going to work, shopping, 
cooking, use of transportation, pursuing a hobby, etc. 
Usual Social & Functional Activities – Young Children: Activities that are age and culturally appropriate (e.g., social 
interactions, play activities, learning tasks, etc.). 
 


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PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-THREATENING 
Pruritis associated 
with injection  
See also Skin: Pruritis 
(itching - no skin 
lesions) 
Itching localized to 
injection site AND 
Relieved 
spontaneously or with 
< 48 hours treatment  
Itching beyond the 
injection site but not 
generalized OR 
Itching localized to 
injection site requiring 
 48 hours treatment  
Generalized itching 
causing inability to 
perform usual social & 
functional activities 
NA 
SKIN – DERMATOLOGICAL 
Alopecia 
Thinning detectable 
by study participant 
(or by caregiver for 
young children and 
disabled adults) 
Thinning or patchy 
hair loss detectable by 
health care provider 
Complete hair loss 
NA 
Cutaneous reaction – 
rash 
Localized macular 
rash  
Diffuse macular, 
maculopapular, or 
morbilliform rash OR 
Target lesions  
Diffuse macular, 
maculopapular, or 
morbilliform rash with 
vesicles or limited 
number of bullae OR 
Superficial ulcerations 
of mucous membrane 
limited to one site 
Extensive or generalized 
bullous lesions OR 
Stevens-Johnson 
syndrome OR Ulceration 
of mucous membrane 
involving two or more 
distinct mucosal sites 
OR Toxic epidermal 
necrolysis (TEN) 
Hyperpigmentation 
Slight or localized 
Marked or generalized 
NA 
NA 
Hypopigmentation 
Slight or localized  
Marked or generalized 
NA 
NA 
Pruritis (itching – no 
skin lesions)  
(See also Injection 
Site Reactions: 
Pruritis associated 
with injection) 
Itching causing no or 
minimal interference 
with usual social & 
functional activities 
Itching causing greater 
than minimal 
interference with usual 
social & functional 
activities 
Itching causing inability 
to perform usual social 
& functional activities  
NA 
 
CARDIOVASCULAR 
Cardiac arrhythmia 
(general) 
(By ECG or physical 
exam) 
Asymptomatic AND 
No intervention 
indicated 
Asymptomatic AND 
Non-urgent medical 
intervention indicated 
Symptomatic, non-life-
threatening AND Non-
urgent medical 
intervention indicated  
Life-threatening 
arrhythmia OR Urgent 
intervention indicated 
Cardiac-
ischemia/infarction 
NA 
NA 
Symptomatic ischemia 
(stable angina) OR 
Testing consistent with 
ischemia  
Unstable angina OR 
Acute myocardial 
infarction 
Basic Self-care Functions – Adult: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding. 
Basic Self-care Functions – Young Children: Activities that are age and culturally appropriate (e.g., feeding self with culturally 
appropriate eating implement). 
Usual Social & Functional Activities – Adult: Adaptive tasks and desirable activities, such as going to work, shopping, 
cooking, use of transportation, pursuing a hobby, etc. 
Usual Social & Functional Activities – Young Children: Activities that are age and culturally appropriate (e.g., social 
interactions, play activities, learning tasks, etc.). 
 


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PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-THREATENING 
Hemorrhage (significant 
acute blood loss) 
NA 
Symptomatic AND No 
transfusion indicated 
Symptomatic AND 
Transfusion of  2 units 
packed RBCs (for children 
 10 cc/kg) indicated  
Life-threatening 
hypotension OR 
Transfusion of > 2 units 
packed RBCs (for children > 
10 cc/kg) indicated 
Hypertension 
Adult > 17 years 
(with repeat testing at 
same visit) 
140 – 159 mmHg 
systolic 
OR 
90 – 99 mmHg diastolic 
160 – 179 mmHg systolic 
OR 
100 – 109 mmHg 
diastolic 
≥ 180 mmHg systolic 
OR 
≥ 110 mmHg diastolic 
 
Life-threatening 
consequences (e.g., 
malignant hypertension) 
OR Hospitalization 
indicated (other than 
emergency room visit) 
Correction: in Grade 2 to 160 - 179 from > 160-179 (systolic) and to  100 -109 from > 100-109 (diastolic) and in Grade 3 to  180 from > 180 
(systolic) and to   110  from > 110 (diastolic). 
Pediatric  17 years 
(with repeat testing at 
same visit) 
 
NA 
91st –  94th percentile 
adjusted for age, height, 
and gender (systolic 
and/or diastolic) 
≥ 95th percentile adjusted 
for age, height, and gender 
(systolic and/or diastolic) 
Life-threatening 
consequences (e.g., 
malignant hypertension) 
OR Hospitalization 
indicated (other than 
emergency room visit) 
Hypotension 
NA 
Symptomatic, 
corrected with oral 
fluid replacement 
Symptomatic, IV fluids 
indicated 
Shock requiring use of 
vasopressors or 
mechanical assistance 
to maintain blood 
pressure 
Pericardial effusion 
Asymptomatic, small 
effusion requiring no 
intervention 
Asymptomatic, 
moderate or larger 
effusion requiring no 
intervention 
Effusion with non-life 
threatening physiologic 
consequences OR 
Effusion with non-urgent 
intervention indicated 
Life-threatening 
consequences (e.g., 
tamponade) OR Urgent 
intervention indicated 
Prolonged PR interval 
Adult > 16 years 
PR interval  
0.21 – 0.25 sec 
PR interval 
> 0.25 sec 
Type II 2nd degree AV 
block OR Ventricular 
pause > 3.0 sec 
Complete AV block 
Pediatric ≤ 16 years 
1st degree AV block 
(PR > normal for age 
and rate) 
Type I 2nd degree AV 
block  
Type II 2nd degree AV 
block  
Complete AV block 
Basic Self-care Functions – Adult: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding. 
Basic Self-care Functions – Young Children: Activities that are age and culturally appropriate (e.g., feeding self with culturally 
appropriate eating implement). 
Usual Social & Functional Activities – Adult: Adaptive tasks and desirable activities, such as going to work, shopping, 
cooking, use of transportation, pursuing a hobby, etc. 
Usual Social & Functional Activities – Young Children: Activities that are age and culturally appropriate (e.g., social 
interactions, play activities, learning tasks, etc.). 
 
 


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PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-THREATENING 
Prolonged QTc 
Adult > 16 years 
 
Asymptomatic, QTc 
interval 0.45 – 0.47 
sec OR Increase 
interval < 0.03 sec 
above baseline 
Asymptomatic, QTc 
interval 0.48 – 0.49 
sec OR Increase in 
interval 0.03 – 0.05 
sec above baseline 
Asymptomatic, QTc 
interval  0.50 sec OR 
Increase in interval  
 0.06 sec above baseline 
Life-threatening 
consequences, e.g. 
Torsade de pointes or 
other associated serious 
ventricular dysrhythmia 
Pediatric ≤ 16 years 
Asymptomatic, QTc 
interval 0.450 –  
0.464 sec  
Asymptomatic, QTc 
interval 0.465 –  
0.479 sec  
Asymptomatic, QTc 
interval  0.480 sec  
Life-threatening 
consequences, e.g.  
Torsade de pointes  or 
other associated serious 
ventricular dysrhythmia 
Thrombosis/embolism 
NA 
Deep vein thrombosis 
AND No intervention 
indicated (e.g., 
anticoagulation, lysis 
filter, invasive 
procedure)  
Deep vein thrombosis 
AND Intervention 
indicated (e.g., 
anticoagulation, lysis 
filter, invasive 
procedure)  
Embolic event (e.g., 
pulmonary embolism, 
life-threatening 
thrombus)  
Vasovagal episode 
(associated with a 
procedure of any kind) 
Present without loss 
of consciousness  
Present with transient 
loss of consciousness 
NA  
NA 
Ventricular 
dysfunction 
(congestive heart 
failure) 
NA 
Asymptomatic 
diagnostic finding AND 
intervention indicated 
New onset with 
symptoms OR Worsening 
symptomatic congestive 
heart failure 
Life-threatening 
congestive heart failure 
GASTROINTESTINAL 
Anorexia 
Loss of appetite 
without decreased 
oral intake 
Loss of appetite 
associated with 
decreased oral intake 
without significant 
weight loss 
Loss of appetite 
associated with 
significant weight loss 
Life-threatening 
consequences OR 
Aggressive intervention 
indicated [e.g., tube 
feeding or total parenteral 
nutrition (TPN)] 
Comment: Please note that, while the grading scale provided for Unintentional Weight Loss may be used as a guideline when 
grading anorexia, this is not a requirement and should not be used as a substitute for clinical judgment.  
Ascites 
Asymptomatic 
Symptomatic AND 
Intervention indicated 
(e.g., diuretics or 
therapeutic 
paracentesis) 
Symptomatic despite 
intervention 
Life-threatening 
consequences 
 
Basic Self-care Functions – Adult: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding. 
Basic Self-care Functions – Young Children: Activities that are age and culturally appropriate (e.g., feeding self with culturally 
appropriate eating implement). 
Usual Social & Functional Activities – Adult: Adaptive tasks and desirable activities, such as going to work, shopping, 
cooking, use of transportation, pursuing a hobby, etc. 
Usual Social & Functional Activities – Young Children: Activities that are age and culturally appropriate (e.g., social 
interactions, play activities, learning tasks, etc.). 
 


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PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-THREATENING 
Cholecystitis 
NA 
Symptomatic AND 
Medical intervention 
indicated 
Radiologic, endoscopic, 
or operative intervention 
indicated 
Life-threatening 
consequences (e.g., 
sepsis or perforation)  
Constipation  
NA 
Persistent constipation 
requiring regular use 
of dietary 
modifications, 
laxatives, or enemas  
Obstipation with manual 
evacuation indicated 
Life-threatening 
consequences (e.g., 
obstruction) 
Diarrhea 
Adult and Pediatric 
 1 year 
Transient or 
intermittent episodes 
of unformed stools 
OR Increase of ≤ 3 
stools over baseline 
per 24-hour period 
Persistent episodes of 
unformed to watery 
stools OR Increase of 
4 – 6 stools over 
baseline per 24-hour 
period 
Bloody diarrhea OR 
Increase of ≥ 7 stools 
per 24-hour period OR 
IV fluid replacement 
indicated 
Life-threatening 
consequences (e.g., 
hypotensive shock) 
Pediatric < 1 year 
Liquid stools (more 
unformed than usual) 
but usual number of 
stools 
Liquid stools with 
increased number of 
stools OR Mild 
dehydration 
Liquid stools with 
moderate dehydration 
Liquid stools resulting in 
severe dehydration with 
aggressive rehydration 
indicated OR 
Hypotensive shock 
Dysphagia-
Odynophagia  
Symptomatic but able 
to eat usual diet 
Symptoms causing 
altered dietary intake 
without medical 
intervention indicated 
Symptoms causing 
severely altered dietary 
intake with medical 
intervention indicated 
Life-threatening 
reduction in oral intake 
Mucositis/stomatitis  
(clinical exam) 
Indicate site (e.g., 
larynx, oral) 
See Genitourinary for 
Vulvovaginitis  
See also Dysphagia-
Odynophagia and 
Proctitis 
Erythema of the 
mucosa 
Patchy 
pseudomembranes or 
ulcerations  
Confluent 
pseudomembranes or 
ulcerations OR Mucosal 
bleeding with minor 
trauma 
Tissue necrosis OR 
Diffuse spontaneous 
mucosal bleeding OR 
Life-threatening 
consequences (e.g., 
aspiration, choking) 
Nausea  
Transient (< 24 hours) 
or intermittent nausea 
with no or minimal 
interference with oral 
intake 
Persistent nausea 
resulting in decreased 
oral intake for 24 – 48 
hours 
Persistent nausea 
resulting in minimal oral 
intake for > 48 hours 
OR Aggressive 
rehydration indicated 
(e.g., IV fluids) 
Life-threatening 
consequences (e.g., 
hypotensive shock) 
Basic Self-care Functions – Adult: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding. 
Basic Self-care Functions – Young Children: Activities that are age and culturally appropriate (e.g., feeding self with culturally 
appropriate eating implement). 
Usual Social & Functional Activities – Adult: Adaptive tasks and desirable activities, such as going to work, shopping, 
cooking, use of transportation, pursuing a hobby, etc. 
Usual Social & Functional Activities – Young Children: Activities that are age and culturally appropriate (e.g., social 
interactions, play activities, learning tasks, etc.). 
 


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PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-THREATENING 
Pancreatitis 
NA 
Symptomatic AND 
Hospitalization not 
indicated (other than 
emergency room visit) 
Symptomatic AND 
Hospitalization indicated 
(other than emergency 
room visit) 
Life-threatening 
consequences (e.g., 
circulatory failure, 
hemorrhage, sepsis) 
Proctitis (functional- 
symptomatic) 
Also see 
Mucositis/stomatitis  
for clinical exam 
Rectal discomfort 
AND No intervention 
indicated 
Symptoms causing 
greater than minimal 
interference with usual 
social & functional 
activities OR Medical 
intervention indicated  
Symptoms causing 
inability to perform usual 
social & functional 
activities OR Operative 
intervention indicated  
Life-threatening 
consequences (e.g., 
perforation) 
 
Vomiting 
Transient or 
intermittent vomiting 
with no or minimal 
interference with oral 
intake 
Frequent episodes of 
vomiting with no or 
mild dehydration 
Persistent vomiting 
resulting in orthostatic 
hypotension OR 
Aggressive rehydration 
indicated (e.g., IV fluids) 
Life-threatening 
consequences (e.g., 
hypotensive shock) 
NEUROLOGIC 
Alteration in 
personality-behavior 
or in mood (e.g., 
agitation, anxiety, 
depression, mania, 
psychosis) 
Alteration causing no 
or minimal 
interference with 
usual social & 
functional activities  
Alteration causing 
greater than minimal 
interference with usual 
social & functional 
activities  
Alteration causing 
inability to perform usual 
social & functional 
activities  
Behavior potentially 
harmful to self or others 
(e.g., suicidal and 
homicidal ideation or 
attempt, acute 
psychosis) OR Causing 
inability to perform basic 
self-care functions  
Altered Mental Status  
For Dementia, see 
Cognitive and 
behavioral/attentional 
disturbance (including 
dementia and 
attention deficit 
disorder) 
Changes causing no 
or minimal 
interference with 
usual social & 
functional activities 
Mild lethargy or 
somnolence causing 
greater than minimal 
interference with usual 
social & functional 
activities 
Confusion, memory 
impairment, lethargy, or 
somnolence causing 
inability to perform usual 
social & functional 
activities 
Delirium OR 
obtundation, OR coma 
Ataxia  
Asymptomatic ataxia 
detectable on exam 
OR Minimal ataxia 
causing no or minimal 
interference with 
usual social & 
functional activities 
Symptomatic ataxia 
causing greater than 
minimal interference 
with usual social & 
functional activities 
Symptomatic ataxia 
causing inability to 
perform usual social & 
functional activities  
Disabling ataxia causing 
inability to perform basic 
self-care functions 
Basic Self-care Functions – Adult: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding. 
Basic Self-care Functions – Young Children: Activities that are age and culturally appropriate (e.g., feeding self with culturally 
appropriate eating implement). 
Usual Social & Functional Activities – Adult: Adaptive tasks and desirable activities, such as going to work, shopping, 
cooking, use of transportation, pursuing a hobby, etc. 
Usual Social & Functional Activities – Young Children: Activities that are age and culturally appropriate (e.g., social 
interactions, play activities, learning tasks, etc.). 


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Page 56 of 66                                                                                   Version: October 10, 2014 
 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-THREATENING 
Cognitive and 
behavioral/attentional 
disturbance (including 
dementia and 
attention deficit 
disorder)  
Disability causing no 
or minimal 
interference with 
usual social & 
functional activities 
OR Specialized 
resources not 
indicated 
Disability causing 
greater than minimal 
interference with usual 
social & functional 
activities OR 
Specialized resources 
on part-time basis 
indicated 
Disability causing 
inability to perform usual 
social & functional 
activities OR 
Specialized resources 
on a full-time basis 
indicated 
Disability causing 
inability to perform basic 
self-care functions OR 
Institutionalization 
indicated 
CNS ischemia 
(acute) 
NA 
NA 
Transient ischemic 
attack 
Cerebral vascular 
accident (CVA, stroke) 
with neurological deficit  
Developmental delay 
– Pediatric  16 
years 
Mild developmental 
delay, either motor or 
cognitive, as 
determined by 
comparison with a 
developmental 
screening tool 
appropriate for the 
setting  
Moderate 
developmental delay,  
either motor or 
cognitive, as 
determined by 
comparison with a 
developmental 
screening tool 
appropriate for the 
setting  
Severe developmental 
delay, either motor or 
cognitive, as determined 
by comparison with a 
developmental 
screening tool 
appropriate for the 
setting  
Developmental 
regression, either motor 
or cognitive, as 
determined by 
comparison with a 
developmental 
screening tool 
appropriate for the 
setting 
Headache  
Symptoms causing no 
or minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
greater than minimal 
interference with usual 
social & functional 
activities 
Symptoms causing 
inability to perform usual 
social & functional 
activities 
Symptoms causing 
inability to perform basic 
self-care functions OR 
Hospitalization indicated 
(other than emergency 
room visit) OR 
Headache with 
significant impairment of 
alertness or other 
neurologic function  
Insomnia 
NA 
Difficulty sleeping 
causing greater than 
minimal interference 
with usual social & 
functional activities 
Difficulty sleeping 
causing inability to 
perform usual social & 
functional activities 
Disabling insomnia 
causing inability to 
perform basic self-care 
functions 
Neuromuscular 
weakness  
(including myopathy & 
neuropathy)  
Asymptomatic with 
decreased strength 
on exam OR Minimal 
muscle weakness 
causing no or minimal 
interference with 
usual social & 
functional activities 
Muscle weakness 
causing greater than 
minimal interference 
with usual social & 
functional activities 
Muscle weakness 
causing inability to 
perform usual social & 
functional activities  
Disabling muscle 
weakness causing 
inability to perform basic 
self-care functions OR 
Respiratory muscle 
weakness impairing 
ventilation 
Basic Self-care Functions – Adult: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding. 
Basic Self-care Functions – Young Children: Activities that are age and culturally appropriate (e.g., feeding self with culturally 
appropriate eating implement). 
Usual Social & Functional Activities – Adult: Adaptive tasks and desirable activities, such as going to work, shopping, 
cooking, use of transportation, pursuing a hobby, etc. 
Usual Social & Functional Activities – Young Children: Activities that are age and culturally appropriate (e.g., social 
interactions, play activities, learning tasks, etc.). 


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Confidential 
 
Page 57 of 66                                                                                   Version: October 10, 2014 
 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-THREATENING 
Neurosensory 
alteration (including 
paresthesia and 
painful neuropathy) 
Asymptomatic with 
sensory alteration on 
exam or minimal 
paresthesia causing 
no or minimal 
interference with 
usual social & 
functional activities  
Sensory alteration or 
paresthesia causing 
greater than minimal 
interference with usual 
social & functional 
activities  
Sensory alteration or 
paresthesia causing 
inability to perform usual 
social & functional 
activities 
Disabling sensory 
alteration or paresthesia 
causing inability to 
perform basic self-care 
functions 
 
Seizure: (new onset)  
– Adult ≥ 18 years 
See also Seizure: 
(known pre-existing 
seizure disorder) 
NA 
1 seizure  
2 – 4 seizures  
Seizures of any kind 
which are prolonged, 
repetitive (e.g., status 
epilepticus), or difficult to 
control (e.g., refractory 
epilepsy) 
Seizure: (known pre-
existing seizure 
disorder)  
– Adult ≥ 18 years 
For worsening of 
existing epilepsy the 
grades should be 
based on an increase 
from previous level of 
control to any of these 
levels. 
NA 
Increased frequency 
of pre-existing 
seizures (non-
repetitive) without 
change in seizure 
character OR 
Infrequent break-
through seizures while 
on stable medication 
in a previously 
controlled seizure 
disorder 
Change in seizure 
character from baseline 
either in duration or 
quality (e.g., severity or  
focality)  
Seizures of any kind 
which are prolonged, 
repetitive (e.g., status 
epilepticus), or difficult to 
control (e.g., refractory 
epilepsy) 
Seizure  
– Pediatric < 18 
years 
Seizure, generalized 
onset with or without 
secondary 
generalization, lasting 
< 5 minutes with < 24 
hours post ictal state 
Seizure, generalized 
onset with or without 
secondary 
generalization, lasting 
5 – 20 minutes with  
< 24 hours post ictal 
state 
Seizure, generalized 
onset with or without 
secondary 
generalization, lasting  
> 20 minutes  
Seizure, generalized 
onset with or without 
secondary 
generalization, requiring 
intubation and sedation 
Syncope (not 
associated with a 
procedure) 
NA 
Present 
NA 
NA 
Vertigo 
Vertigo causing no or 
minimal interference 
with usual social & 
functional activities 
Vertigo causing 
greater than minimal 
interference with usual 
social & functional 
activities  
Vertigo causing inability 
to perform usual social 
& functional activities 
Disabling vertigo 
causing inability to 
perform basic self-care 
functions 
Basic Self-care Functions – Adult: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding. 
Basic Self-care Functions – Young Children: Activities that are age and culturally appropriate (e.g., feeding self with culturally 
appropriate eating implement). 
Usual Social & Functional Activities – Adult: Adaptive tasks and desirable activities, such as going to work, shopping, 
cooking, use of transportation, pursuing a hobby, etc. 
Usual Social & Functional Activities – Young Children: Activities that are age and culturally appropriate (e.g., social 
interactions, play activities, learning tasks, etc.). 


Sangamo BioSciences, Inc. 
Phase 1/2 Protocol SB-728mR-1401  
Confidential 
 
Page 58 of 66                                                                                   Version: October 10, 2014 
 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-THREATENING 
RESPIRATORY 
Bronchospasm (acute) 
FEV1 or peak flow 
reduced to  
70 – 80% 
FEV1 or peak flow  
50 – 69% 
FEV1 or peak flow  
25 – 49%  
Cyanosis OR FEV1 or 
peak flow < 25% OR 
Intubation 
Dyspnea or respiratory distress 
Adult ≥ 14 years 
Dyspnea on exertion 
with no or minimal 
interference with 
usual social & 
functional activities  
Dyspnea on exertion 
causing greater than 
minimal interference 
with usual social & 
functional activities  
Dyspnea at rest causing 
inability to perform usual 
social & functional 
activities  
Respiratory failure with 
ventilatory support 
indicated 
Pediatric < 14 years 
Wheezing OR 
minimal increase in 
respiratory rate for 
age 
Nasal flaring OR 
Intercostal retractions 
OR Pulse oximetry 90 
– 95% 
Dyspnea at rest causing 
inability to perform usual 
social & functional 
activities OR Pulse 
oximetry < 90% 
Respiratory failure with 
ventilatory support 
indicated 
MUSCULOSKELETAL 
Arthralgia 
See also Arthritis 
Joint pain causing no 
or minimal 
interference with 
usual social & 
functional activities 
Joint pain causing 
greater than minimal 
interference with usual 
social & functional 
activities 
Joint pain causing 
inability to perform usual 
social & functional 
activities 
Disabling joint pain 
causing inability to 
perform basic self-care 
functions 
Arthritis 
See also Arthralgia 
Stiffness or joint 
swelling causing no or 
minimal interference 
with usual social & 
functional activities 
Stiffness or joint 
swelling causing 
greater than minimal 
interference with usual 
social & functional 
activities 
Stiffness or joint 
swelling causing 
inability to perform usual 
social & functional 
activities 
Disabling joint stiffness 
or swelling causing 
inability to perform basic 
self-care functions  
Bone Mineral Loss 
Adult ≥ 21 years 
BMD t-score  
-2.5 to -1.0  
BMD t-score < -2.5 
Pathological fracture 
(including loss of 
vertebral height) 
Pathologic fracture 
causing life-threatening 
consequences  
Pediatric < 21 years 
BMD z-score  
-2.5 to -1.0 
BMD z-score < -2.5 
Pathological fracture 
(including loss of 
vertebral height) 
Pathologic fracture 
causing life-threatening 
consequences  
Myalgia 
(non-injection site) 
Muscle pain causing 
no or minimal 
interference with 
usual social & 
functional activities 
Muscle pain causing 
greater than minimal 
interference with usual 
social & functional 
activities 
Muscle pain causing 
inability to perform usual 
social & functional 
activities 
Disabling muscle pain 
causing inability to 
perform basic self-care 
functions 
Basic Self-care Functions – Adult: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding. 
Basic Self-care Functions – Young Children: Activities that are age and culturally appropriate (e.g., feeding self with culturally appropriate 
eating implement). 
Usual Social & Functional Activities – Adult: Adaptive tasks and desirable activities, such as going to work, shopping, cooking, use of 
transportation, pursuing a hobby, etc. 
Usual Social & Functional Activities – Young Children: Activities that are age and culturally appropriate (e.g., social interactions, play 
activities, learning tasks, etc.). 


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PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-THREATENING 
Osteonecrosis 
NA 
Asymptomatic with 
radiographic findings 
AND No operative 
intervention indicated 
Symptomatic bone pain 
with radiographic 
findings OR Operative 
intervention indicated 
Disabling bone pain with 
radiographic findings 
causing inability to 
perform basic self-care 
functions 
GENITOURINARY 
Cervicitis  
(symptoms) 
(For use in studies 
evaluating topical  
study agents)  
For other cervicitis see 
Infection: Infection 
(any other than HIV 
infection)  
Symptoms causing no 
or minimal 
interference with 
usual social & 
functional activities  
Symptoms causing 
greater than minimal 
interference with usual 
social & functional 
activities  
Symptoms causing 
inability to perform usual 
social & functional 
activities  
 
Symptoms causing 
inability to perform basic 
self-care functions  
Cervicitis  
(clinical exam) 
(For use in studies 
evaluating topical  
study agents)  
For other cervicitis see 
Infection: Infection 
(any other than HIV 
infection)  
Minimal cervical 
abnormalities on 
examination 
(erythema, 
mucopurulent 
discharge, or friability) 
OR Epithelial 
disruption  
< 25% of total surface 
Moderate cervical 
abnormalities on 
examination 
(erythema, 
mucopurulent 
discharge, or friability) 
OR Epithelial 
disruption of 25 – 49% 
total surface 
Severe cervical 
abnormalities on 
examination (erythema, 
mucopurulent 
discharge, or friability) 
OR Epithelial disruption  
50 – 75% total surface 
Epithelial disruption  
> 75% total surface 
Inter-menstrual 
bleeding (IMB) 
Spotting observed by 
participant OR 
Minimal blood 
observed during 
clinical or colposcopic 
examination 
Inter-menstrual 
bleeding not greater in 
duration or amount 
than usual menstrual 
cycle 
Inter-menstrual bleeding 
greater in duration or 
amount than usual 
menstrual cycle 
Hemorrhage with life-
threatening hypotension 
OR Operative 
intervention indicated 
Urinary tract 
obstruction (e.g., 
stone) 
NA 
Signs or symptoms of 
urinary tract 
obstruction without  
hydronephrosis or 
renal dysfunction 
Signs or symptoms of 
urinary tract obstruction 
with hydronephrosis or 
renal dysfunction 
Obstruction causing life-
threatening 
consequences 
Basic Self-care Functions – Adult: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding. 
Basic Self-care Functions – Young Children: Activities that are age and culturally appropriate (e.g., feeding self with culturally 
appropriate eating implement). 
Usual Social & Functional Activities – Adult: Adaptive tasks and desirable activities, such as going to work, shopping, 
cooking, use of transportation, pursuing a hobby, etc. 
Usual Social & Functional Activities – Young Children: Activities that are age and culturally appropriate (e.g., social 
interactions, play activities, learning tasks, etc.). 
 


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Phase 1/2 Protocol SB-728mR-1401  
Confidential 
 
Page 60 of 66                                                                                   Version: October 10, 2014 
 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-THREATENING 
Vulvovaginitis  
(symptoms) 
(Use in studies 
evaluating topical 
study agents)  
For other 
vulvovaginitis see 
Infection: Infection 
(any other than HIV 
infection) 
Symptoms causing no 
or minimal 
interference with 
usual social & 
functional activities  
Symptoms causing 
greater than minimal 
interference with usual 
social & functional 
activities  
Symptoms causing 
inability to perform usual 
social & functional 
activities  
 
Symptoms causing 
inability to perform basic 
self-care functions  
Vulvovaginitis  
(clinical exam) 
(Use in studies 
evaluating topical study 
agents)  
For other vulvovaginitis 
see Infection: Infection 
(any other than HIV 
infection) 
Minimal vaginal 
abnormalities on 
examination OR 
Epithelial disruption  
< 25% of total surface 
Moderate vaginal 
abnormalities on 
examination OR 
Epithelial disruption of 
25 - 49% total surface 
Severe vaginal 
abnormalities on 
examination OR Epithelial 
disruption  
50 - 75% total surface 
Vaginal perforation OR 
Epithelial disruption 
> 75% total surface 
OCULAR/VISUAL 
Uveitis 
Asymptomatic but 
detectable on exam 
Symptomatic anterior 
uveitis OR Medical 
intervention indicated 
Posterior or pan-uveitis 
OR Operative 
intervention indicated 
Disabling visual loss in 
affected eye(s)  
Visual changes (from 
baseline) 
Visual changes 
causing no or minimal 
interference with usual 
social & functional 
activities 
Visual changes causing 
greater than minimal 
interference with usual 
social & functional 
activities 
Visual changes causing 
inability to perform usual 
social & functional 
activities 
Disabling visual loss in 
affected eye(s) 
ENDOCRINE/METABOLIC 
Abnormal fat 
accumulation 
(e.g., back of neck, 
breasts, abdomen) 
Detectable by study 
participant (or by 
caregiver for young 
children and disabled 
adults) 
Detectable on physical 
exam by health care 
provider 
Disfiguring OR Obvious 
changes on casual visual 
inspection 
NA 
Diabetes mellitus 
NA 
New onset without need 
to initiate medication 
OR Modification of 
current medications to 
regain glucose control 
New onset with initiation 
of medication indicated 
OR Diabetes uncontrolled 
despite treatment 
modification 
Life-threatening 
consequences (e.g., 
ketoacidosis, 
hyperosmolar non-ketotic 
coma)  
Basic Self-care Functions – Adult: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding. 
Basic Self-care Functions – Young Children: Activities that are age and culturally appropriate (e.g., feeding self with culturally 
appropriate eating implement). 
Usual Social & Functional Activities – Adult: Adaptive tasks and desirable activities, such as going to work, shopping, 
cooking, use of transportation, pursuing a hobby, etc. 
Usual Social & Functional Activities – Young Children: Activities that are age and culturally appropriate (e.g., social 
interactions, play activities, learning tasks, etc.). 
 


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Phase 1/2 Protocol SB-728mR-1401  
Confidential 
 
Page 61 of 66                                                                                   Version: October 10, 2014 
 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-THREATENING 
Gynecomastia 
Detectable by study 
participant or caregiver 
(for young children and 
disabled adults) 
Detectable on physical 
exam by health care 
provider 
Disfiguring OR Obvious 
on casual visual 
inspection 
NA 
Hyperthyroidism  
Asymptomatic 
 
Symptomatic causing 
greater than minimal 
interference with usual 
social & functional 
activities OR Thyroid 
suppression therapy 
indicated 
Symptoms causing 
inability to perform usual 
social & functional 
activities OR Uncontrolled 
despite treatment 
modification  
Life-threatening 
consequences (e.g., 
thyroid storm) 
Children: Activities that are age and culturally appropriate (e.g., social interactions, play activities, learning tasks, etc.). 
Hypothyroidism 
Asymptomatic 
Symptomatic causing 
greater than minimal 
interference with usual 
social & functional 
activities OR Thyroid 
replacement therapy 
indicated 
Symptoms causing 
inability to perform usual 
social & functional 
activities OR 
Uncontrolled despite 
treatment modification  
Life-threatening 
consequences (e.g., 
myxedema coma) 
Lipoatrophy 
(e.g., fat loss from the 
face, extremities, 
buttocks) 
Detectable by study 
participant (or by 
caregiver for young 
children and disabled 
adults) 
Detectable on physical 
exam by health care 
provider 
Disfiguring OR Obvious 
on casual visual 
inspection 
NA 
Basic Self-care Functions – Adult: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding. 
Basic Self-care Functions – Young Children: Activities that are age and culturally appropriate (e.g., feeding self with culturally 
appropriate eating implement). 
Usual Social & Functional Activities – Adult: Adaptive tasks and desirable activities, such as going to work, shopping, 
cooking, use of transportation, pursuing a hobby, etc. 
Usual Social & Functional Activities – Young Children: Activities that are age and culturally appropriate (e.g., social 
interactions, play activities, learning tasks, etc.). 
 
 
 


Sangamo BioSciences, Inc. 
Phase 1/2 Protocol SB-728mR-1401  
Confidential 
 
Page 62 of 66                                                                                   Version: October 10, 2014 
 
 
 
LABORATORY 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-THREATENING 
HEMATOLOGY 
Standard International Units are listed in italics 
Absolute CD4+ count  
– Adult and Pediatric  
> 13 years 
(HIV NEGATIVE ONLY) 
300 – 400/mm3 
300 – 400/µL 
200 –  299/mm3 
200 – 299/µL 
100 – 199/mm3 
100 – 199/µL 
< 100/mm3 
< 100/µL 
Absolute lymphocyte 
count  
– Adult and Pediatric  
> 13 years 
(HIV NEGATIVE ONLY) 
600 – 650/mm3 
0.600 x 109 – 
0.650 x 109/L 
500 – 599/mm3 
0.500 x 109 –  
0.599 x 109/L 
350 – 499/mm3 
0.350 x 109 –   
0.499 x 109/L 
< 350/mm3 
< 0.350 x 109/L 
Comment:  Values in children ≤ 13 years are not given for the two parameters above because the absolute counts are variable. 
Absolute neutrophil count (ANC)  
Adult and Pediatric,  
> 7 days 
1,000 – 1,300/mm3 
1.000 x 109 – 
1.300 x 109/L 
750 – 999/mm3 
0.750  x 109 –  
0.999 x 109/L 
500 – 749/mm3 
0.500  x 109 –  
0.749 x 109/L   
< 500/mm3 
< 0.500 x 109/L 
Infant†, 2 –  7 days 
1,250 – 1,500/mm3 
1.250  x 109 –  
1.500 x 109/L 
1,000 – 1,249/mm3 
1.000 x 109 –  
1.249 x 109/L 
750 – 999/mm3 
0.750  x 109 –  
0.999  x 109/L 
< 750/mm3 
< 0.750 x 109/L 
Infant†, ≤1 day 
4,000 – 5,000/mm3 
4.000 x 109 –  
5.000 x 109/L 
3,000 – 3,999/mm3 
3.000 x 109 –  
3.999 x109/L 
1,500 – 2,999/mm3 
1.500 x 109 –  
2.999 x 109/L 
< 1,500/mm3 
< 1.500 x 109/L 
Comment:  Parameter changed from “Infant, < 1 day” to “Infant, ≤1 day” 
Fibrinogen, decreased 
100 – 200 mg/dL 
1.00 – 2.00 g/L 
OR 
0.75 – 0.99 x LLN 
75 – 99 mg/dL 
0.75 – 0.99 g/L 
OR 
0.50 – 0.74 x LLN 
50 – 74 mg/dL 
0.50 – 0.74 g/L 
OR 
0.25 – 0.49 x LLN 
< 50 mg/dL  
< 0.50 g/L 
OR 
< 0.25 x LLN 
OR  
Associated with gross 
bleeding  
 Values are for term infants.  Preterm infants should be assessed using local normal ranges. 
† Use age and sex appropriate values (e.g., bilirubin). 
 
 
 


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Phase 1/2 Protocol SB-728mR-1401  
Confidential 
 
Page 63 of 66                                                                                   Version: October 10, 2014 
 
LABORATORY 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-THREATENING 
Hemoglobin (Hgb) 
Comment:  The Hgb values in mmol/L have changed because the conversion factor used to convert g/dL to mmol/L has been 
changed from 0.155 to 0.6206 (the most commonly used conversion factor).  For grading Hgb results obtained by an analytic 
method with a conversion factor other than 0.6206, the result must be converted to g/dL using the appropriate conversion factor 
for that lab. 
Adult and Pediatric 
 57 days 
 
(HIV POSITIVE ONLY) 
8.5 – 10.0 g/dL 
5.24 – 6.23 mmol/L 
 
7.5 – 8.4 g/dL 
4.62–5.23 mmol/L 
 
6.50 – 7.4 g/dL 
4.03–4.61 mmol/L 
 
< 6.5 g/dL 
< 4.03 mmol/L 
 
Adult and Pediatric  
 57 days  
(HIV NEGATIVE ONLY)  
10.0 – 10.9 g/dL 
6.18 – 6.79 mmol/L 
OR 
Any decrease  
2.5 – 3.4 g/dL 
1.58 – 2.13 mmol/L 
9.0 – 9.9 g/dL 
5.55 - 6.17 mmol/L 
OR 
Any decrease  
3.5 – 4.4 g/dL 
2.14 – 2.78 mmol/L 
7.0 – 8.9 g/dL 
4.34 - 5.54 mmol/L 
OR 
Any decrease  
 4.5 g/dL 
> 2.79 mmol/L 
< 7.0 g/dL 
< 4.34 mmol/L 
 
Comment:  The decrease is a decrease from baseline 
Infant†, 36 – 56 days 
(HIV POSITIVE OR 
NEGATIVE) 
8.5 – 9.4 g/dL 
5.24 – 5.86 mmol/L 
7.0 –  8.4 g/dL 
4.31 – 5.23 mmol/L 
6.0 – 6.9 g/dL 
3.72 – 4.30 mmol/L 
< 6.00 g/dL 
< 3.72 mmol/L 
Infant†, 22 – 35 days 
(HIV POSITIVE OR 
NEGATIVE) 
9.5 – 10.5 g/dL 
5.87 - 6.54 mmol/L 
8.0 – 9.4 g/dL 
4.93 – 5.86 mmol/L 
7.0 – 7.9 g/dL 
4.34 – 4.92 mmol/L 
< 7.00 g/dL 
< 4.34 mmol/L 
Infant†, ≤ 21 days 
(HIV POSITIVE OR 
NEGATIVE) 
12.0 – 13.0 g/dL 
7.42 – 8.09 mmol/L 
10.0 – 11.9 g/dL 
6.18 – 7.41 mmol/L 
9.0 – 9.9 g/dL 
5.59- 6.17 mmol/L 
< 9.0 g/dL 
< 5.59 mmol/L 
Correction:  Parameter changed from “Infant < 21 days” to “Infant ≤ 21 days” 
International Normalized 
Ratio of prothrombin time 
(INR) 
1.1 – 1.5 x ULN 
1.6 – 2.0 x ULN 
2.1 – 3.0 x ULN 
> 3.0 x ULN 
Methemoglobin 
5.0 – 10.0% 
10.1 – 15.0% 
15.1 – 20.0% 
> 20.0% 
Prothrombin Time (PT) 
1.1 – 1.25 x ULN 
1.26 – 1.50 x ULN 
1.51 – 3.00 x ULN 
> 3.00 x ULN 
Partial Thromboplastin 
Time (PTT) 
1.1 – 1.66 x ULN 
1.67 – 2.33 x ULN 
2.34 – 3.00 x ULN 
> 3.00 x ULN 
Platelets, decreased 
100,000 –  
124,999/mm3 
100.000 x 109 – 
124.999 x 109/L 
50,000 –  
99,999/mm3 
50.000 x 109 – 
99.999 x 109/L 
25,000 –  
49,999/mm3 
25.000 x 109 – 
49.999 x 109/L 
< 25,000/mm3 
< 25.000 x 109/L 
WBC, decreased 
2,000 – 2,500/mm3 
2.000 x 109 –  
2.500 x 109/L 
1,500 – 1,999/mm3 
1.500 x 109 –  
1.999 x 109/L 
1,000 – 1,499/mm3 
1.000 x 109 –  
1.499 x 109/L 
< 1,000/mm3 
< 1.000 x 109/L 
 Values are for term infants.  Preterm infants should be assessed using local normal ranges. 
† Use age and sex appropriate values (e.g., bilirubin). 
 
 


Sangamo BioSciences, Inc. 
Phase 1/2 Protocol SB-728mR-1401  
Confidential 
 
Page 64 of 66                                                                                   Version: October 10, 2014 
 
LABORATORY 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-THREATENING 
CHEMISTRIES 
 
Standard International Units are listed in italics  
Acidosis 
NA 
pH < normal, but  7.3 
pH < 7.3 without life-
threatening 
consequences 
pH < 7.3 with life-
threatening 
consequences 
Albumin, serum, low 
3.0 g/dL – < LLN 
30 g/L – < LLN 
2.0 – 2.9 g/dL 
20 – 29 g/L 
< 2.0 g/dL 
< 20 g/L 
NA 
Alkaline Phosphatase 
1.25 – 2.5 x ULN† 
2.6 – 5.0 x ULN† 
5.1 – 10.0 x ULN† 
> 10.0 x ULN† 
Alkalosis 
NA 
pH > normal, but  7.5 
pH > 7.5 without life-
threatening 
consequences 
pH > 7.5 with life-
threatening 
consequences  
ALT (SGPT) 
1.25 – 2.5 x ULN 
2.6 – 5.0 x ULN 
5.1 – 10.0 x ULN 
> 10.0 x ULN 
AST (SGOT) 
1.25 – 2.5 x ULN 
2.6 – 5.0 x ULN 
5.1 – 10.0 x ULN 
> 10.0 x ULN 
Bicarbonate, serum, low 
16.0 mEq/L – < LLN 
16.0 mmol/L – < LLN 
11.0 – 15.9 mEq/L 
11.0 – 15.9 mmol/L 
8.0 – 10.9 mEq/L 
8.0 – 10.9 mmol/L 
< 8.0 mEq/L 
< 8.0 mmol/L 
Comment:  Some laboratories will report this value as Bicarbonate (HCO3) and others as Total Carbon Dioxide (CO2).  These 
are the same tests; values should be graded according to the ranges for Bicarbonate as listed above. 
Bilirubin (Total) 
Adult and Pediatric > 
14 days 
1.1 – 1.5 x ULN 
1.6 – 2.5 x ULN 
2.6 – 5.0 x ULN 
> 5.0 x ULN 
Infant†, ≤ 14 days 
(non-hemolytic) 
NA 
20.0 – 25.0 mg/dL 
342 – 428 µmol/L 
25.1 – 30.0 mg/dL 
429 – 513 µmol/L 
> 30.0 mg/dL 
> 513.0 µmol/L 
Infant†, ≤ 14 days 
(hemolytic) 
NA 
NA 
20.0 – 25.0 mg/dL 
342 – 428 µmol/L 
> 25.0 mg/dL 
> 428 µmol/L 
Calcium, serum, high 
Adult and Pediatric  
≥ 7 days 
10.6  – 11.5 mg/dL 
2.65 – 2.88 mmol/L 
11.6  – 12.5 mg/dL 
2.89 – 3.13 mmol/L 
12.6  – 13.5 mg/dL 
3.14 – 3.38 mmol/L 
> 13.5 mg/dL 
> 3.38 mmol/L 
Infant†, < 7 days 
11.5 – 12.4 mg/dL 
2.88 – 3.10 mmol/L 
12.5 – 12.9 mg/dL 
3.11 – 3.23 mmol/L 
13.0 – 13.5 mg/dL 
3.245 – 3.38 mmol/L 
> 13.5 mg/dL 
> 3.38 mmol/L 
Calcium, serum, low  
Adult and Pediatric  
≥ 7 days  
7.8  – 8.4 mg/dL 
1.95 – 2.10 mmol/L 
7.0  – 7.7 mg/dL 
1.75 – 1.94 mmol/L 
6.1  – 6.9 mg/dL 
1.53 – 1.74 mmol/L 
< 6.1 mg/dL 
< 1.53 mmol/L 
Infant†, < 7 days 
6.5 – 7.5 mg/dL 
1.63 – 1.88 mmol/L 
6.0 – 6.4 mg/dL 
1.50 – 1.62 mmol/L 
5.50 – 5.90 mg/dL 
1.38 – 1.51 mmol/L 
< 5.50 mg/dL 
< 1.38 mmol/L 
Comment:  Do not adjust Calcium, serum, low or Calcium, serum, high for albumin 
 Values are for term infants.  Preterm infants should be assessed using local normal ranges. 
† Use age and sex appropriate values (e.g., bilirubin). 
 


Sangamo BioSciences, Inc. 
Phase 1/2 Protocol SB-728mR-1401  
Confidential 
 
Page 65 of 66                                                                                   Version: October 10, 2014 
 
LABORATORY 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-THREATENING 
Cardiac troponin I (cTnI) 
NA 
NA 
NA 
Levels consistent with 
myocardial infarction or 
unstable angina as 
defined by the 
manufacturer 
Adult ≥ 18 years 
200 – 239 mg/dL 
5.18 – 6.19 mmol/L 
240 – 300 mg/dL 
6.20 – 7.77 mmol/L 
> 300 mg/dL 
> 7.77 mmol/L 
NA 
Pediatric < 18 years 
170 – 199 mg/dL 
4.40 – 5.15 mmol/L 
200 – 300 mg/dL 
5.16 – 7.77 mmol/L 
> 300 mg/dL 
> 7.77 mmol/L 
NA 
Creatine Kinase 
3.0 – 5.9 x ULN† 
6.0 – 9.9 x ULN† 
10.0 – 19.9 x ULN† 
 20.0 x ULN† 
Creatinine 
1.1 – 1.3 x ULN† 
1.4 – 1.8 x ULN† 
1.9 – 3.4 x ULN† 
 3.5 x ULN† 
 
 
LABORATORY 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-THREATENING 
Glucose, serum, high  
Nonfasting 
116 – 160 mg/dL 
6.44 – 8.88 mmol/L 
161 – 250 mg/dL 
8.89 – 13.88 mmol/L 
251 – 500 mg/dL 
13.89 – 27.75 mmol/L 
> 500 mg/dL 
> 27.75 mmol/L 
     
Fasting 
110 – 125 mg/dL 
6.11 – 6.94 mmol/L 
126 – 250 mg/dL 
6.95 – 13.88 mmol/L 
251 – 500 mg/dL 
13.89 – 27.75 mmol/L 
> 500 mg/dL 
> 27.75 mmol/L 
Adult and Pediatric  
≥ 1 month 
55 – 64 mg/dL 
3.05 – 3.55 mmol/L 
40 – 54 mg/dL 
2.22 – 3.06 mmol/L 
30 – 39 mg/dL 
1.67 – 2.23 mmol/L 
< 30 mg/dL 
< 1.67 mmol/L 
Infant†, < 1 month 
50 – 54 mg/dL 
2.78 – 3.00 mmol/L 
40 – 49 mg/dL 
2.22 – 2.77 mmol/L 
30 – 39 mg/dL 
1.67 – 2.21 mmol/L 
< 30 mg/dL 
< 1.67 mmol/L 
Lactate 
ULN - < 2.0 x ULN 
without acidosis 
 2.0 x ULN without 
acidosis 
Increased lactate with 
pH < 7.3 without life-
threatening 
consequences  
Increased lactate with 
pH < 7.3 with life-
threatening 
consequences  
Comment: Added ULN to Grade 1 parameter  
LDL cholesterol (fasting) 
Adult ≥ 18 years 
130 – 159 mg/dL 
3.37 – 4.12 mmol/L 
160 – 190 mg/dL 
4.13 – 4.90 mmol/L 
 190 mg/dL 
 4.91 mmol/L 
NA 
Pediatric > 2 - < 18 
years 
110 – 129 mg/dL  
2.85 – 3.34 mmol/L 
130 – 189 mg/dL 
3.35 – 4.90 mmol/L 
≥ 190 mg/dL 
≥ 4.91 mmol/L 
NA 
Lipase 
1.1 – 1.5 x ULN 
1.6 – 3.0 x ULN 
3.1 – 5.0 x ULN 
> 5.0 x ULN 
Magnesium, serum, low 
1.2  – 1.4 mEq/L 
0.60 – 0.70 mmol/L 
0.9 – 1.1 mEq/L 
0.45 – 0.59 mmol/L 
0.6 – 0.8 mEq/L 
0.30 – 0.44 mmol/L 
< 0.60 mEq/L 
< 0.30 mmol/L 
 Values are for term infants.  Preterm infants should be assessed using local normal ranges. 
† Use age and sex appropriate values (e.g., bilirubin). 
 


Sangamo BioSciences, Inc. 
Phase 1/2 Protocol SB-728mR-1401  
Confidential 
 
Page 66 of 66                                                                                   Version: October 10, 2014 
 
LABORATORY 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-THREATENING 
Pancreatic amylase 
1.1 – 1.5 x ULN 
1.6 – 2.0 x ULN 
2.1 – 5.0 x ULN 
> 5.0 x ULN 
Phosphate, serum, low 
Adult and Pediatric  
> 14 years 
2.5 mg/dL – < LLN 
0.81 mmol/L – < LLN 
2.0 – 2.4 mg/dL 
0.65 – 0.80 mmol/L 
1.0 – 1.9 mg/dL 
0.32 – 0.64 mmol/L 
< 1.00 mg/dL 
< 0.32 mmol/L 
Pediatric 1 year – 14 
years  
3.0 – 3.5 mg/dL 
0.97 – 1.13 mmol/L 
2.5 – 2.9 mg/dL 
0.81 – 0.96 mmol/L 
1.5 – 2.4 mg/dL 
0.48 – 0.80 mmol/L 
< 1.50 mg/dL 
< 0.48 mmol/L 
Pediatric < 1 year 
3.5 – 4.5 mg/dL 
1.13 – 1.45 mmol/L 
2.5 – 3.4 mg/dL 
0.81 – 1.12 mmol/L 
1.5 – 2.4 mg/dL 
0.48 – 0.80 mmol/L 
< 1.50 mg/dL 
< 0.48 mmol/L 
Potassium, serum, high 
5.6 – 6.0 mEq/L 
5.6 – 6.0 mmol/L 
6.1 – 6.5 mEq/L 
6.1 – 6.5 mmol/L 
6.6 – 7.0 mEq/L 
6.6 – 7.0 mmol/L 
> 7.0 mEq/L 
> 7.0 mmol/L 
Potassium, serum, low 
3.0 – 3.4 mEq/L 
3.0 – 3.4 mmol/L 
2.5 – 2.9 mEq/L 
2.5 – 2.9 mmol/L 
2.0 – 2.4 mEq/L 
2.0 – 2.4 mmol/L 
< 2.0 mEq/L 
< 2.0 mmol/L 
Sodium, serum, high 
146 – 150 mEq/L 
146 – 150 mmol/L 
151 – 154 mEq/L 
151 – 154 mmol/L 
155 – 159 mEq/L 
155 – 159 mmol/L 
 160 mEq/L 
 160 mmol/L 
Sodium, serum, low 
130 – 135 mEq/L 
130 – 135 mmol/L 
125 – 129 mEq/L 
125 – 129 mmol/L 
121 – 124 mEq/L 
121 – 124 mmol/L 
 120 mEq/L 
 120 mmol/L 
Triglycerides (fasting) 
NA 
500 – 750 mg/dL 
5.65 – 8.48 mmol/L 
751 – 1,200 mg/dL 
8.49 – 13.56 mmol/L 
> 1,200 mg/dL 
> 13.56 mmol/L 
Uric acid 
7.5 – 10.0 mg/dL 
0.45 – 0.59 mmol/L 
10.1 – 12.0 mg/dL 
0.60 – 0.71 mmol/L 
12.1 – 15.0 mg/dL 
0.72 – 0.89 mmol/L 
> 15.0 mg/dL 
> 0.89 mmol/L 
URINALYSIS 
 
Standard International Units are listed in italics 
Hematuria (microscopic) 
 6 – 10 RBC/HPF 
> 10 RBC/HPF 
Gross, with or without 
clots OR with RBC 
casts 
Transfusion indicated 
Proteinuria, random 
collection 
1 + 
2 – 3 + 
4 + 
NA 
Proteinuria, 24 hour collection 
Adult and Pediatric  
 10 years 
200 – 999 mg/24 h 
0.200 – 0.999 g/d 
1,000 – 1,999 mg/24 h 
1.000 – 1.999 g/d 
2,000 – 3,500 mg/24 h 
2.000 – 3.500 g/d 
> 3,500 mg/24 h 
> 3.500 g/d 
Pediatric > 3 mo -  
< 10 years 
201 – 499 mg/m2/24 h 
0.201 – 0.499 g/d 
500 – 799 mg/m2/24 h 
0.500 – 0.799 g/d 
800 – 1,000  
mg/m2/24 h 
0.800 – 1.000 g/d 
> 1,000 mg/ m2/24 h 
> 1.000 g/d 
 Values are for term infants.  Preterm infants should be assessed using local normal ranges. 
† Use age and sex appropriate values (e.g., bilirubin). 
 

Prot_000.pdf: