A Phase 1/2, Open-label Randomized Study of Ulocuplumab (BMS-936564) in Combination With Low Dose Cytarabine in Subjects With Newly Diagnosed Acute Myeloid Leukemia
Phase: PHASE1
Conditions: Leukemia
Sponsor: Bristol-Myers Squibb

Page:
1
Protocol Number:
CA212016
IND Number:
103,261
Ex-US
Non-IND
EUDRACT Number
2016-004275-40
Date:
02-Sep-2014
Revised Date
27-Jul-2017
CLINICAL PROTOCOL CA212016
A Phase 1/2, Open-label Randomized Study of Ulocuplumab (BMS-936564) In Combination 
with Low Dose Cytarabine in Subjects with Newly Diagnosed Acute Myeloid Leukemia
Revised Protocol Number: 06
Study Director/Central Medical Monitor
Daniela Buglio, MD, PhD
This document is the confidential and proprietary information of Bristol-Myers Squibb 
Company and its global affiliates (BMS). By reviewing this document, you agree to keep it 
confidential and to use and disclose it solely for the purpose of assessing whether your 
organization will participate in and/or the performance of the proposed BMS-sponsored 
study. Any permitted disclosures will be made only on a confidential "need to know" basis 
within your organization or to your independent ethics committee(s). Any other use, 
copying, disclosure or dissemination of this information is strictly prohibited unless 
expressly authorized in writing by BMS. Any supplemental information (eg, amendments) 
that may be added to this document is also confidential and proprietary to BMS and must 
be kept in confidence in the same manner as the contents of this document. Any person 
who receives this document without due authorization from BMS is requested to return it 
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to BMS or promptly destroy it. All other rights reserved. References to BMS in this 
protocol may apply to partners to which BMS has transferred obligations, eg, a Contract 
Research Organization (CRO).
Replace all previous version(s) of the protocol with this revised protocol and please provide 
a copy of this revised protocol to all study personnel under your supervision, and archive 
the previous versions.
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DOCUMENT HISTORY
Document
Date of Issue
Summary of Change
Revised 
Protocol 06
27-Jul-2017
•
The exclusion criteria was revised to specify allogeneic transplants in 
patients who received prior hematopoietic stem cell transplantation
•
The schedule for the collection of hematology samples during 
treatment cycles 1 and 2 was revised to eliminate the requirement for 
10 days consecutive days of hematology collections, and to allow 
hematology sample collection flexibility up to 72 hours before 
infusion of ulocuplumab  
•
Peripheral blood and serum/plasma collection criteria during End of 
study treatment and follow-up assessment were revised from 
mandatory status to include exceptions listed in Section 5.7.2 and 
Table 5.7.2 1
•
Buccal swab procedure was added to treatment procedural outline and 
biomarkers sampling schedule for the expansion cohort
•
Time and assessment ranges were revised to reflect current standards 
in Sections 4.6.1.1 and 4.6.1.2 and Table 4.6.1.2-1
•
Removed bone marrow collection for TCR sequencing.
Revised 
Protocol 05
29-Mar-2017
Incorporates Amendment 06
Amendment 06
29-Mar-2017
This amendment implements the following changes: revises synopsis to 
align with revisions in sections 3.1, 8.3.1 and 8.3.2; revises study design 
description; revises study treatment and dose timing sections to clarify 
when LDAC only arm may add ulocuplumab; revises discontinuation, 
dose modifications, infusion delays, and missed doses sections; adds 
whole exome sequencing to bone marrow and peripheral blood 
biomarker testing; revises Tables 5.1-2, 5.1-3, 5.7.2-1; moves
cytogenetic testing to other assessments section; adds ECG analyses 
section; adds whole exome sequencing to biomarker analyses section; 
revises primary endpoint analysis details; revises secondary endpoint 
details; moves ECG analyses details from biomarker analyses section to 
a new section; adds cytogenetic analyses section.
Revised 
Protocol 04
10-Feb-2017
Incorporates Amendment(s) 05
Amendment 05
10-Feb-2017
This amendment implements the following changes: revises the 
telephone/fax numbers and location of the BMS Medical Monitor; 
corrects study title in synopsis; clarifies that exclusion criterion 2b is 
applicable; clarifies dose modifications and addition of ulocuplumab to 
LDAC alone arm; clarifies local lab bone marrow results sent to BMS; 
clarifies standard of care testing for extramedullary disease; adds central 
lab cytogenetic testing; deletes local cytogenetic testing; clarifies time 
point for end of cycle leukemia assessment; clarifies bone marrow 
aspirate is sufficient for leukemia evaluation; reduces pregnancy test 
requirement (WOBCP) to once per cycle and monthly during dose 
delays; adds pregnancy test to EOT; clarifies and/or corrects Time and 
Events Schedule footnotes; clarifies hematology blast percentage is 
included in hematology lab tests; clarifies PK, ADA, and receptor 
occupancy samples are not collected for subjects randomized to the 
LDAC alone arm; clarifies footnotes in PK and biomarker tables; 
clarifies safety and serial ECG requirements; provides details of 
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Document
Date of Issue
Summary of Change
biomarker testing; Appendices 1 and 3 updated.
Revised 
Protocol 03
02-Nov-2016
Incorporates Amendment(s) 03
Amendment 03
02-Nov-2016
This amendment expands the study globally to provide insights of safety 
and efficacy of two different dose levels of ulocuplumab (800 mg and 
1000 mg) in combination with low dose cytarabine (LDAC) and LDAC 
alone for the treatment of Acute Myeloid Leukemia (AML). The 
expansion will enroll subjects (≥18 years old) with newly diagnosed 
AML that are unfit for high induction chemotherapy or stem cell 
transplant because of age or comorbidities. The changes include addition 
of a Phase 2 (expansion cohort) with 1:1:1 randomization of 
approximately 120 subjects, 40 subjects per treatment group, to assess 
preliminary efficacy by complete remission with blast count reduction   
< 5% (CR) or complete remission with incomplete blood count recovery 
(CRi) and overall survival (OS). The changes include collection of 
samples for exploratory biomarker assessment such as CXR4, receptor 
occupancy and evaluation
of ulocuplumab pharmacokinetics and 
interaction with LDAC. For safety, DLTs will be evaluated and ECG 
evaluation was added for a subset of subjects to measure QT intervals by 
Fridericia method.
Revised 
Protocol 02
07-May-2015
Incorporates Administrative Letter 01 and Amendment(s) 02
Amendment 02
07-May-2015
This amendment of the protocol is to implement following changes: 
modify the target population to remove the restriction on AML (newly 
diagnosed, elderly), extend the period of contraception use, modify prior 
therapy related criteria, and modify hepatitis B and C infection criteria to 
only exclude active infection.
Administrative 
Letter 01
05-Jan-2015
To change Medical Monitor 
Revised 
Protocol 01
24-Oct-2014
Incorporates Amendment(s) 01
Amendment 01
24-Oct-2014
This amendment of the protocol is in response to the 30-day review by 
Pharmaceuticals and Medical Devices Association (PMDA) for Clinical 
Trial Notification. Additional changes for a clarification purpose are also 
incorporated in this amendment.
Original 
Protocol
02-Sep-2014
Not applicable
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OVERALL RATIONALE FOR THE REVISED PROTOCOL 06
The rationale for Revised Protocol 06 is to allow flexibility with regard to the hematology testing 
window and to add buccal swab collection as germline control for whole exome sequencing 
analysis. In addition, clarification of exclusion criteria for prior hematopoietic stem cell 
transplantation, peripheral blood collection during end of treatment (EOT) and Follow-up period
were made. 
SUMMARY OF KEY CHANGES OF REVISED PROTOCOL 06
Section Number & 
Title
Description of Change
Brief Rationale
Section 3.3.2 Exclusion 
Criteria, item 2 e
This exclusion criterion was revised to 
specify allogeneic transplants in patients who 
received prior hematopoietic stem cell 
transplantation
Section 4.6.1.1 Treatment 
Discontinuation Criteria;
Section 4.6.1.2 Dose 
Modifications, Infusion 
Delays and Missed Doses;
Table 4.6.1.2-1 Dose 
Delay and 
Discontinuation Criteria 
for Ulocuplumab-related 
Adverse Events.
Time and assessment ranges were revised as 
follows: 
•
Discontinuation due to prolonged bone
marrow suppression was revised from 
> 56 days to ≥56 days
•
For dose delay, the definitions of 
m ye l o s u p p r e s s i o n as ANC
<500/μL or platelet count <10 x109/L
in a normal bone marrow with < 5% 
blasts were revised from < to ≤ in all 
instances 
•
Discontinuation due to QT prolongation 
was revised from QTcF > 500 msec  ≥
500 msec.  
•
For dose delay and discontinuation, 
definition of Grade 3 baseline neutrophil
count was revised from  < 1000 cells/μL 
to ≤1000 cells/μL
•
Definition of continuous study treatment
delay was revised from > 56 days to ≥ 56
days.
Section 5.1 Flow 
Chart/Time and Events 
Schedule; Table 5.1-2 
Treatment Procedural 
Outline (CA212016), 
Hematology
The schedule for the collection of 
hematology samples during treatment cycles 
1 and 2 was revised to eliminate the 
requirement for 10 consecutive days of 
hematology collections.  
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SUMMARY OF KEY CHANGES OF REVISED PROTOCOL 06
Section Number & 
Title
Description of Change
Brief Rationale
Section 5.1 Flow 
Chart/Time and  Events 
Schedule; Table 5.1-2
Treatment Procedural 
Outline (CA212016), 
Peripheral blood and 
serum/plasma; Table 5.1-
3: Follow-up Assessments 
(CA212016), Peripheral 
blood and serum/plasma
Peripheral blood and serum/plasma collection 
criteria during study treatment and follow-up 
assessment were revised from mandatory 
status to include exceptions listed in Section
5.7.2 and Table 5.7.2-1.
Section 5.7.1 Bone 
Marrow Testing
Section 8.4.7 Biomarker 
Analyses
Revised to remove bone marrow collection 
for TCR sequencing 
All
Minor formatting and typographical 
corrections
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SYNOPSIS
Clinical Protocol CA212016
Protocol Title: A Phase 1/2, Randomized Open-label Study of Ulocuplumab (BMS-936564) in Combination with 
Low Dose Cytarabine in Subjects with Newly Diagnosed Acute Myeloid Leukemia
Investigational Product(s), Dose and Mode of Administration, Duration of Treatment with Investigational 
Product(s): Ulocuplumab (600 mg-escalation cohort and 800 mg-escalation and expansion cohorts, 1000 mg 
expansion cohort) will be administered as a single intravenous (IV) infusion over approximately 60 minutes on Day 
1, 8, and 15 in combination with low dose cytarabine (LDAC) (20 mg BID [(40 mg/day], SC) administered on Day 1-
10 for each cycle (28 days/cycle) of the initial 2 cycles (Cycle 1-2). For Cycle 3 and subsequent cycles (28 days/cycle), 
subjects will receive ulocuplumab (600, 800 or 1000 mg, IV) on Day 1 and 8 in combination with LDAC (20 mg BID, 
SC) on Day 1 - 10. Subjects who are tolerating study treatment, clinically stable and not progressing rapidly at the end 
of each cycle may continue additional cycles until disease progression, development of unacceptable toxicity, 
intercurrent illness preventing treatment, or patient/physician request. For subjects randomized to the LDAC only arm, 
they will receive LDAC (20 mg BID, SC) on Day 1-10.
Study Phase: 1/2
Research Hypothesis: The study has no formal research hypothesis to be statistically tested.
Rationale: The first 6 AML subjects (3 de novo, 1 AML relapsed, 2 secondary AML to myelodysplasia and 
myelofibrosis) in the escalation cohort of this trial (CA212016) were treated at dose levels of 600 mg and 800 mg 
ulocuplumab in combination with LDAC 20 mg BID. Overall complete remission/complete remission with incomplete 
blood count (CR/CRi), as assessed by the investigator, was observed in 4 of 6 evaluable subjects (66%), with 1 of 4 
responders treated at 60 0mg and 3 of 4 responders at 800 mg. Based on the results from the escalation cohort, a Phase 
2 ( expansion cohort) was added to this protocol
In the Phase 2 (expansion  cohort), a randomization ratio of 1:1:1 was selected to include two doses of ulocuplumab 
(800 mg and 1000 mg) in combination with LDAC and LDAC alone. In each arm a sample size of approximately 
40 subjects per treatment group will allow estimation of the complete response rate.
Primary Objective: 
In Phase 1 (escalation cohort): To assess the safety and tolerability of ulocuplumab in combination with low-dose 
cytarabine (LDAC) in subjects with AML.
In Phase 2 (expansion cohort): To estimate preliminary efficacy in terms of complete remission (CR/CRi=CR+CRi) 
in subjects treated at two different dose levels of ulocuplumab, 800 mg and 1000 mg, in combination with low-dose 
cytarabine (LDAC).
Secondary Objectives:  
•
To characterize the immunogenicity of ulocuplumab.
•
To characterize the PK profiles of ulocuplumab in combination with LDAC.
•
To evaluate the effects of ulocuplumab on ECG intervals, including QTc intervals
•
In Phase 1 (escalation cohort): To evaluate the preliminary efficacy on the basis of objective response in subjects 
treated with ulocuplumab in combination with LDAC.
•
To assess overall survival (OS) in subjects treated with ulocuplumab 800 mg or 1000 mg in combination with 
LDAC.
•
In Phase 2 (expansion cohort): To assess the safety and tolerability of ulocuplumab in subjects with AML treated 
with ulocuplumab at two different dose levels 800 mg and 1000 mg in combination with LDAC.
•
In Phase 2 (expansion cohort): To assess rates of overall remission (OR=PR+CR+CRi) as well as duration of 
complete remission (CR/CRi) in subjects treated with ulocuplumab at two different dose levels 800 mg and 1000 
mg in combination with LDAC.
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•
In Phase 2 (expansion cohort): To assess efficacy (in terms of rates of CR/CRi and OR and duration of remission, 
respectively, in subjects treated with LDAC alone, to compare with historical controls of LDAC in the same 
patient population. Overall survival will also be assessed in this group.
 
 
 
 
Study Design: In the escalation phase, this was a Phase 1, open-label study to assess the safety and tolerability of 
ulocuplumab in subjects with AML. The study consisted of 3 periods: Screening (up to 28 days), Treatment
(28 days/cycle) and Follow-up (at least 30 days following the end of treatment visit). Escalation phase subjects will 
be followed for overall survival (OS) for at least 2 years. The dose of ulocuplumab chosen to be explored in the 
escalation cohort of this study (600 mg and 800 mg) was selected based on the results from a Phase 1 study 
(CA212001).
Based upon the CA212016 escalation cohort results, the protocol is revised to include an exploratory, non-comparative 
open-label Phase 2 expansion cohort of up to approximately an additional 120 AML subjects. Expansion cohort 
subjects will be randomized to 1 of 3 treatment arms: LDAC alone or either 800 mg or 1000 mg ulocuplumab in 
combination with LDAC 20 mg BID. Escalation cohort subjects who are continuing treatment will continue at their 
assigned dose. In the expansion cohort, randomization will be suspended in the ulocuplumab 1000 mg arm while 
safety data from the first 6 subjects in this arm are evaluated for DLTs. For the escalation and expansion cohorts, 
DLTs and all other toxicities were defined and evaluated using the National Cancer Institute Common Terminology 
Criteria for Adverse Events Version 4.03 (NCI CTCAE v4.03). DLTs were defined based upon events that were 
considered to be related to ulocuplumab in combination with LDAC and that occurred during the first cycle of drug 
administration (28 days).  
The Screening Period is defined as the 28 days following initiation of screening assessments and before administration 
of the first dose of any study drug, during which subjects are evaluated for study eligibility.
During the Treatment Period of the escalation and expansion arms, ulocuplumab (600, 800 or 1000 mg, IV) will be 
administered on Day 1, 8 and 15 in combination with LDAC (20 mg BID (40 mg/day), SC) administered on Day 1-10 
for each cycle (28 days/cycle) of the initial 2 cycles (Cycle 1-2). For Cycle 3 and subsequent cycles (28 days/cycle), 
subjects will receive ulocuplumab (600, 800 or 1000 mg, IV) on Day 1 and 8 in combination with LDAC (20 mg BID, 
SC) on Day 1 - 10. Subjects who are tolerating study treatment, clinically stable and not progressing rapidly at the end 
of each cycle may continue additional cycles until disease progression, development of unacceptable toxicity, 
intercurrent illness preventing treatment, or patient request or investigator decision to stop treatment. Delay of 
subsequent cycles for recovery from myelosuppression (or other AE) is allowed at investigator discretion. For subjects 
randomized to the LDAC alone arm, they will receive LDAC (20 mg BID, SC) on Day 1-10.
Leukemia response assessment will be evaluated for each cycle using the 2003 International Working Group Response 
Criteria for AML (AML IWG 2003). The results of the response assessments must be reviewed and documented 
before the first dose of the next cycle.
Subjects who experience study drug-related AEs that are ongoing at the follow-up visit will continue to be followed 
until the AEs are (i) resolved to baseline, (ii) stabilized, or (iii) have been deemed irreversible unless further anti-cancer 
treatment are administered.
Subjects who discontinue study treatment for any reasons will be followed for 30 days after the end of treatment visit 
for AEs. Subjects will be followed for overall survival for 2 years.
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The last visit for each subject will be defined as the end of follow up visit which is no less than 30 days after the 
subject’s end-of-treatment visit.
The study will end after the last subject completes the last visit.
A total number of up to approximately 126 (6 escalation cohort and 120 expansion cohort) subjects will be treated in 
this study. The entire study (Screening, Treatment and Follow-up) is expected to last approximately 7 years, with the 
addition of the expansion cohort and overall survival follow up.
The expansion phase of the study will include approximately 120 subjects in order to randomize subjects in a 1:1:1 
ratio: 40 subjects in the ulocuplumab 800mg  plus LDAC arm, 40 subjects in the ulocuplumab 1000 mg plus LDAC 
arm and 40 subjects in the LDAC alone arm (Figure 2). The randomization will be suspended in the ulocuplumab 
1000 mg arm while the safety data on the first 6 subjects on this arm are evaluated for DLTs. Randomization will 
continue in the other 2 arms while the data is reviewed therefore total numbers randomized is approximate. 
Randomization to the 1000 mg ulocuplumab arm will resume if ≤33% of subjects experience a DLT. If > 33% of 
subjects are observed with DLTs, this treatment arm will not accrue additional subjects.
Subjects in the LDAC alone arm will be permitted to add ulocuplumab 800 mg into their treatment regimen if they do 
not achieve complete remission (CR or complete remission with incomplete blood count recovery [CRi]) confirmed 
by blast count reduction after 4 treatment cycles or if they relapse after achieving complete remission. If ulocuplumab 
is added to the LDAC alone arm, the treatment schedule is LDAC 20 mg BID from day 1 to 10 of each cycle and 
ulocuplumab 800mg on Day 1, 8 and 15 for the first 2 cycles then ulocuplumab 800 mg on Day 1 and 8 for subsequent 
cycles.
The study design schematic is presented in Figure 1.
Figure 1:
Study Design Schematic
Figure 2:
Phase 2 Study Design Schematic
Frontline 
unfit for 
intensive 
chemo
(age 
comorbidities)
1:1:1
Ulocuplumab
800 mg + LDAC
LDAC (low dose 
cytarabine)
•
Treat to progression
n=40
Ulocuplumab
800 mg + LDAC
Ulocuplumab
1000 mg + LDAC
n=40
n=40
BMS-936564:
LDAC:
End of
Treatment
End of
Follow-up
(Last Visit)
Screening
Treatment (28 days/cycle)
BMS-936564 in combination with LDAC
Follow-up
(+ 30 days)
Cycle 1 (DLT Assessment) and Cycle 2
Cycle 3 and after
Day -28
Day 1
Day 8
Day 15
Day 22
Day 1
Day 8
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Physical examinations/measurements, vital sign measurements, 12-lead electrocardiograms (ECG), and clinical 
laboratory evaluations will be performed at selected times. Subjects will be closely monitored for AEs throughout the 
study. Blood samples will be collected for PK, RO and immunogenicity analyses. Blood and bone marrow aspirate 
samples will be collected for biomarker analyses. A minimum of 15 subjects each from the 800 mg and 1000 mg 
expansion cohorts are required to provide serial blood samples and time-matched ECGs to further characterize the PK 
of ulocuplumab and its effect on ECG intervals in combination with LDAC (Serial PK/ECG Subset).
The expansion cohort will treat approximately an additional 120 subjects at a dose of 800 mg or 1000 mg ulocuplumab 
in combination with LDAC or LDAC alone. All assessments from the escalation cohort will be performed and 
additional assessments will be completed (e.g., biomarkers, overall survival, serial ECGs).
Follow-up
•
Begins when the decision to discontinue a subject from study therapy is made (no further treatment with study 
therapy).
•
Subjects will have one follow-up visit for safety. Follow-up visit 1(X01) will be completed 30 days (± 7 days) 
from the last dose of study therapy. After X01, subjects will be followed every 3 months for ongoing drug-related 
AEs until resolved, return to baseline or deemed irreversible, or until lost to follow-up or withdrawal of study 
consent. Subjects will also be followed every 3 months for survival for up to two years, until death, lost to follow-
up or withdrawal of study consent.
•
PK, immunogenicity and biomarker samples will be collected at the 30 day follow-up visit.
Dose Escalation:
In the escalation cohort, enrollment of subjects adhered to a Modified Toxicity Probability Interval (mTPI) design. 
The study design set a 20% target DLT rate with an equivalence interval of 15 - 25%. Initially 3 subjects treated at the 
dose level of 600 mg. No additional subjects were added to the same dose level (i.e., a total number of 3 subjects were
treated for a given dose level). A decision to consider the next higher dose level or the next lower dose level or to stop 
the enrollment upon judging the current dose to be safe was guided by the number of subjects with DLTs observed 
during the DLT evaluation period based on the mTPI design (Table 1).
Table 1:
Guidance for Safety Monitoring Based on Observed Toxicity 
Outcomes (Escalation Cohort Only)
Number of Subjects Treated at 
Given Dose Level
3
Number of Subjects with DLTs
0
E
1
E
2
DU
3
DU
At Starting Dose (600 mg):
E: Escalate and enroll subjects to the next higher dose level
DU: The current dose is too toxic. Discuss of proceeding with the next lower dose level
At Maximum Dose (800 mg): 
E: The current dose level is safe and stop enrollment
DU: The current dose is too toxic
No subject will be permitted intra-subject dose escalations. Subjects who withdraw from the study during Cycle 1 for 
reasons other than a DLT may be replaced. Subjects who have not received complete doses (all the doses of
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ulocuplumab and cytarabine specified in the protocol) during Cycle 1 may also be replaced. Depending on toxicity, 
an additional dose level may be defined after discussion with the BMS Medical Monitor and investigators.
In the expansion cohort, there is no dose escalation provision.
Study Population: Subjects with AML.
Study Drug: Includes both Investigational [Medicinal] Products (IP/IMP) and Non-investigational [Medicinal] 
Products (Non-IP/Non-IMP) as listed:
Study Drug CA212016
Medication 
Potency 
IP/Non-IP 
Ulocuplumab Injection
10 mg/mL
IP
Cytarabine
Refer to package insert
IP
Study Assessments:  
Safety Outcome Measures: 
The following safety assessments will be performed during the study: vital sign measurements, clinical laboratory 
tests, bone marrow tests, Eastern Cooperative Oncology Group (ECOG) performance status evaluations, physical 
examinations/measurements, ECGs (12-lead), concomitant medications, transfusions, and the incidence and severity 
of AEs.
Efficacy Measures:
Efficacy assessments will be determined by changes in bone marrow aspirate/biopsy, hematological laboratory tests, 
red blood cell transfusion dependency, and assessments for extramedullary disease (if applicable). Leukemia response 
assessment will be evaluated using AML IWG 2003. Rate and duration of complete remission will be summarized. 
Overall survival (OS) will also be assessed. Primary efficacy analyses will be based on the best overall response.
PK Measures:
Serial and sparse PK samples will be collected in all subjects from the escalation and expansion cohorts.
PK parameters including Cmax, Ctrough, Tmax, AUC(0-T), AUC(TAU), AUC(INF), CLT, and Vss will be derived 
from serum concentration versus actual time data for ulocuplumab. AUC(INF) after first dosing and T-HALF will be 
calculated when possible. Individual subject PK parameter values will be derived by non-compartmental methods by 
a validated PK analysis program.
Immunogenicity Assessments:
Development of anti-drug antibodies (ADA) to ulocuplumab will be evaluated.
Biomarker Assessments (Expansion Cohort only)
Exploratory biomarkers in bone marrow aspirate and peripheral blood will be evaluated, including receptor occupancy 
(RO).
Other Assessments
Serial ECGs will be obtained from a subset of subjects in the expansion cohort (a minimum of 15 subjects per dose 
level, Serial PK/ECG Subset) and will be assessed by an independent core laboratory.
Statistical Considerations
Sample Size: 
The size of the study is not based on testing a formal statistical hypothesis. The Escalation Cohort is a Phase 1 safety 
phase and the sample size cannot be precisely determined and depends on the observed toxicities; it is estimated that 
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a total of 6 subjects will be treated in this cohort, assuming 600 mg and 800 mg are explored. For the Expansion 
Cohort (Phase 2), a sample size of 40 subjects per treatment group will allow estimation of the response rate with the 
following degree of precision, where response is defined by complete remission (CR/CRi=CR+CRi). A response rate 
of 0.6 will be estimated with the following 95% exact confidence interval (CI): 0.43 - 0.75. If the response rate is 0.45, 
then the associated 95% CI will be 0.29 - 0.62.
Endpoints:  
Primary Endpoints:
•
Phase 1 (escalation cohort): DLTs in Cycle 1, and AEs, ≥ Grade 3 AEs, AEs leading to discontinuation, SAEs, 
deaths and laboratory abnormalities in combination therapy during the Treatment period plus 30 days of follow-
up will be the primary endpoints for this study. AEs will be graded according to NCI CTCAE v4.03
•
Phase 2 (expansion cohort): Investigator will assess best overall response. The primary endpoint will be based on 
the rate of Complete Remission (CR/CRi) prior to the initiation of any alternative therapy (including any 
subsequent ulocuplumab 800 mg for subjects in the LDAC alone arm). The primary analysis will be conducted
after all patients had an opportunity for 6 months of follow-up.
Secondary Endpoints: 
•
Phase 1 (escalation cohort): Investigator assessed best overall response prior to the initiation of any alternative 
therapy. 
•
Phase 2 (expansion cohort): Safety and tolerability will be assessed through AEs, AEs leading to discontinuation, 
SAEs, deaths and laboratory abnormalities in combination therapy during the Treatment period plus 30 days of 
follow-up will be the primary endpoints for this study. AEs will be graded according to NCI CTCAE v4.03.
•
ADA positive for ulocuplumab. 
•
The PK parameters including Cmax, Ctrough, Tmax, AUC(0-T), AUC(TAU), AUC(INF), T-HALF, CLT and 
Vss.
•
In Phase 2 (expansion cohort): To assess rates of Overall Remission (OR=PR+CR +CRi) as well as duration of 
complete remission (CR/ CRi) in subjects treated with ulocuplumab at two different dose levels 800 mg and 1000 
mg in combination with LDAC.
•
In Phase 2 (expansion cohort): To assess efficacy (in terms of rates of CR/CRi and OR and duration of remission, 
respectively, in subjects treated with LDAC alone, to compare with historical controls of LDAC in the same 
patient population. Overall survival will also be assessed in this group.
•
Duration of remission (DoR) is defined as the time from the date of first documented CR or CRi to the date of 
death or relapse. For subjects who remain alive and have not relapsed following remission, DoR will be censored 
on the date of last relapse-related assessment prior to the initiation of alternative anti-cancer therapy. 
•
The primary ECG endpoint is ΔQTcF, the change from baseline in QTcF, the QT interval normalized using 
Fridericia’s heart rate correction. Other endpoints include QTcF, QT, QRS, PR, HR (heart rate), and QTcB as 
well as ΔQT, ΔQRS, ΔPR, ΔHR (heart rate), ΔQTcB, the associated changes from baseline. (Note: QTcB is the 
QT interval normalized using Bazett’s hear rate correction.)
•
Overall survival (OS) will also be summarized. OS is defined as the time between the first date of treatment and 
the date of death due to any cause. A subject who has not died will be censored at the last known alive date.
 
 
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Analyses:  
Safety Analysis:
All recorded AEs will be listed and tabulated by system organ class, preferred term and treatment. Vital signs, clinical 
laboratory test results and any significant physical examination findings will be listed and summarized by treatment. 
ECG readings will be evaluated by the Investigator and abnormalities, if present, will be listed. To assess the effects 
of ulocuplumab on heart rate, PR, QRS, QT, QTcF, and ΔQTcF intervals, the frequency distribution for maximum 
QTcF, PR, QRS and the maximum ΔQTcF will be tabulated. For QTcF a linear regression of ΔQTcF on drug 
concentration will be estimated. Summary statistics will be tabulated for all ECG parameters and changes from 
baseline. The plots of mean and mean changes from baseline versus time or ulocuplumab concentration may be
provided. A two-sided 90% confidence interval will be constructed for the population mean of ΔQTcF at each time 
point.
PK Analysis:
Summary statistics will be tabulated for the PK parameters and RO by treatment and study day. Geometric means and 
coefficients of variation will be presented for Cmax, AUC and CL. Medians, minimum, and maximum will be 
presented for Tmax. Means and standard deviations will be provided for the remaining PK parameters. Individual as 
well as mean concentration-time plots will be depicted.
The distribution of Ctrough concentrations will be summarized using descriptive statistics by treatment and study day. 
To assess the attainment of steady state, geometric mean Ctrough values will be plotted by treatment and study day.
Changes of CXCR4 RO is related to the dose and exposure of ulocuplumab. The association between the percent of 
RO and ulocuplumab serum concentration in peripheral blood and, when possible, bone marrow will be explored.
Efficacy Analysis:
Individual tumor responses will be listed by treatment and study day. Bone marrow blast and its percent change from 
baseline will be listed. 
In addition, for the expansion cohort, best overall response prior to the initiation of any alternative therapy (including 
any subsequent ulocuplumab 800 mg for subjects in the LDAC alone arm) will be tabulated. The rate of subjects with 
complete remission (CR/CRi) will be summarized by a binomial response rate and corresponding two-sided 95% 
exact CI using the Clopper and Pearson method. The combined rate of subjects with responses of either CR or CRi or 
PR will similarly be summarized.
OS and DoR will be summarized descriptively using Kaplan-Meier methodology. Median values of OS, along with 
two-sided 95% CIs using the Brookmeyer and Crowley method considering a log-log transformation, will be 
calculated. 
Immunogenicity Analysis: Listings for ADA positive response will be provided by treatment.
 
Interim Analysis:
For the dose expansion cohort, an interim assessment of safety will be assessed by Sponsor or designee on the first 
6 patients treated on the 1000 mg ulocuplumab/LDAC combination arm. These must have had an opportunity for at 
least 28 days of follow-up. The review will be based all available safety data including DLTs reported during the first 
28 days of follow-up. Randomization to the 1000 mg ulocuplumab combination arm will be suspended until the safety 
review is complete. Randomization to the other 2 arms will continue on a 1:1 basis until a decision is reached to 
resume randomization to all 3 arms.
In addition, an interim analysis of efficacy and safety will be conducted when 60 patients (i.e., 50% of the sample 
size) will have had an opportunity for 2 months of treatment and follow-up.
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Data Monitoring Committee
An independent data monitoring committee (DMC) will be constituted for review of safety information and 
assessment of overall benefit/risk balance in this study. Specific data to be reviewed and timing of the reviews by the 
DMC will be described in a DMC Charter.
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TABLE OF CONTENTS 
TITLE PAGE ................................................................................................................ 
DOCUMENT HISTORY .............................................................................................. 
OVERALL RATIONALE FOR THE REVISED PROTOCOL 06 ............................. 
SUMMARY OF KEY CHANGES OF REVISED PROTOCOL 06............................ 
SYNOPSIS .................................................................................................................... 
TABLE OF CONTENTS .............................................................................................. 
1 INTRODUCTION AND STUDY RATIONALE ..................................................... 
 
 
 
1.2 Research Hypothesis ......................................................................................... 
1.3 Objectives(s) ..................................................................................................... 
1.3.1 Primary Objectives .................................................................................. 
1.3.2 Secondary Objectives ............................................................................... 
1.3.3 Exploratory Objectives ............................................................................ 
 
 
 
 
 
 
 
 
1.5 Overall Risk/Benefit Assessment ..................................................................... 
2 ETHICAL CONSIDERATIONS ............................................................................... 
2.1 Good Clinical Practice ...................................................................................... 
2.2 Institutional Review Board/Independent Ethics Committee ............................. 
2.3 Informed Consent.............................................................................................. 
3 INVESTIGATIONAL PLAN .................................................................................... 
3.1 Study Design and Duration ............................................................................... 
3.1.1 Dose Escalation ....................................................................................... 
3.2 Post Study Access to Study Drug ..................................................................... 
3.3 Study Population ............................................................................................... 
3.3.1 Inclusion Criteria ..................................................................................... 
3.3.2 Exclusion Criteria .................................................................................... 
3.3.3 Women of Childbearing Potential ........................................................... 
3.4 Concomitant Treatments ................................................................................... 
3.4.1 Permitted Treatments ............................................................................... 
3.4.2 Prohibited and/or Restricted Treatments................................................. 
3.4.3 Other Restrictions and Precautions ......................................................... 
3.5 Discontinuation of Subjects from Treatment .................................................... 
3.6 Post Study Drug Study Follow up .................................................................... 
3.6.1 Withdrawal of Consent ............................................................................ 
3.6.2 Lost to Follow-Up .................................................................................... 
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4 STUDY DRUG .......................................................................................................... 
4.1 Investigational Product ..................................................................................... 
4.2 Non-investigational Product ............................................................................. 
4.3 Storage and Dispensing..................................................................................... 
4.4 Study Treatments .............................................................................................. 
4.4.1 Preparation of Study Drug....................................................................... 
4.5 Method of Assigning Subject Identification ..................................................... 
4.6 Selection and Timing of Dose for Each Subject ............................................... 
4.6.1 Discontinuation, Dose Modifications, Infusion Delays and Missed Doses
.....................................................................................................................
4.6.1.1 Treatment Discontinuation Criteria ............................................... 
4.6.1.2 Dose Modifications, Infusion Delays and Missed Doses ................ 
4.7 Blinding/Unblinding ......................................................................................... 
4.8 Treatment Compliance ...................................................................................... 
4.9 Destruction of Study Drug ................................................................................ 
4.10 Return of Study Drug ...................................................................................... 
5 STUDY ASSESSMENTS AND PROCEDURES ..................................................... 
5.1 Flow Chart/Time and Events Schedule ............................................................. 
5.1.1 Retesting During Screening or Lead-in Period ....................................... 
5.2 Study Materials ................................................................................................. 
5.3 Safety Assessments ........................................................................................... 
5.3.1 Evaluation and Reporting of Dose Limiting Toxicity (DLT) ................... 
5.3.2 Laboratory Test Assessments ................................................................... 
5.3.3 Other Assessments ................................................................................... 
5.3.4 Additional Data to be Collected during Trial .......................................... 
5.3.5 Imaging Assessment for the Study............................................................ 
5.4 Efficacy Assessments ........................................................................................ 
5.4.1 Primary Efficacy Assessment ................................................................... 
5.4.2 Secondary Efficacy Assessments .............................................................. 
5.5 Pharmacokinetic Assessments .......................................................................... 
5.5.1 Pharmacokinetics Collection and Processing and ECG Measurements . 
5.5.2 Pharmacokinetic Sample Analysis ........................................................... 
5.5.3 Labeling and Shipping of Biological Samples ......................................... 
5.6 ECG Assessments ............................................................................................. 
 
 
 
5.8 Immunogenicity Assessments ........................................................................... 
5.9 Outcomes Research Assessments ..................................................................... 
5.10 Other Assessments .......................................................................................... 
5.10.1 Additional Research ............................................................................... 
5.10.2 Cytogenetic and Molecular Assessments ............................................... 
5.11 Results of Central Assessments ...................................................................... 
6 ADVERSE EVENTS ................................................................................................. 
6.1 Serious Adverse Events .................................................................................... 
6.1.1 Serious Adverse Event Collection and Reporting .................................... 
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6.2 Nonserious Adverse Events .............................................................................. 
6.2.1 Nonserious Adverse Event Collection and Reporting .............................. 
6.3 Laboratory Test Result Abnormalities .............................................................. 
6.4 Pregnancy .......................................................................................................... 
6.5 Overdose ........................................................................................................... 
6.6 Potential Drug Induced Liver Injury (DILI) ..................................................... 
6.7 Other Safety Considerations ............................................................................. 
7 DATA MONITORING COMMITTEE AND OTHER EXTERNAL COMMITTEES
................................................................................................................................. 
8 STATISTICAL CONSIDERATIONS....................................................................... 
8.1 Sample Size Determination ............................................................................... 
8.2 Populations for Analyses .................................................................................. 
8.3 Endpoints .......................................................................................................... 
8.3.1 Primary Endpoint(s) ................................................................................ 
8.3.2 Secondary Endpoint(s) ............................................................................. 
 
8.4 Analyses ............................................................................................................ 
8.4.1 Demographics and Baseline Characteristics........................................... 
8.4.2 Efficacy Analyses ..................................................................................... 
8.4.3 Safety Analyses......................................................................................... 
8.4.4 Immunogenicity Analyses ......................................................................... 
8.4.5 Pharmacokinetic Analyses and Receptor Occupancy .............................. 
8.4.6 ECG Analyses .......................................................................................... 
 
8.4.8 Outcomes Research Analyses .................................................................. 
8.4.9 Other Analyses ......................................................................................... 
8.5 Interim Analyses ............................................................................................... 
9 STUDY MANAGEMENT ........................................................................................ 
9.1 Compliance ....................................................................................................... 
9.1.1 Compliance with the Protocol and Protocol Revisions ........................... 
9.1.2 Monitoring ............................................................................................... 
9.1.2.1 Source Documentation .................................................................... 
9.2 Records ............................................................................................................. 
9.2.1 Records Retention .................................................................................... 
9.2.2 Study Drug Records ................................................................................. 
9.2.3 Case Report Forms .................................................................................. 
9.3 Clinical Study Report and Publications ............................................................ 
10 GLOSSARY OF TERMS ........................................................................................ 
11 LIST OF ABBREVIATIONS .................................................................................. 
 
APPENDIX 1 2003 IWG RESPONSE CRITERIA FOR AML ................................... 
APPENDIX 2 SIMULATION TO EXAMINE MTPI VS. TRADITIONAL 3+3 
DESIGN FOR DOSE ESCALATION STUDY WITH 2 DOSE LEVELS ........... 
APPENDIX 3 WHO CLASSIFICATION OF AML .................................................... 
APPENDIX 4 ECOG PERFORMANCE STATUS ..................................................... 
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APPENDIX 5 WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND 
METHODS OF CONTRACEPTION ..................................................................... 
APPENDIX 6 HEMATOPOIETIC CELL TRANSPLANTATION (HCT) - SPECIFIC 
COMORBIDITY INDEX ....................................................................................... 
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1
INTRODUCTION AND STUDY RATIONALE
This Phase 1/2 randomized study will evaluate the safety and tolerability of ulocuplumab 
(BMS-936564) in subjects with acute myeloid leukemia (AML). Ulocuplumab (600 mg, 800 mg
and 1000 mg) will be administered as a single intravenous (IV) infusion on Day 1, 8 and 15 in 
combination with low dose cytarabine (LDAC) at a total daily dose of 40 mg subcutaneously (SC) 
administered twice daily (20 mg BID) on Day 1 - 10 for the initial 2 cycles (28 days/cycle). This 
will be followed by ulocuplumab administered on Day 1 and 8 in combination with LDAC on 
Day 1 - 10 for subsequent cycles. In addition, the efficacy, pharmacokinetics (PK) and 
immunogenicity of ulocuplumab when added to LDAC will be assessed. The phase 1 dose 
escalation includes newly diagnosed or relapsed subjects with AML unfit for intensive 
chemotherapy.  The phase 2 expansion cohorts will include newly diagnosed AML patients unfit 
for intensive chemotherapy.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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1.2
Research Hypothesis 
The study has no formal research hypothesis to be statistically tested. 
1.3
Objectives(s)
1.3.1
Primary Objectives
In Phase 1 (escalation cohort): To assess the safety and tolerability of ulocuplumab in combination 
with low-dose cytarabine (LDAC) in subjects with AML.
In Phase 2 (expansion cohort): To estimate preliminary efficacy in terms of complete remission 
(CR/CRi=CR+CRi) in subjects treated at two different dose levels of ulocuplumab, 800 mg and 
1000 mg, in combination with low-dose cytarabine (LDAC).
1.3.2
Secondary Objectives
•
To characterize the immunogenicity of ulocuplumab.
•
To characterize the PK profiles of ulocuplumab in combination with LDAC.
•
To evaluate the effects of ulocuplumab on ECG intervals, including QTc intervals
•
In Phase 1 (escalation cohort): To evaluate the preliminary efficacy on the basis of objective 
response in subjects treated with ulocuplumab in combination with LDAC.
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•
To assess overall survival (OS) in subjects treated with ulocuplumab 800 mg or 1000 mg in 
combination with LDAC.
•
In Phase 2 (expansion cohort): To assess the safety and tolerability of ulocuplumab in subjects 
with AML treated with ulocuplumab at two different dose levels 800 mg and 1000 mg in 
combination with LDAC.
•
In Phase 2 (expansion cohort): To assess rates of overall remission (OR=PR+CR+CRi) as well 
as duration of complete remission (CR/CRi) in subjects treated with ulocuplumab at two 
different dose levels 800 mg and 1000 mg in combination with LDAC.
•
In Phase 2 (expansion cohort): To assess efficacy (in terms of rates of CR/CRi and OR and 
duration of remission, respectively, in subjects treated with LDAC alone, to compare with 
historical controls of LDAC in the same patient population. Overall survival will also be 
assessed in this group. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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1.5
Overall Risk/Benefit Assessment
Patients with AML who are unfit for intensive chemotherapy have treatment options with low 
complete response rates without prolonged survival.  This majority of patients with AML 
represents a high unmet medical need. Allogeneic stem cell transplant is not a treatment option for 
patients who are unfit for intensive chemotherapy. The potential benefit to subjects who are treated 
in this study is the possibility that clinical response will be achieved. However, experience with 
ulocuplumab to date is limited.
Primary safety concerns identified for ulocuplumab in pivotal 1-month repeat dose toxicology 
studies in monkeys were anaphylactic reactions, leukocytosis, alterations in trafficking of B- and 
T-lymphocytes within lymphoid tissues, and transient thrombocytopenia.  
As of 26-Feb-2016, data in 73 subjects with relapsed/refractory AML from CA212001 indicate 
that ulocuplumab was well tolerated in these subjects as monotherapy and in combination with 
MEC chemotherapy.  In the escalation phase and initial safety expansion, 30 relapsed AML 
subjects were treated at dose levels of 0.3, 1, 3, and 10 mg/kg. Overall complete 
remission/complete remission with incomplete blood count (CR/CRi) was observed in 18-50% of 
subjects at the dose levels evaluated.  In the dose expansion component, 9% of subjects attained 
CR/CRi after a single dose of ulocuplumab. Additionally, relapsed AML subjects treated with 
combination ulocuplumab and MEC chemotherapy were studied in 2 cohorts: those with 
CR1 > 6 months (n = 23) and those with CR1 ≤6 months or primary induction failure (n = 20). 
The overall complete remission rate (CR/CRi) was 51%. The complete remission rate was 70% 
and 30% among subject with CR1 > 6 months and ≤6 months, respectively.
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Preliminary efficacy data are available from the escalation cohort of this trial, CA212016. In the 
escalation cohort, 6 AML subjects were treated at dose levels of 600 mg and 800 mg in 
combination with LDAC 20 mg BID. Overall complete remission/complete remission with 
incomplete blood count (CR/CRi) was observed in 4 of 6 evaluable subjects (66%), with 1 of 
4 responders treated at 600 mg and 3 of 4 responders at 800 mg.
Based on data from CA212016 escalation phase data and nonclinical toxicology studies of 
ulocuplumab, there is a possibility of hematologic toxicity. Intensive safety monitoring is included 
in CA212016 to allow investigators to recognize toxicities that may be related to ulocuplumab or 
to the potentiating of chemotherapy-associated toxicities. The protocol contained inclusion and 
exclusion criteria appropriate to the population, instructions for screening tests, AE monitoring 
and dose modification guidelines. AEs and SAEs were reviewed on an ongoing basis by the BMS 
Medical Monitor to look for and identify significant trends and safety issues at the earliest point.
Because there was a single Grade 3 infusion-related reaction in a DLBCL subject in CA212001, 
if a subject experiences a Grade 2 infusion reaction with ulocuplumab, the subject is required to 
receive prophylactic premedication for subsequent infusions of ulocuplumab. The pre-medications 
included, but not limited to, diphenhydramine, acetaminophen, and low-dose corticosteroids, 
which pose minimal risk to subjects in the dose and frequency given. If a subject experiences a 
Grade ≥3 infusion reaction, the subject discontinued the study treatment. Therefore, the overall 
risk/benefit assessment did not change.
Based on preliminary clinical experience with another CXCR4-targeted agent, non-clinical studies 
of ulocuplumab that indicate anti-tumor activity in AML models, and the acceptable clinical safety 
profile and preliminary efficacy data for AML subjects observed in CA212001 and CA212016 to 
date, ulocuplumab in combination with chemotherapy may be a promising therapeutic approach 
for further investigation and its potential benefits appear to outweigh any potential risks.
2
ETHICAL CONSIDERATIONS
2.1
Good Clinical Practice
This study will be conducted in accordance with Good Clinical Practice (GCP), as defined by the 
International Conference on Harmonisation (ICH) and in accordance with the ethical principles 
underlying European Union Directive 2001/20/EC and the United States Code of Federal 
Regulations, Title 21, Part 50 (21CFR50) and applicable local requirements.
The study will be conducted in compliance with the protocol. The protocol and any amendments 
and the subject informed consent will receive Institutional Review Board/Independent Ethics
Committee (IRB/IEC) approval/favorable opinion prior to initiation of the study.
All potential serious breaches must be reported to Sponsor or designee immediately. A serious 
breach is a breach of the conditions and principles of GCP in connection with the study or the 
protocol, which is likely to affect, to a significant degree, the safety or physical or mental integrity 
of the subjects of the study or the scientific value of the study.
Personnel involved in conducting this study will be qualified by education, training, and
experience to perform their respective tasks.
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This study will not use the services of study personnel where sanctions have been invoked or where 
there has been scientific misconduct or fraud (eg, loss of medical licensure, debarment). 
2.2
Institutional Review Board/Independent Ethics Committee
Before study initiation, the investigator must have written and dated approval/favorable opinion
from the IRB/IEC
for the protocol, consent form, subject recruitment materials 
(eg, advertisements), and any other written information to be provided to subjects. The investigator 
or BMS should also provide the IRB/IEC with a copy of the Investigator Brochure or product 
labeling information to be provided to subjects and any updates. 
The investigator, Sponsor or designee should provide the IRB/IEC with reports, updates and other 
information (eg, expedited safety reports, amendments, and administrative letters) according to 
regulatory requirements or institution procedures.
2.3
Informed Consent
Investigators must ensure that subjects are clearly and fully informed about the purpose, potential 
risks, and other critical issues regarding clinical studies in which they volunteer to participate. 
In situations where consent cannot be given to subjects, their legally acceptable representatives (as 
per country guidelines) are clearly and fully informed about the purpose, potential risks, and other 
critical issues regarding clinical studies in which the subject volunteers to participate.
Sponsor or designee will provide the investigator with an appropriate sample informed consent 
form which will include all elements required by ICH, GCP and applicable regulatory 
requirements. The sample informed consent form will adhere to the ethical principles that have 
their origin in the Declaration of Helsinki.
Investigators must:
1) Provide a copy of the consent form and written information about the study in the language in 
which the subject is most proficient prior to clinical study participation. The language must be 
non-technical and easily understood. 
2) Allow time necessary for subject or subject's legally acceptable representative to inquire about 
the details of the study.
3) Obtain an informed consent signed and personally dated by the subject or the subject's legally 
acceptable representative and by the person who conducted the informed consent discussion. 
4) Obtain the IRB/IEC’s written approval of the written informed consent form and any other 
information to be provided to the subjects, via the head of the study site, prior to the beginning 
of the study, and after any revisions are completed for new information.
5) If informed consent is initially given by a subject’s legally acceptable representative or legal 
guardian, and the subject subsequently becomes capable of making and communicating his or 
her informed consent during the study, consent must additionally be obtained from the subject.
6) Revise the informed consent whenever important new information becomes available that is 
relevant to the subject's consent. The investigator, or a person designated by the head of the 
study site, should fully inform the subject or the subject's legally acceptable representative or 
legal guardian, of all pertinent aspects of the study and of any new information relevant to the 
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subject's willingness to continue participation in the study. This communication should be 
documented. 
The confidentiality of records that could identify subjects must be protected, respecting the privacy 
and confidentiality rules applicable to regulatory requirements, and the subjects' signed ICF.
The consent form must also include a statement that BMS, the IRB/IEC, and regulatory authorities 
have direct access to subject records. 
The rights, safety, and well-being of the study subjects are the most important considerations and 
should prevail over interests of science and society.
3
INVESTIGATIONAL PLAN
3.1
Study Design and Duration
In the escalation phase, this was a Phase 1, open-label study to assess the safety and tolerability of 
ulocuplumab in subjects with AML. The study consisted of 3 periods: Screening (up to 28 days), 
Treatment (28 days/cycle) and Follow-up (at least 30 days following the end of treatment visit). 
Escalation phase subjects will be followed for overall survival (OS) for at least 2 years. The dose 
of ulocuplumab chosen to be explored in the escalation cohort of this study (600 mg and 800 mg) 
was selected based on the results from a Phase 1 study (CA212001). 
Based upon the CA212016 escalation cohort results, the protocol is revised to include an 
exploratory, non-comparative open-label Phase 2 expansion cohort of up to approximately an 
additional 120 AML subjects. Expansion cohort subjects will be randomized to 1 of 3 treatment 
arms: LDAC alone or either 800 mg or 1000 mg ulocuplumab in combination with LDAC 20 mg 
BID (Figure 3.1-2). Escalation cohort subjects who are continuing treatment will continue at their 
assigned dose. In the expansion cohort, randomization will be suspended in the ulocuplumab 1000 
mg arm while safety data from the first 6 subjects in this arm are evaluated for DLTs. For the 
escalation and expansion cohorts, DLTs and all other toxicities were defined and evaluated using 
the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.03 
(NCI CTCAE v4.03). DLTs were defined based upon events that were considered to be related to 
ulocuplumab in combination with LDAC and that occurred during the first cycle of drug 
administration (28 days).
The Screening Period is defined as the 28 days following initiation of screening assessments and 
before administration of the first dose of any study drug, during which subjects are evaluated for 
study eligibility.
During the Treatment Period of the escalation and expansion arms, ulocuplumab (600, 800 or 
1000 mg, IV) will be administered on Day 1, 8 and 15 in combination with LDAC (20 mg BID 
(40 mg/day), SC) administered on Day 1-10 for each cycle (28 days/cycle) of the initial 2 cycles 
(Cycle 1-2). For Cycle 3 and subsequent cycles (28 days/cycle), subjects will receive ulocuplumab
(600, 800 or 1000 mg, IV) on Day 1 and 8 in combination with LDAC (20 mg BID, SC) on 
Day 1 - 10. Subjects who are tolerating study treatment, clinically stable and not progressing 
rapidly at the end of each cycle may continue additional cycles until disease progression, 
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development of unacceptable toxicity, intercurrent illness preventing treatment, or patient request
or investigator decision to stop treatment. Delay of subsequent cycles for recovery from 
myelosuppression (or other AE) is allowed at investigator discretion. For subjects randomized to 
the LDAC alone arm, they will receive LDAC (20 mg BID, SC) on Day 1-10.
Leukemia response assessment will be evaluated for each cycle using the AML IWG 2003
(Appendix 1). The results of the response assessments must be reviewed and documented before 
the first dose of the next cycle.
Subjects who experience study drug-related AEs that are ongoing at the follow-up visit will
continue to be followed until the AEs are (i) resolved to baseline, (ii) stabilized, or (iii) have been 
deemed irreversible unless further anti-cancer treatment are administered.
Subjects who discontinue study treatment for any reasons will be followed for 30 days after the 
end of treatment visit for AEs. Subjects will be followed for overall survival for 2 years.29
The last visit for each subject will be defined as the end of follow up visit which is no less than 
30 days after the subject’s end-of-treatment visit.
The study will end after the last subject completes the last visit.
A total number of up to approximately 126 (6 escalation cohort and 120 expansion cohort) subjects 
will be treated in this study. The entire study (Screening, Treatment and Follow-up) is expected to 
last approximately 7 years, with the addition of the expansion cohort and overall survival follow 
up.
The expansion phase of the study will include approximately 120 subjects in order to randomize 
subjects in a 1:1:1 ratio: 40 subjects in the ulocuplumab 800 mg  plus LDAC arm, 40 subjects in 
the ulocuplumab 1000 mg plus LDAC arm and 40 subjects in the LDAC alone arm (Figure 3.1-2). 
The randomization will be suspended in the ulocuplumab 1000 mg arm while the safety data on 
the first 6 subjects on this arm are evaluated for DLTs. Randomization will continue in the other 
2 arms while the data is reviewed therefore total numbers randomized is approximate.
Randomization to the 1000 mg ulocuplumab arm will resume if ≤33% of subjects experience a 
DLT. If > 33% of subjects are observed with DLTs, this treatment arm will not accrue additional 
subjects.
Subjects in the LDAC alone arm will be permitted to add ulocuplumab 800 mg into their treatment 
regimen if they do not achieve complete remission (CR or complete remission with incomplete 
blood count recovery [CRi]) confirmed by blast count reduction after 4 treatment cycles or if they 
relapse after achieving complete remission. If ulocuplumab is added to the LDAC alone arm, the 
treatment schedule is LDAC 20 mg BID from Day 1 to 10 of each cycle and ulocuplumab 800 mg 
on day 1, 8 and 15 for the first 2 cycles then ulocuplumab 800 mg on Day 1 and 8 for subsequent 
cycles.
The study design schematic is presented in Figure 3.1-1.
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Figure 3.1-1:
Study Design Schematic
Figure 3.1-2:
Phase 2 Study Design Schematic
Physical examinations/measurements, vital sign measurements, 12-lead electrocardiograms 
(ECG), and clinical laboratory evaluations will be performed at selected times. Subjects will be 
closely monitored for AEs throughout the study. Blood samples will be collected for PK, RO and 
immunogenicity analyses. Blood and bone marrow aspirate samples will be collected for 
biomarker analyses. A minimum of 15 subjects each from the 800 mg and 1000 mg expansion 
cohorts are required to provide serial blood samples and time-matched ECGs to further 
characterize the PK of ulocuplumab and its effect on ECG intervals in combination with LDAC
(Serial PK/ECG Subset, Table 5.5.1-1). 
The expansion cohort will treat approximately an additional 120 subjects at a dose of 800 mg or 
1000 mg ulocuplumab in combination with LDAC or LDAC alone. Sample size is discussed in 
Section 8.1. All assessments from the escalation cohort will be performed and additional 
assessments (eg, biomarkers) are noted in Table 5.1-1, Table 5.1-2, Table 5.1-3, Table 5.5.1-1, 
Table 5.5.1-2, and Table 5.7.2-1.
Follow-up
•
Begins when the decision to discontinue a subject from study therapy is made (no further 
treatment with study therapy).
•
Subjects will have one follow-up visit for safety. Follow-up visit 1(X01) will be completed
30 days (± 7 days) from the last dose of study therapy. After X01, subjects will be followed 
Frontline 
unfit for 
intensive 
chemo
(age 
comorbidities)
1:1:1
Ulocuplumab
800 mg + LDAC
LDAC (low dose 
cytarabine)
•
Treat to progression
n=40
Ulocuplumab
800 mg + LDAC
Ulocuplumab
1000 mg + LDAC
n=40
n=40
BMS-936564:
LDAC:
End of
Treatment
End of
Follow-up
(Last Visit)
Screening
Treatment (28 days/cycle)
BMS-936564 in combination with LDAC
Follow-up
(+ 30 days)
Cycle 1 (DLT Assessment) and Cycle 2
Cycle 3 and after
Day -28
Day 1
Day 8
Day 15
Day 22
Day 1
Day 8
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every 3 months for ongoing drug-related AEs until resolved, return to baseline or deemed 
irreversible, or until lost to follow-up or withdrawal of study consent. Subjects will also be 
followed every 3 months for survival for up to two years, until death, lost to follow-up or 
withdrawal of study consent.
•
PK, immunogenicity and biomarker samples will be collected at the 30 day follow-up visit.
3.1.1
Dose Escalation
In the escalation cohort, enrollment of subjects adhered to a Modified Toxicity Probability Interval 
(mTPI) design. The study design set a 20% target DLT rate with an equivalence interval of 
15 - 25%. Initially 3 subjects were treated at the dose level of 600 mg. No additional subjects were
added to the same dose level (ie, a total number of 3 subjects were treated for a given dose level). 
A decision to consider the next higher dose level or the next lower dose level or to stop the 
enrollment upon judging the current dose to be safe was guided by the number of subjects with 
DLTs observed during the DLT evaluation period based on the mTPI design (see Table 3.1.1-1).
The performance of the design is reported in Appendix 2.
Table 3.1.1-1:
Guidance for Safety Monitoring Based on Observed 
Toxicity Outcomes (Escalation Cohort Only)
Number of Subjects Treated at Given 
Dose Level
3
Number of Subjects 
with DLTs
0
E
1
E
2
DU
3
DU
At Starting Dose (600 mg):
E: Escalate and enroll subjects to the next higher dose level
DU: The current dose is too toxic. Discuss of proceeding with the next lower dose level
At Maximum Dose (800 mg): 
E: The current dose level is safe and stop enrollment
DU: The current dose is too toxic
•
No subject will be permitted intra-subject dose escalations.
•
Subjects who experience a DLT during Cycle 1 (DLT evaluation period) will not receive 
further study treatment. Subjects who withdraw from the study during Cycle 1 for reasons other 
than a DLT may be replaced. Subjects who have not received complete doses (all the doses of 
ulocuplumab and cytarabine specified in the protocol) during Cycle 1 may also be replaced.
•
Depending on toxicity, an additional dose level may be defined after discussion with the BMS
Medical Monitor and investigators. 
In the expansion cohort, there is no dose escalation provision.
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3.2
Post Study Access to Study Drug
At the conclusion of the study, subjects who continue to demonstrate clinical benefit will be 
eligible to receive BMS supplied study drug. Study drug will be provided via an extension of the 
study, a rollover study requiring approval by responsible health authority and ethics committee or 
through another mechanism at the discretion of BMS. BMS reserves the right to terminate access 
to BMS supplied study drug if any of the following occur: a) the marketing application is rejected 
by responsible health authority; b) the study is terminated due to safety concerns; c) the subject 
can obtain medication from a government sponsored or private health program; or d) therapeutic 
alternatives become available in the local market.
3.3
Study Population
For entry into the study, the following criteria MUST be met prior to dosing on Day 1 of Cycle 1.
No exceptions will be granted.
3.3.1
Inclusion Criteria
1. Signed Written Informed Consent
a) The signed informed consent form. Willing and able to give informed consent; this must 
be obtained before performing protocol-related procedures that are not part of standard 
patient care.
2. Target Population
a) Subjects who were newly diagnosed with acute myeloid leukemia based on WHO 
classification (de novo or secondary) with minimum blast count of 20% (Appendix 3).
b) Investigator considers that subject is inappropriate for intensive remission induction 
therapy30 and eligible for LDAC treatment if at least one of the following criteria are met:
i)
Age older than 70 years31,32
ii) ECOG performance status 3
iii) Congestive heart failure or documented cardiomyopathy with an EF ≤50%
iv) Creatinine ≥1.3 mg/dL
v) Hematopoietic Cell Transplant-comorbidity index (HCT-CI) ≥333,34 (Appendix 6)
vi) Any other comorbidity that the physician judges to be incompatible with conventional 
intensive chemotherapy
c) Not eligible for stem cell transplantation (SCT).
d) Radiation therapy to chloromas allowed but irradiated lesion may not be used to assess 
response.
e) Screening laboratory values must meet the following criteria:
i)
WBC < 100,000/μL
ii) Creatinine ≤ 2.0 mg/dL 
iii) Aspartate aminotransferase (AST) ≤ 3 × upper limit of normal (ULN)
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iv) Alanine aminotransferase (ALT) ≤ 3 × ULN
v) Total bilirubin ≤ 2.0 mg/dL
f)
Life expectancy at least 12 weeks.
g) Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 3 (Appendix 4).
h) Not positive for human immunodeficiency virus (HIV).
i)
No active hepatitis B or C infection. (Does not include positive serologies resulting from 
passive transfer of antibodies, eg IVIG).
j)
Subject Re-enrollment: This study permits the re-enrollment of a subject that has 
discontinued the study as a pre-treatment failure (ie, subject has not been randomized / has 
not been treated). If re-enrolled, the subject must be re-consented.
3. Age and Reproductive Status
a) Adults age ≥18 years of age
b) Women of childbearing potential (WOCBP) must have a negative serum or urine 
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours 
prior to the start of study drug.
c) Women must not be breastfeeding (Even if breastfeeding is discontinued, the participation 
to the study is not allowed).
d) WOCBP must agree to follow instructions for method(s) of contraception for the duration 
of treatment with study drug (s), ulocuplumab and LDAC, plus 5 half-lives of study drug 
(48 days) plus 30 days (duration of ovulatory cycle) for a total of 78 days post-treatment 
completion.
e) Males who are sexually active with WOCBP must agree to follow instructions for 
method(s) of contraception for the duration of treatment with study drug (s), ulocuplumab
and LDAC, plus 5 half-lives of the study drug (48 days) plus 90 days (duration of sperm 
turnover) for a total of 138 days post-treatment completion.
f)
Azoospermic males are exempt from contraceptive requirements. WOCBP who are
continuously not heterosexually active are also exempt from contraceptive requirements 
(except in Japan), and still must undergo pregnancy testing as described in this section.
Investigators shall counsel WOCBP and male subjects who are sexually active with WOCBP on 
the importance of pregnancy prevention and the implications of an unexpected pregnancy 
Investigators shall advise WOCBP and male subjects who are sexually active with WOCBP on the 
use of highly effective methods of contraception (Appendix 5). Highly effective methods of 
contraception have a failure rate of < 1% when used consistently and correctly.
3.3.2
Exclusion Criteria
1. Target Disease Exceptions
a) Acute promyelocytic leukemia (FAB classification M3).
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b) Current Myelodysplastic Syndrome (MDS) with blast percentage < 20%
2. Previous and Concurrent Therapies
a) Prior therapy for AML, except for hydroxyurea which can be continued up to Day 21 of 
Cycle 1. 
b) No new investigational therapies for any reason shall be initiated within 4 weeks prior to 
the first dose of ulocuplumab and also while the subject is participating in the study.
c) Concomitant use of other AML systemic therapy may not be used while the subject is 
participating in the study while receiving ulocuplumab or LDAC as part of treatment 
period.
d) Subjects taking oral or parenteral corticosteroids must be tapered off this medication prior 
to the first dose of ulocuplumab and must remain discontinued from all oral and parenteral 
corticosteroids while participating in the study (unless used for treatment of infusion 
reactions, rash or antiemetic prophylaxis or subjects on low-dose corticosteroids [< 20 mg 
prednisone or equivalent] for chronic conditions).
e) Prior allogeneic hematopoietic stem cell transplant 
3. Medical History and Concurrent Diseases
a) AML subjects with signs or symptoms of leukostasis/hyperleukocytosis that could be 
exacerbated by ulocuplumab.
b) Unstable angina or uncontrolled congestive heart failure.
c) Any of the following on 12-lead electrocardiogram (ECG) prior to ulocuplumab
administration, confirmed by repeat:
i)
PR ≥220 msec
ii) QRS ≥120 msec
iii) QT ≥500 msec
iv) QTc ≥450 msec (Fridericia correction)35
d) Any other malignancy, excluding basal or squamous cell carcinoma of the skin, in situ 
melanoma, cervical carcinoma in situ, localized prostate cancer, or superficial bladder 
cancer stage 0, from which the subject has not been disease-free for at least 3 years.
e) Known central nervous system involvement by malignancy.
f)
Life-threatening active bleeding.
g) Known current drug or alcohol abuse.
h) Apparent active or latent tuberculosis (TB) infection (purified protein derivative [PPD] test 
is not required) as indicated by any of the following: PPD recently converted to positive; 
chest x-ray with evidence of infectious infiltrate; recent unexplained changes in fever/chill 
patterns.
i)
Respiratory disease requiring continuous supplemental oxygen.
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j)
Underlying medical conditions that, in the investigator’s opinion, will make the 
administration of ulocuplumab hazardous or obscure the interpretation of toxicity 
determination or AEs.
k) Active infection (viral, bacterial, or fungal) requiring systemic therapy within 7 days before 
receiving the first dose of ulocuplumab (prophylactic antibiotic therapy is allowed); 
Subjects who are judged by the investigator to be clinically well but are obligated to 
complete a course of antimicrobial therapy would not be considered to have active 
infection.
l)
Any major surgery within 4 weeks of ulocuplumab administration.
m) Inability to tolerate venous access.
n) Any other sound medical, psychiatric and/or social reason as determined by the 
investigator.
o) Presence of active graft versus host disease -Not applicable as per Protocol Amendment 03
p) Documented pulmonary disease with diffusing capacity of the lungs for carbon monoxide
(DLCO) ≤65% or FEV1 ≤65%
4. Allergies and Adverse Drug Reaction
a) History of Grade 4 hypersensitivity reactions to other monoclonal antibodies, related 
compounds, or excipients of ulocuplumab.
b) History of any significant drug allergy (such as anaphylaxis or hepatotoxicity).
5. Other Exclusion Criteria
a) Prisoners or subjects who are involuntarily incarcerated
b) Subjects who are compulsorily detained for treatment of either a psychiatric or physical 
(eg, infectious disease) illness.
Eligibility criteria for this study have been carefully considered to ensure the safety of the study 
subjects and that the results of the study can be used. It is imperative that subjects fully meet all 
eligibility criteria.
3.3.3
Women of Childbearing Potential
Refer to Appendix 5.
3.4
Concomitant Treatments
3.4.1
Permitted Treatments
The following therapies are permitted during the study:
a) Prophylactic antiemetics may be administered at the discretion of the treating physician prior 
to all doses of ulocuplumab, except the initial infusion of ulocuplumab in Cycle 1. 
b) If a subject experiences a Grade 2 infusion reaction with ulocuplumab, the subjects will be 
required to receive the prophylactic premedications for subsequent infusion of ulocuplumab. 
The pre-medications including, but not limited to, IV or oral diphenhydramine 50 mg (or 
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equivalent), acetaminophen 2 x 325 mg orally, and corticosteroids (25 mg of IV hydrocortisone 
or equivalent) should be administered at least 30 minutes before ulocuplumab administration.
c) Subjects are permitted to use topical, ocular, intra-articular, intranasal, and inhalational 
corticosteroids (with minimal systemic absorption). Physiologic replacement doses of systemic 
corticosteroids are permitted, even if > 20 mg/day prednisone equivalents. A brief course of 
corticosteroids for prophylaxis (eg, contrast dye allergy) or for treatment of non-autoimmune 
conditions (eg, delayed-type hypersensitivity reaction caused by contact allergen) is permitted.
d) Radiation therapy to chloromas allowed, but irradiated lesion may not be used to assess 
response.
e) Hydroxyurea can be administered up to Day 21 of Cycle 1, if clinically indicated, at the 
investigator’s discretion as per institutional guidelines.
3.4.2
Prohibited and/or Restricted Treatments
Prohibited and/or restricted medications taken prior to ulocuplumab administration in the study 
are described below. Medications taken within 4 weeks prior to ulocuplumab administration must 
be recorded on the CRF. Any concomitant medications (prescription, over-the-counter or herbal) 
administered during the study must be recorded on the CRF.
The following therapies are prohibited during the study:
a) Concomitant use of other systemic anti-cancer therapy may not be used while the subject is 
participating in the study except the follow-up period. Radiation therapy for bone pain will be 
discussed with the BMS Medical Monitor. No new investigational therapies for any reason 
shall be initiated while the subject is participating in the study.
b) Subjects taking oral or parenteral corticosteroids must be tapered off this medication prior to 
the first dose of ulocuplumab and must remain discontinued from all oral and parenteral 
corticosteroids while participating in the study except the follow-up period (unless used for 
treatment of infusion reactions, rash or antiemetic prophylaxis or subjects on low-dose 
corticosteroids [< 20 mg prednisone or equivalent] for chronic conditions. Investigators should 
discuss individual cases with the BMS Medical Monitor).
c) Concomitant use of medications which may prolong QT intervals are prohibited during Cycle 1 
and 2 in subjects participating the serial QTc assessment (Serial PK/ECG Subset). A list of 
prohibited drugs that prolong QTc will be provided in a separate study guidance document.
3.4.3
Other Restrictions and Precautions
Subjects in the escalation cohort and the expansion cohort may be required to stay in the clinical 
facility for Day 1 - 15 of Cycle 1. Subjects will be discharged from the clinical facility at the 
discretion of the investigator based on the available safety data and physical conditions on Day 15. 
Additionally, subjects may be admitted to the clinical facility for the purpose of including but not 
limited to study drug administration, sample collection or other study related procedures. Subjects 
are required to remain in the clinical facility at up to 4 hours after completion of infusion dependent 
upon presence or absence of infusion reactions from previous ulocuplumab doses.
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Subjects should refrain from strenuous physical activity and use of (methyl) xanthines (eg, coffee, 
tea, cola, chocolate) or alcohol on the days when ECG measurements will be obtained.
3.5
Discontinuation of Subjects from Treatment
Subjects MUST discontinue investigational product (and non-investigational product at the 
discretion of the investigator) for any of the following reasons:
•
Subject’s request to stop study treatment
•
Any clinical adverse event (AE), laboratory abnormality or intercurrent illness which, in the 
opinion of the investigator, indicates that continued participation in the study is not in the best 
interest of the subject
•
Termination of the study by Bristol-Myers Squibb (BMS)
•
Loss of ability to freely provide consent through imprisonment or involuntarily incarceration 
for treatment of either a psychiatric or physical (eg, infectious disease) illness
•
Withdrawal of informed consent (subject’s decision to withdraw for any reason)
•
Pregnancy
•
Inability to comply with protocol
•
Discretion of the investigator
•
Disease progression
•
New extramedullary disease
•
Elective stem cell transplant (SCT)
•
Subject is lost to follow up
•
Death
•
DLT
•
AEs which require discontinuation according to Section 4.6.1
•
Need for any treatment not allowed by the protocol.
In the case of pregnancy, the investigator must immediately notify Sponsor or designee of this 
event. In most cases, the study drug will be permanently discontinued in an appropriate manner. 
Please contact the Sponsor or designee within 24 hours of awareness of pregnancy. If the 
investigator determines a possible favorable benefit/risk ratio that warrants continuation of study 
drug, a discussion between the investigator and the Sponsor or designee must occur.
All subjects who discontinue study drug should comply with protocol specified follow-up 
procedures as outlined in Section 5. The only exception to this requirement is when a subject 
withdraws consent for all study procedures including post-treatment study follow-up or loses the 
ability to consent freely (ie, is imprisoned or involuntarily incarcerated for the treatment of either 
a psychiatric or physical illness).
If study drug is discontinued prior to the subject’s completion of the study, the reason for the 
discontinuation must be documented in the subject’s medical records and entered on the 
appropriate case report form (CRF) page.
If a subject was withdrawn before completing the study, the reason for withdrawal must be entered 
on the appropriate CRF page.
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3.6
Post Study Drug Study Follow up
In this study, overall survival (OS) and duration of remission (DoR) is a key endpoint of the study. 
Post treatment study follow-up is of critical importance and is essential to preserving subject safety 
and the integrity of the study. Subjects who discontinue study treatment must continue to be 
followed for collection of outcome and/or survival follow-up data as required and in line with 
Section 5 until death or the conclusion of the study.
Subjects who discontinue study drug may continue to be followed.
3.6.1
Withdrawal of Consent
Subjects who request to discontinue study drug will remain in the study and must continue to be 
followed for protocol specified follow-up procedures. The only exception to this is when a subject 
specifically withdraws consent for any further contact with him/her or persons previously 
authorized by subject to provide this information. Subjects should notify the investigator of the 
decision to withdraw consent from future follow-up in writing, whenever possible. The 
withdrawal of consent should be explained in detail in the medical records by the investigator, as 
to whether the withdrawal is from further treatment with study drug only or also from study 
procedures and/or post treatment study follow-up, and entered on the appropriate CRF page. In the 
event that vital status (whether the subject is alive or dead) is being measured, publicly available 
information should be used to determine vital status only as appropriately directed in accordance 
with local law.
3.6.2
Lost to Follow-Up
All reasonable efforts must be made to locate subjects to determine and report their ongoing status. 
This includes follow-up with persons authorized by the subject as noted above. Lost to follow-up 
is defined by the inability to reach the subject after a minimum of three documented phone calls, 
faxes, or emails as well as lack of response by subject to one registered mail letter. All attempts 
should be documented in the subject’s medical records. If it is determined that the subject has died, 
the site will use permissible local methods to obtain the date and cause of death.
If investigator’s use of third-party representative to assist in the follow-up portion of the study has 
been included in the subject’s informed consent, then the investigator may use a Sponsor-retained 
third-party representative to assist site staff with obtaining subject’s contact information or other 
public vital status data necessary to complete the follow-up portion of the study. The site staff and 
representative will consult publicly available sources, such as public health registries and 
databases, in order to obtain updated contact information. If after all attempts, the subject remains 
lost to follow-up, then the last known alive date as determined by the investigator should be 
reported and documented in the subject’s medical records.
4
STUDY DRUG
Study drug includes both Investigational [Medicinal] Product (IP/IMP) and Non-investigational 
[Medicinal] Products (Non-IP/Non-IMP) and can consist of the following:
•
All products, active or placebo, being tested or used as a comparator in a clinical trial.
•
Study required premedication, and 
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•
Other drugs administered as part of the study that are critical to claims of efficacy (eg, 
background therapy, rescue medications)
•
Diagnostic agents (such as glucose for glucose challenge) given as part of the protocol 
requirements.
Product description and storage information of study drugs used in this study are described in
Table 4-1.
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Table 4-1:
Study Drugs for CA212016
Product Description
and Dosage Form
Potency
IP/Non-IMP
Blinded or 
Open Label
Packaging/
Appearance
Storage Conditions
(per label)
Ulocuplumaba (BMS-
936564) Injection, 
100 mg/vial (10 mg/mL)
10 mg/ml
IP
Open Label
Single-use 10 mL vial with 100 
mg ulocuplumab
Colorless, clear to slightly 
opalescent solution, essentially 
free of particles
Store at 2°C to 8°C, protect 
from light and protect from 
freezing
Cytarabineb
Refer to package 
insert
IP
Open Label
Various packing 
configurations/Commercial
Refer to label on container 
or package insert/summary 
of product characteristics
a The clinical label will reflect the product as “BMS-936564” to be linked with the product description.
b Cytarabine may be obtained by the investigating site’s standard prescribing procedures as allowed.
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4.1
Investigational Product
An investigational product, also known as investigational medicinal product in some regions, is 
defined a pharmaceutical form of an active substance or placebo being tested or used as a reference 
in a clinical study, including products already with a marketing authorization but used or 
assembled (formulated or packaged) differently than the authorized form, or used for an 
unauthorized indication, or when used to gain further information about the authorized form.
The investigational product should be stored in a secure area according to local regulations. It is 
the responsibility of the investigator to ensure that investigational product is only dispensed to 
study subjects. The investigational product must be dispensed only from official study sites by 
authorized personnel according to local regulations. 
In this protocol, investigational products are: ulocuplumab and LDAC.
BMS will provide ulocuplumab to all investigating sites as BMS is the manufacturer and provider 
of the supplies. BMS may also provide LDAC to investigating sites outside of the US. For study 
drugs not provided by BMS and obtained commercially by the site, storage should be in accordance 
with the product label.
4.2
Non-investigational Product
Other medications used as support or escape medication for preventative, diagnostic, or therapeutic 
reasons, as components of the standard of care for a given diagnosis, may be considered as non-
investigational products. 
In this protocol, non-investigational product is: premedications for infusion reaction 
(eg, diphenhydramine, acetaminophen and corticosteroids).
The Sponsor will not be providing these medications since they are part of subject’s standard of 
care.
4.3
Storage and Dispensing
The product storage manager should ensure that the study drug is stored in accordance with the 
environmental conditions (temperature, light, and humidity) as determined by BMS. If concerns 
regarding the quality or appearance of the study drug arise, the study drug should not be dispensed 
and contact BMS immediately.
Study drug not supplied by BMS will be stored in accordance with the package insert.
Investigational product documentation (whether supplied by BMS or not) must be maintained that 
includes all processes required to ensure drug is accurately administered. This includes
documentation of drug storage, administration and, as applicable, storage temperatures, 
reconstitution, and use of required processes (eg, required diluents, administration sets).
Please refer to Section 9.2.2 for guidance on IP records and documentation and Section 4.9 for 
return and destruction instructions.
Ulocuplumab vials must be stored refrigerated 2°C to 8°C in a tightly closed container and must 
be protected from light and freezing. If stored in a glass front refrigerator, vials should be stored 
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in the carton. Once the ulocuplumab injection is transferred to the IV bag, it can be stored for a 
maximum of 12 hours at room temperature/under ambient light at 15°C to 25°C. If the solution in 
the IV bag cannot be used for infusion within the 12 hours at room temperature, it must be 
refrigerated at 2°C to 8°C, not to exceed 12 hours maximum in the refrigerator. The solution is 
stable for a total storage combination time of 24 hours. 
Following transfer to the IV bag, preparation time of dilution to the end time of infusion should 
not exceed 24 hours as the diluted solution of ulocuplumab once prepared, must be infused within 
a 24 hour timeframe. 
Any temperature deviations from the recommended storage conditions would require the site to 
contact the Sponsor for further instruction and disposition.
4.4
Study Treatments
See Section 3.4.1 regarding prophylaxis prior to infusion of ulocuplumab. 
Escalation Cohort
•
Ulocuplumab (600 mg and 800 mg) was administered as a single IV infusion over 
approximately 60 minutes on Day 1, 8, and 15 of the first 2 cycles and on Day 1 and 8 of each 
cycle thereafter.
•
When administered in combination with LDAC, ulocuplumab was administered prior to the 
dose of LDAC. It was recommended that LDAC be administered at least 1 hour after 
completion of ulocuplumab infusion. 
•
LDAC (low dose cytarabine) (20 mg BID [40 mg total daily dose]) was subcutaneously 
administered on Day 1 - 10 for all cycles.
Expansion Cohort
•
Ulocuplumab (800 mg or 1000 mg) will be administered as a single IV infusion over 
approximately 60 minutes on Day 1, 8, and 15 of the first 2 cycles and on Day 1 and 8 of each 
cycle thereafter.
•
When administered in combination with LDAC (cytarabine), ulocuplumab will be 
administered prior to the first dose of LDAC (cytarabine). Cytarabine should be administered 
at least 1 hour after completion of ulocuplumab infusion. 
•
LDAC (low dose cytarabine) (20 mg BID [40 mg total daily dose]) will be subcutaneously 
administered on Day 1 - 10 for all cycles. The second dose of LDAC will be administered per 
investigator decision, however a minimum of six (6) hours after the first dose LDAC dose is 
required.
•
Subjects in the LDAC only arm will be permitted to add ulocuplumab 800 mg into their 
treatment regimen if they do not achieve complete remission (CR or complete remission with 
incomplete blood count recovery [CRi]) confirmed by blast count reduction after 4 treatment 
cycles or if they relapse after achieving complete remission. 
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4.4.1
Preparation of Study Drug
Ulocuplumab will be supplied as a single use vial with the 100 mg/vial (10 mg/mL) potency. Allow 
the appropriate number of ulocuplumab vials to stand at room temperature for approximately 
30 minutes before preparation. Dilution of ulocuplumab must be performed using sterile 
disposable syringes and include 0.9% sodium chloride injection (normal saline). Instructions for 
dilution of the drug product are provided in the pharmacy manual.
Ulocuplumab must be infused using a volumetric pump through an IV solution infusion set with a 
sterile, non-pyrogenic, low protein binding 0.2 μm in-line filter. The infusion rate of the infusion 
pump should be adjusted to allow for a total infusion time of approximately 60 minutes. 
Ulocuplumab must not be administered as an IV push or bolus injection. Additionally, care must 
be taken to ensure the sterility of the prepared solution, as the drug product does not contain 
anti-microbial preservatives or bacteriostatic agents. A sufficient excess of drug product is 
included in each vial to account for withdrawal losses.
Preparation and administration of cytarabine will follow the instruction outlined in the Pharmacy 
Manual and/or according to the clinical label. 
Further details of drug preparation and administration will be described in the pharmacy dosing 
manual.
4.5
Method of Assigning Subject Identification
After informed consent has been obtained and the subject’s initial eligibility is established, the 
subject must be enrolled into the study by entering information into IWRS to obtain the subject 
number. Every subject that signs the informed consent form must be assigned a subject number in 
IWRS. Specific instructions for using IWRS will be provided to the investigational site in a 
separate document. The investigator or designee will be register the subject for enrollment by 
following the enrollment procedures established by BMS. The following information is required 
for enrollment: 
•
Date that informed consent was obtained
•
Date of birth
•
Gender at birth
Following completion of all Screening Phase evaluations, site personnel will make a call to the 
IWRS to obtain a treatment assignment. The IWRS will randomly assign subjects to 1:1:1 
treatment groups (ulocuplumab 800 mg + LDAC, ulocuplumab 1000 mg + LDAC or LDAC
alone). The randomization to the ulocuplumab 1000 mg + LDAC arm may be suspended while the 
safety of the first 6 patients on this dose is assessed.
Further details of subject enrollment will be described in the procedure manual.
4.6
Selection and Timing of Dose for Each Subject
Subjects were/will be assigned to a dose cohort in the order they enter the study. 
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Subjects in the escalation cohort received ulocuplumab at 600 or 800 mg administered as a single
IV infusion on Day 1, 8 and 15 and LDAC at 20 mg BID (40 mg/day) subcutaneously administered 
on Day 1 - 10 in Cycle 1 (DLT evaluation period) and Cycle 2. Subjects then received ulocuplumab 
at 600 or 800 mg on Day 1 and 8 in combination with LDAC at 20 mg BID (40 mg/day) on 
Day 1 - 10 in Cycle 3 and subsequent cycles. A total of 3 subjects were treated at the dose level of 
600 mg. A decision to consider the next higher dose level or the next lower dose level or to stop 
the enrollment upon judging the current dose to be safe was guided by the number of subjects with 
DLTs observed during the DLT evaluation period based on the mTPI design (see Section 3.1.1).
Subjects in the expansion cohort will receive ulocuplumab or LDAC alone. Subjects assigned to 
ulocuplumab arms will receive ulocuplumab 800 mg or ulocuplumab 1000 mg administered as a
single IV infusion on Day 1, 8 and 15 and LDAC at 20 mg BID (40 mg/day) subcutaneously 
administered on Day 1 - 10 in Cycle 1 and Cycle 2.  These subjects will then receive ulocuplumab 
at 800 mg or 1000 mg on Day 1 and 8 in combination with LDAC at 20 mg BID (40 mg/day) on 
Day 1 - 10 in Cycle 3 and subsequent cycles. 
Subjects assigned to the LDAC alone arm will receive 20 mg BID (40 mg/day) on Day 1-10 in 
every cycle. If ulocuplumab is added to the LDAC alone arm after Cycle 4, the treatment schedule 
is LDAC 20 mg BID from Day 1 to 10 of each cycle and ulocuplumab 800 mg on day 1, 8 and 15 
for the first 2 cycles then ulocuplumab 800 mg on Day 1 and 8 for subsequent cycles. Follow 
Treatment Procedural Outline (Table 5.1-2).
4.6.1
Discontinuation, Dose Modifications, Infusion Delays and Missed 
Doses
Subjects will be monitored continuously for AEs while on study therapy.
Subjects will be 
instructed to notify their study physician immediately for any and all AEs. Assessment of causality 
(chronology, confounding factors such as disease, concomitant medications, diagnostic tests and 
previous experience with the agent) must be determined. Reasons for discontinuation or delays, 
the supportive measures taken and the outcome must be documented in the subject’s chart and 
recorded in the CRF.
If the dose of one drug in the regimen (ie, ulocuplumab or LDAC) is delayed or discontinued, after 
Cycle 1, the treatment with the other drug may continue as scheduled. Subjects experiencing 
continuous dose delay greater than 56 days in all study drugs (ulocuplumab and LDAC) due to an 
adverse event(s) related to study treatment must be discontinued from study drug.
4.6.1.1
Treatment Discontinuation Criteria
Subjects will discontinue study treatment upon development of following ulocuplumab-related 
AEs:
•
Prolonged bone marrow suppression (≥ 56 days)
•
Grade ≥ 3 infusion reaction
•
QTcF ≥500 msec confirmed by at least one repeat ECG.
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4.6.1.2
Dose Modifications, Infusion Delays and Missed Doses
No subject will be permitted dose modifications of ulocuplumab and LDAC during Cycle 1. After 
Cycle 1, if the dose of ulocuplumab or LDAC is interrupted or discontinued, the treatment with 
the other drug may continue as scheduled. Each cycle is 28 days. Missed doses should be skipped, 
not delayed, if not given within the allowed window. Please consult the BMS Medical Monitor for 
any questions regarding dose interruption or study therapy discontinuation.
Ulocuplumab: 
The study allows dose delays of ulocuplumab but does not allow dose reductions or escalations 
throughout the treatment period. Dose delays of ulocuplumab are not permitted during Cycle 1.
Criteria to start a new cycle:
•
After Cycle 1, every effort should be made to give the first dose of ulocuplumab and LDAC in 
Cycle 2 within 7 days of the end of the previous cycle in order to maximize dose intensity.  
Dose delays up to a maximum of 28 days are allowable for grade 3 or 4 non-hematologic 
toxicities, with resumption of dosing when resolved to grade 1 or less. This does not include 
situations when the subject’s marrow has not yet recovered from effects of chemotherapy from 
a previous cycle. A dose delay of up to a maximum of 42 days is allowable for prolonged 
myelosuppression defined by ANC ≤ 500/μL or platelet count ≤ 10 x109/L in a normal bone 
marrow with ≤ 5% blasts and no evidence of disease or dysplasia .   
•
At Cycle 3 and beyond, dose delay for recovery from myelosuppression (or other AE) up to a 
maximum of 56 days is allowed for grade 3 or 4 non-hematologic toxicities, or prolonged 
myelosuppression as defined above. 
Once a treatment cycle is begun:
•
For Cycles 1 and 2, a window of -1 to +3 days is permitted for ulocuplumab administration on 
Days 8 and 15. 
•
Beginning with Cycle 3 and beyond, a window of -1 to +7 days is permitted for ulocuplumab 
administration on Day 8.
•
Infusions of ulocuplumab that cannot be administered in that window period will be considered 
a missed dose, and the subject should come in for their next, regularly scheduled visit relative 
to Day 1 of the next cycle. 
A subject should be discontinued from ulocuplumab if they do not receive a dose within 56 days 
of the last ulocuplumab dose. 
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Table 4.6.1.2-1:
Dose Delay and Discontinuation Criteria for 
Ulocuplumab-related Adverse Events
Adverse Event
Action
* Prolonged myelosuppression defined by ANC ≤500/μL 
or platelet count ≤10 x 109/L in a normal bone marrow 
with ≤5% blasts and no evidence of disease or dysplasia 
(≥56 days) a
* Grade ≥3 infusion reaction
* QTcF ≥500 msec confirmed by at least one repeat 
ECG.
Discontinue Ulocuplumab
Grade 4 hematologic toxicity (anemia, neutropenia, 
leukopenia, or thrombocytopenia) a
Hold Ulocuplumab until returns to baseline
≥Grade 3 non-hematologic adverse event in subjects 
receiving maximum medical management.
Hold Ulocuplumab until resolves to 
baseline or ≤Grade 1
a Hematologic parameter changes must be interpreted by the Investigator in the context of the subject’s disease status. 
For example, baseline neutrophil counts may be Grade 3 [〈≤1000 cells/μL] and a decrease to Grade 4 may not be 
considered clinically significant and would not be considered an adverse event, or may be attributed to the 
underlying disease. Thus, the risk/benefit of interruption must be assessed by the Investigator for each subject.
LDAC: 
After Cycle 1, every effort should be made to give the first dose of ulocuplumab and LDAC in 
Cycle 2 within 7 days of the end of the previous cycle in order to maximize dose intensity.  For 
subsequent doses, delays in the administration of LDAC and dose adjustments in LDAC are 
permitted as clinically indicated at the discretion of the investigator. 
Continuous Study Treatment Delay ≥56 Days:
A study treatment related continuous treatment interruption or delay of ≥56 days will result in 
permanent discontinuation from study treatment, unless the patient is demonstrating clinical 
benefit, at the discretion of the investigator and after consultation with the BMS Medical Monitor.
4.7
Blinding/Unblinding
Not applicable.
4.8
Treatment Compliance
The investigator or their designated study personnel will maintain a log drug accountability log of 
all study drug(s) received, dispensed, destroyed, and the amount returned to the Sponsor or supply 
depot. The investigator and the study personnel will ensure that each subject receives ulocuplumab 
as well as LDAC (low dose cytarabine). 
Drug supplies will be inventoried and accounted for throughout the study. The Drug 
Accountability Log will be reviewed by the study monitor during site visits and at the completion 
of the study. Any discrepancy should be brought to the attention of the Sponsor.
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The treatment compliance in this study will be done at the study site where records of compliance 
will be maintained.
4.9
Destruction of Study Drug
For this study, study drugs (those supplied by BMS or sourced by the investigator) such as partially 
used study drug containers, vials and syringes may be destroyed on site. 
Any unused study drugs can only be destroyed after being inspected and reconciled by the 
responsible Study Monitor unless study drug containers must be immediately destroyed as required 
for safety, or to meet local regulations (eg, cytotoxics or biologics). 
On-site destruction is allowed provided the following minimal standards are met:
•
On-site disposal practices must not expose humans to risks from the drug.
•
On-site disposal practices and procedures are in agreement with applicable laws and 
regulations, including any special requirements for controlled or hazardous substances.
•
Written procedures for on-site disposal are available and followed. The procedures must be
filed with the site’s SOPs and a copy provided to BMS upon request.
•
Records are maintained that allow for traceability of each container, including the date 
disposed of, quantity disposed, and identification of the person disposing the containers. The 
method of disposal, ie, incinerator, licensed sanitary landfill, or licensed waste disposal vendor 
must be documented.
•
Accountability and disposal records are complete, up-to-date, and available for the Monitor to 
review throughout the clinical trial period.
If conditions for destruction cannot be met the responsible Study Monitor will make arrangements 
for return of study drug.
It is the study drug storage manager’s responsibility to arrange for disposal of all empty containers, 
provided that procedures for proper disposal have been established according to applicable local, 
and institutional guidelines and procedures, and provided that appropriate records of disposal are 
kept.
4.10
Return of Study Drug
If study drug will not be destroyed upon completion or termination of the study, all unused and/or 
partially used study drug that was supplied by BMS must be returned to BMS. The return of study 
drug will be arranged by the responsible Study Monitor. 
It is the study drug storage manager’s responsibility to arrange for disposal of all empty containers, 
provided that procedures for proper disposal have been established according to applicable local, 
and institutional guidelines and procedures, and provided that appropriate records of disposal are 
kept. 
Arrangements for the return of study drug will be made by the responsible Study Monitor.
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5
STUDY ASSESSMENTS AND PROCEDURES
5.1
Flow Chart/Time and Events Schedule
The Treatment Period of the study is divided into cycles with associated evaluations and 
procedures that must be performed at specific timepoints (see Table 5.1-1, Table 5.1-2, and Table 
5.1-3. 
Every effort should be made to schedule visits within the protocol specified windows. For infusion 
delays or missed doses, see Section 4.6.1 for administration details.
Laboratory assessments, blood sampling, and vital signs defined in Table 5.1-1, Table 5.1-2, Table 
5.1-3, Table 5.5.1-1, and Table 5.5.1-2 should occur within ± 10% of the defined timepoint (eg, a 
blood sample scheduled for 60 minutes should occur within 6 minutes of the 60-minute mark; eg,
a blood sample scheduled for 24 hours should occur within 2.4 hours of the 24-hour mark).
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Table 5.1-1:
Screening Procedural Outline (CA212016)
Procedure
Screening
Visit
(Day -28 to -1)
Notes
Eligibility Assessments
Informed Consent
X
A subject is considered enrolled only when a protocol specific-informed consent is signed.
Medical History
X
Includes demographics, disease diagnosis, prior treatment, any toxicities or allergy related to 
previous treatments, and prior and concurrent medical conditions.
Baseline signs and symptoms
X
Pre-dose events will be collected.
Inclusion/Exclusion Criteria
X
It must be confirmed that subjects meet all of the inclusion criteria and none of the exclusion 
criteria prior to dosing on Cycle 1 Day 1.
Safety Assessments
Physical Examination
X
All abnormal findings are to be collected.
Physical Measurement
X
Height will be measured at screening only. Weight is to be measured at the Screening visit and at 
each day of ulocuplumab infusion.
Vital Signs
X
Includes body temperature, heart rate, and systolic and diastolic blood pressures. These should be 
measured after a subject has been rested quietly for at least 5 minutes.
ECOG Performance Status
X
See Appendix 4.
HCT-CI
X
See Appendix 6.
12-lead Electrocardiogram (ECG)
X
Must be performed using QTc (Fridericia correction).  
Serology
X
Serum for Hepatitis C antibody, Hepatitis B surface antigen, Hepatitis B core antibody (In the 
case of positive Hepatitis B core antibody, if Hepatitis B DNA by quantitative PCR is 
undetectable, subjects are eligible), HIV antibody.
Hematology
X
Laboratory results must be reviewed before the first dose of ulocuplumab. Samples may be 
drawn up to 72 hours before infusion to meet this requirement. Please refer to Section 5.3.2.
Chemistry
X
Laboratory results must be reviewed before the first dose of ulocuplumab. Samples may be 
drawn up to 72 hours before infusion to meet this requirement. Please refer to Section 5.3.2.
Urinalysis
X
Laboratory results must be reviewed before the first dose of ulocuplumab. Samples may be
collected up to 72 hours before infusion to meet this requirement Please refer to Section 5.3.2.
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Table 5.1-1:
Screening Procedural Outline (CA212016)
Procedure
Screening
Visit
(Day -28 to -1)
Notes
Pregnancy Test
X
WOCBP only. WOCBP must have a negative serum or urine pregnancy test (minimum
sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of study drug.
Pregnancy test must be negative to continue.
Concomitant medications
X
Medications taken within 28 days prior to study drug administration and concurrent medications
must be recorded on the CRF. Includes medical treatment procedures also.
Adverse Event Reporting
Serious Adverse Events Assessment
X
All serious adverse events (SAEs) must be collected from the date of subject’s written consent 
until 30 days after discontinuation of dosing. 
All SAEs must be collected that occur within 30 days of the last visit for screen failures.
Efficacy Assessments
Bone marrow aspirate/biopsy
X
Baseline bone marrow aspirate/biopsy (local lab) performed as part of the subject’s previous 
routine care before signing the informed consent form and completed within 28 days before the 
administration of ulocuplumab need not be repeated. Report will be sent to BMS.
Diagnostic testing for extramedullary 
disease
X
Testing for extramedullary disease as part of subject’s routine care, if clinically indicated.
RBC transfusion dependency
X
RBC transfusion taken within 28 days prior to study drug administration must be recorded on the 
CRF. The threshold for transfusion will be determined at the investigator’s discretion.
Other Assessments
Central Lab Cytogenetic testing
X
Bone marrow aspirate will be collected (karyotype).
C-Reactive Protein (CRP)
X
May be obtained during screening or prior to first dose.
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Table 5.1-2:
Treatment Procedural Outline (CA212016)
Procedurea
Treatment (28 days/cycle)
EOT
b
Notes
Cycle 1-2c
Cycle 3 and subsequent cyclesc
All 
Cycles
D1d
D
2-7
D 8e
D
9-10
D
15e f
D1d
D
2-7
D8g h
D
9-10
D
24-28
i
Other 
Assessments
C-Reactive 
Protein
X
CRP must be obtained prior to first dose if 
CRP has not been collected at screening.
Safety 
Assessments
Physical 
Examination
X
X
X
X
X
All abnormal findings and any new or 
worsening signs and/or symptoms are to 
be recorded as AEs after study drug 
administration.
Physical 
Measurement
X
X
X
X
X
X
Weight only.
Vital Signs
X
X
X
X
X
X
Includes body temperature, heart rate, and 
systolic and diastolic blood pressures. 
These should be measured after a subject 
has been rested quietly for at least 
5 minutes.
Vital signs will be obtained with the 
following schedule: Cycle 1: before 
ulocuplumab infusion, 15 and 30 minutes 
during the infusion, at the completion of 
infusion, at 60 minutes after the 
completion of infusion on the day of 
ulocuplumab infusion.
Cycle 2 and subsequent cycles: before 
ulocuplumab infusion and at the 
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Table 5.1-2:
Treatment Procedural Outline (CA212016)
Procedurea
Treatment (28 days/cycle)
EOT
b
Notes
Cycle 1-2c
Cycle 3 and subsequent cyclesc
All 
Cycles
D1d
D
2-7
D 8e
D
9-10
D
15e f
D1d
D
2-7
D8g h
D
9-10
D
24-28
i
completion of infusion on the day of 
ulocuplumab infusion.
ECOG 
Performance 
Status
X
X
X
See Appendix 4.
HCT-CI
X
See Appendix 6.
12-lead ECG
X
X
X
For all subjects, for Day 1 of each cycle, 
ECG tests will be performed at pre-dose. 
On Day 1 of Cycle 1, it will also be 
performed at the completion of 
ulocuplumab infusion.
For subjects in the Serial PK/ECG Subset, 
see Table 5.5.1-1  for ECG/holter monitor
schedule for Cycle 1 and 2.
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Table 5.1-2:
Treatment Procedural Outline (CA212016)
Procedurea
Treatment (28 days/cycle)
EOT
b
Notes
Cycle 1-2c
Cycle 3 and subsequent cyclesc
All 
Cycles
D1d
D
2-7
D 8e
D
9-10
D
15e f
D1d
D
2-7
D8g h
D
9-10
D
24-28
i
Hematology
X
X
X
X
X
X
Laboratory results must be reviewed 
before dosing.
Samples may be collected up to 72 hours 
before infusion of ulocuplumab
Hematology assessment includes complete 
blood count, in addition to the differential 
that enumerates absolute counts of 
circulating tumor cells (if any), 
neutrophils, lymphocytes, monocytes, 
basophils, eosinophils. Absolute counts 
and/or percentages may be reported.
Lab tests associated with efficacy 
assessments may be conducted at 
appropriate timings as needed.
Please refer to Section 5.3.2
Chemistry
X
X
X
X
X
Laboratory results must be reviewed 
before dosing.
Samples may be collected up to 72 hours 
before infusion of ulocuplumab. Please 
refer to Section 5.3.2
Urinalysis
X
X
X
Laboratory results must be reviewed 
before dosing.
Samples may be collected up to 72 hours 
before infusion of ulocuplumab. Please 
refer to Section 5.3.2
Pregnancy Test
X
X
X
WOCBP only.
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Table 5.1-2:
Treatment Procedural Outline (CA212016)
Procedurea
Treatment (28 days/cycle)
EOT
b
Notes
Cycle 1-2c
Cycle 3 and subsequent cyclesc
All 
Cycles
D1d
D
2-7
D 8e
D
9-10
D
15e f
D1d
D
2-7
D8g h
D
9-10
D
24-28
i
Serum or urine pregnancy testing 
immediately before day 1 infusion.
Minimally, monthly pregnancy testing is 
required. During dose delays greater than 4 
weeks, pregnancy testing must be 
completed within 30 days from the date of 
the last pregnancy test until dosing 
resumes.
Concomitant 
medications
X
X
X
X
X
X
X
X
X
X
X
Concurrent medications must be recorded 
on the CRF during the study. Includes 
medical treatment procedures also.
Adverse Event 
Reporting
SAEs
X
X
X
X
X
X
X
X
X
X
X
All SAEs must be collected from the date 
of subject’s written consent until 30 days
after discontinuation of dosing.
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
All abnormal findings and any new or 
worsening signs and/or symptoms are to 
be recorded as AEs after study drug 
administration.
All AEs must be collected from the 
initiation of study drug until 30 days after 
the end of treatment.
Study drug-related AEs that are 
reported/identified during the follow up 
period should be followed to resolution, 
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Table 5.1-2:
Treatment Procedural Outline (CA212016)
Procedurea
Treatment (28 days/cycle)
EOT
b
Notes
Cycle 1-2c
Cycle 3 and subsequent cyclesc
All 
Cycles
D1d
D
2-7
D 8e
D
9-10
D
15e f
D1d
D
2-7
D8g h
D
9-10
D
24-28
i
stabilization, or initiation of new therapy 
or until deemed irreversible.
PK Assessments
Serum sample 
for PK
Applies to Ulocuplumab/LDAC 
combination arms only
See Table 5.5.1-1 and Table 5.5.1-2
Immunogenicity 
Assessments
Serum sample 
for 
immunogenicity
Applies to Ulocuplumab/LDAC 
combination arms only
See  Table 5.5.1-1 and Table 5.5.1-2
Efficacy 
Assessments
Leukemia 
response 
assessment
X
X
Leukemia response assessment will be 
evaluated for each cycle using the AML 
IWG 2003. The results of the response 
assessments must be reviewed and 
documented before the first dose of the 
next cycle.
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Table 5.1-2:
Treatment Procedural Outline (CA212016)
Procedurea
Treatment (28 days/cycle)
EOT
b
Notes
Cycle 1-2c
Cycle 3 and subsequent cyclesc
All 
Cycles
D1d
D
2-7
D 8e
D
9-10
D
15e f
D1d
D
2-7
D8g h
D
9-10
D
24-28
i
Bone marrow 
aspirate/biopsy
X
X
The results of the local lab bone marrow 
aspirate (or biopsy) done as part of routine 
care will be sent to BMS. Bone marrow 
aspirate is sufficient for the leukemia 
response evaluation.
The marrow must be of adequate recovery 
and cellularity for evaluation. If the bone 
marrow has not yet recovered, repeat the 
bone marrow until a leukemia response 
can be determined. The next cycle of 
treatment is delayed until the marrow is of 
adequate recovery and cellularity for a 
response assessment to be completed.
Diagnostic 
testing for 
extramedullary 
disease
X
X
Testing for extramedullary disease as part 
of subject’s routine care, if clinically 
indicated.
RBC transfusion 
requirements
X
X
X
X
X
The threshold for transfusion will be 
determined at the investigator’s discretion.
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ulocuplumab
Table 5.1-2:
Treatment Procedural Outline (CA212016)
Procedurea
Treatment (28 days/cycle)
EOT
b
Notes
Cycle 1-2c
Cycle 3 and subsequent cyclesc
All 
Cycles
D1d
D
2-7
D 8e
D
9-10
D
15e f
D1d
D
2-7
D8g h
D
9-10
D
24-28
i
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ulocuplumab
Table 5.1-2:
Treatment Procedural Outline (CA212016)
Procedurea
Treatment (28 days/cycle)
EOT
b
Notes
Cycle 1-2c
Cycle 3 and subsequent cyclesc
All 
Cycles
D1d
D
2-7
D 8e
D
9-10
D
15e f
D1d
D
2-7
D8g h
D
9-10
D
24-28
i
Clinical Drug 
Supplies
Ulocuplumab 
infusion
X
X
X
X
X
If a subject experiences a Grade 2 infusion 
reaction with ulocuplumab, the subject 
will be required to receive prophylactic 
premedications for subsequent infusions of 
ulocuplumab. The pre-medications 
include, but not limited to,
diphenhydramine, acetaminophen, and 
low-dose corticosteroids.
See Sections 4.4 and 4.6.
Cytarabine 
administration
X
X
X
X
X
X
X
X
Cytarabine is administered on Day 1 - 10
in each cycle. See Sections 4.4 and 4.6.
Study drug 
withdrawal/study 
withdrawal 
procedures
X
End of Treatment visit should be 
performed any time a subject discontinues
study treatment.
a All on-treatment sample collections/assessments are to be done prior to dosing unless otherwise indicated.
b The end of treatment visit should be performed any time a subject discontinues study treatment.
c Subjects who discontinue ulocuplumab treatment for any reasons will be followed for 30 day after the end of treatment visit.
d A window of ± 1 day is permitted.
e For Cycles 1 and 2, a window of -1/+3 days is permitted for Days 8 and 15.
f D15 does not apply to the LDAC-only arm.
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g Beginning with Cycle 3, a window of -1/+7 days is permitted for Day 8.
h If ulocuplumab is not administered on Day 8 of Cycle 3 and/or subsequent cycles due to a dose delay, study treatment should begin with the next cycle and Day 
1 procedures should be completed.
i
Efficacy assessment and associated testing will be conducted at or after Day 24 of a previous cycle prior to Day 1 of each cycle except Cycle 1. Evaluations 
during dose delays may be conducted up to 5 days prior to Day 1 of the next cycle start after the dose delay.
j
Collections at Cycle 3 and every 3 cycles thereafter.
Abbreviations: EOT = End of Treatment; F/U = Follow-up
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ulocuplumab
Table 5.1-3:
Follow-up Assessments (CA212016)
Procedure
X, Follow-up 
Visit -
30 daysa,b
S, Survival 
Follow-up 
Visitsc
Notes
Safety Assessments
Physical Examination
X
All abnormal findings and any new or worsening signs and/or symptoms are to be 
recorded as AEs after study drug administration.
Physical Measurement
X
Weight only.
Vital Signs
X
Includes body temperature, heart rate, and systolic and diastolic blood pressures. These 
should be measured after a subject has been rested quietly for at least 5 minutes.
ECOG Performance Status
X
See Appendix 4.
12-lead ECG
X
Hematology
X
Please refer to Section 5.3.2
Chemistry
X
Please refer to Section 5.3.2
Urinalysis
X
Please refer to Section 5.3.2
Pregnancy Test
X
WOCBP only.
Concomitant medications
X
Concurrent medications must be recorded on the CRF during the study. Includes medical 
treatment procedures also.
Adverse Event Reporting
SAEs
X
All SAEs must be collected from the date of subject’s written consent until 30 days after 
discontinuation of dosing.
Adverse Events
X
All abnormal findings and any new or worsening signs and/or symptoms are to be 
recorded as AEs after study drug administration.
All AEs must be collected from the initiation of study drug until 30 days after the end of 
treatment.
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ulocuplumab
Table 5.1-3:
Follow-up Assessments (CA212016)
Procedure
X, Follow-up 
Visit -
30 daysa,b
S, Survival 
Follow-up 
Visitsc
Notes
Study drug-related AEs that are reported/identified during the follow up period should be 
followed to resolution, stabilization, or initiation of new therapy or until deemed 
irreversible.
PK Assessments
Serum sample for PK
X
Applies to Ulocuplumab/LDAC combination arms only
See Table 5.5.1-1
Immunogenicity 
Assessments
Serum sample for 
immunogenicity
X
Applies to Ulocuplumab/LDAC combination arms only
See  Table 5.5.1-1
Efficacy Assessments
Bone marrow 
aspirate/biopsy
X
The results of the local lab bone marrow aspirate (or biopsy) done as part of routine care 
will be sent to BMS. Bone marrow aspirate is sufficient for the leukemia response 
evaluation.
The marrow must be of adequate recovery and cellularity for evaluation. If the bone 
marrow has not yet recovered, repeat the bone marrow until a leukemia response can be 
determined. The next cycle of treatment is delayed until the marrow is of adequate 
recovery and cellularity for a response assessment to be completed.
Diagnostic testing for 
extramedullary disease
X
Testing for extramedullary disease as part of subject’s routine care, if clinically indicated.
RBC transfusion 
requirements
X
The threshold for transfusion will be determined at the investigator’s discretion.
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ulocuplumab
Table 5.1-3:
Follow-up Assessments (CA212016)
Procedure
X, Follow-up 
Visit -
30 daysa,b
S, Survival 
Follow-up 
Visitsc
Notes
Subject Status
Survival Status
X
X
Every 3 months after X01; may be accomplished by visit or phone contact , to update 
survival information and assess subsequent anti-cancer therapy
a Subjects who discontinue ulocuplumab combination or LDAC alone treatment for any reason will be followed for 30 day after the end of treatment visit.
b A window of ± 7 days is permitted.
c A window of ± 30 days is permitted.
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The end of treatment visit should be performed on the day a decision is made to discontinue study 
treatment. In the event of multiple procedures are required at a single time point, the following is 
a list of procedures from highest priority to low:
1. PK and RO Sampling
2. Safety (ECG)
3. Safety (vital signs)
4. Safety (clinical labs).
5.1.1
Retesting During Screening or Lead-in Period
Retesting of laboratory parameters and/or other assessments within any single Screening or 
Lead-in period will be permitted (in addition to any parameters that require a confirmatory value).
Any new result will override the previous result (ie, the most current result prior to Randomization) 
and is the value by which study inclusion will be assessed as it represents the subject’s most 
current, clinical state.
5.2
Study Materials
The site will provide all required materials for the tests performed locally (ie, relevant clinical 
laboratory tests). The site will have available a well-calibrated scale for recording height and body 
weight, a 12-lead ECG machine, and a calibrated sphygmomanometer and thermometer for vital 
signs assessments. A current and fully-stocked advanced cardiac life support cart will be 
immediately available on the premises. The site will have a refrigerated centrifuge, a monitored 
and alarmed refrigerator, and freezer (-20°C or below), as well as containers and dry ice for storage 
of blood and urine samples. The site will provide all materials required for accurate source 
documentation of study activities and for housing the subjects during the study. The site will have 
the proper equipment for the infusion of ulocuplumab including an infusion pump.
The site will also provide premedication for infusion reaction.
BMS will provide a BMS-approved protocol and any amendments or administrative letters (if 
required), investigator brochure and procedure manuals. Case report forms (electronic or hard 
copy) will be provided by BMS. BMS/The Central Laboratory will provide labels and tubes for 
the collection of blood samples for PK and immunogenicity analysis.
5.3
Safety Assessments
The study is divided into periods with associated evaluations and procedures that must be 
performed at specific timepoints. The Time and Events Schedules (Table 5.1-1, Table 5.1-2, and 
Table 5.1-3) summarizes the frequency and timing of these evaluations and procedures. 
The following safety assessments will be performed during the study for all subjects: vital sign 
measurements, clinical laboratory tests, bone marrow tests, ECOG performance status evaluations 
(Appendix 4), physical examinations/measurements, ECGs (12-lead), concomitant medications, 
transfusions, and the incidence and severity of AEs.
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The incidence of observed AEs will be tabulated and reviewed for potential significance and 
clinical importance.
Subjects will be evaluated for safety if they have received at least 1 dose of study drug. Toxicity 
assessments will be continuous during the treatment phase. During the safety follow-up phase 
(Follow-up visit X01, Table 5.1-3), toxicity assessments should be done in person. Once subjects 
reach the survival follow-up phase either in person or documented telephone calls/emails to assess 
the subject’s status are acceptable.
5.3.1
Evaluation and Reporting of Dose Limiting Toxicity (DLT)
DLT will be determined based on the incidence and intensity of AEs occurring in Cycle 1 using 
NCI CTCAE v4.03. DLT(s) will be defined as any of the following events which are attributed 
(ie, judged to be related) to the ulocuplumab. AEs that are judged by the investigator to be solely 
attributed to cytarabine (based upon clinical experience and the known toxicities of these agents), 
will not be considered DLTs. AEs should be evaluated carefully by the investigator prior to 
attribution. AEs may be attributed to ulocuplumab if, in the judgment of the investigator, the 
nature, severity, or timing is unexpected from LDAC (cytarabine). If the events listed below occur, 
these events will be discussed by the investigator and the BMS Medical Monitor to determine 
whether they qualify as DLT or not considering its clinical significance. Study drugs (ulocuplumab
and LDAC (cytarabine)) will be permanently discontinued for any subject that experiences a DLT.
DLT is defined as:
•
Any ulocuplumab related grade ≥3 nonhematologic toxicity not due to the underlying disease 
occurring during Cycle 1.
•
Marrow that does not adequately recover within 8 weeks from the last study drug 
administration (< 10% cellularity with < 10% blasts) will be considered a hematologic DLT if 
related to ulocuplumab.
•
Any ulocuplumab related grade 4 (life-threatening) hematologic toxicity lasting > 14 days.
The following will not be considered a DLT:
•
Grade 3 nausea or vomiting that are controllable with medications
•
Grade 3 neutropenic fevers or infections
•
Grade ≥3 tumor lysis syndrome
•
Grade ≥3 metabolic derangements attributed to antifungal medications or tumor lysis that 
corrected with IV or oral supplementation
•
Grade 3 stomatitis that resolves within 7 days of discontinuation of chemotherapy
•
Grade ≥3 hypercholesterolemia
•
Grade 3 hyperbilirubinemia or transaminitis that resolves to below grade 2 within 14 days
•
Grade 3 infusion reactions.
Subjects will be considered to have completed a DLT assessment period if they complete all doses 
of ulocuplumab and cytarabine for Cycle 1 (28 days). This does not apply to subjects who 
experience DLTs.
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5.3.2
Laboratory Test Assessments
A local laboratory will perform the analyses including C-Reactive Protein testing and will provide 
reference ranges for these tests.
Results of local clinical laboratory tests must be reviewed prior to infusion.
The following clinical laboratory tests will be performed:
Hematology
Hemoglobin
Hematocrit
Total leukocyte count (and differential)
•
Automated differentials are acceptable, absolute counts reported and/or percentages
of circulating tumor cells (if any), neutrophils, lymphocytes, monocytes, basophils, 
eosinophils.
Platelet count
Blast percentage
Serum Chemistry
Aspartate aminotransferase (AST)
Alanine aminotransferase (ALT)
Total bilirubin
Direct bilirubin
Alkaline phosphatase
Lactate dehydrogenase 
Creatinine
Blood Urea Nitrogen or Urea
Uric acid
Lipase
Amylase
Glucose
Total Protein
Albumin
Sodium
Potassium
Chloride
Calcium
Phosphorus
Creatine kinase
Urinalysis
Protein
Glucose
Blood
Leukocyte esterase
Microscopic examination of the sediment including WBC/high power field (HPF), red 
blood cell (RBC)/HPF if blood, protein or leukocytes esterase are positive on the dipstick
Pregnancy Test (WOCBP only); urinalysis or serum
Serology
Hepatitis C antibody
Hepatitis B surface antigen
Hepatitis B core antibody
HIV antibody
Other: 
C-Reactive Protein
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Results of all laboratory tests required by this protocol must be provided to BMS, either recorded 
on the laboratory pages of the CRF or by another mechanism as agreed upon between the 
investigator and BMS (eg, provided electronically). If the units of a test result differ from those 
printed on the CRF, the recorded laboratory values must specify the correct units. Any abnormal 
laboratory test result considered clinically significant by the investigator must be recorded on the 
appropriate AE page of the CRF (see Section 6.3, Laboratory Test Abnormalities).
5.3.3
Other Assessments
•
ECOG assessment (Appendix 4)
•
HCT-CI assessment (Appendix 6)
•
Physical Examination/Measurement
•
Vital Signs
•
ECG-safety ECGs will be done for all subjects at screening, during the treatment period and 
during follow-up as indicated in Table 5.1-1, Table 5.1-2, and Table 5.1-3 . Serial ECGs will 
be obtained only from a subset of subjects in the expansion cohort (a minimum of 15 subjects 
per dose level, Serial PK/ECG subset) as indicated in Table 5.5.1-1.
•
Concomitant Medications including Medical Treatment Procedures.
5.3.4
Additional Data to be Collected during Trial
Reasons for early discontinuation of any treatment cycle will be collected. This may include but 
not be limited to progression of cytopenias, lymphadenopathy, organomegaly, fever, weight loss, 
night sweats, fatigue, etc.
5.3.5
Imaging Assessment for the Study
Any incidental findings of potential clinical relevance that are not directly associated with the 
objectives of the protocol should be evaluated and handled by the Study Investigator as per 
standard medical/clinical judgment.
5.4
Efficacy Assessments
5.4.1
Primary Efficacy Assessment
Efficacy assessments will be determined by changes in bone marrow aspirate/biopsy, 
hematological laboratory tests, red blood cell transfusion dependency, and assessments for 
extramedullary disease (if applicable). Leukemia response assessment will be evaluated using 
AML IWG 2003 (Appendix 1).
The Time and Events Schedules (Table 5.1-1, Table 5.1-2, and Table 5.1-3) summarizes the 
frequency and timing of efficacy measurements.
Primary efficacy analyses will be based on the best overall response.
5.4.2
Secondary Efficacy Assessments
Duration of remission (DoR) and overall survival are secondary endpoints. Refer to Section 8.3
for the definition of these endpoints. For OS, every effort should be made to collect survival date 
on all randomized subjects including subjects who withdraw from treatment for any reason, who 
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are eligible to participate in the study and who have not withdrawn consent for survival data 
collection. If the death of a subject is not reported every date collected in this study representing a 
date of subject contact will be used in determining the subject's last known alive date.
5.5
Pharmacokinetic Assessments
Blood samples for PK can be obtained from a peripheral IV site or central venous access device. 
PK samples cannot be obtained from the same line used for drug administration or from an IV site 
above the site used for drug administration. When the drug is infused through a multi-lumen 
catheter, the alternate lumen should not be used for sampling due to the risk of drug contamination. 
All post-infusion samples must be collected within ± 10% of the defined timepoints in Table 5.5.1-
1 and except 1.5 h samples after starting infusion which must be collected within 15 minutes of 
the timepoint. Further details of blood collection and processing will be provided to the site in the 
procedure manual.
PK samples are collected from subjects in the ulocuplumab/LDAC combination arms only.  
Subjects in the LDAC alone arm, who add ulocuplumab to their treatment regimen are not required 
to participate in PK measurements.
5.5.1
Pharmacokinetics Collection and Processing and ECG Measurements
Serial blood samples will be collected from the dose escalation cohort. Serial blood samples and 
time-matched ECGs will be collected from a subset of subjects in the expansion cohort (a 
minimum of 15 subjects per dose level, Serial PK/ECG Subset) whereas sparse blood samples will 
be collected in the remaining subjects (sparse sampling subset). Serum for all ADA samples will 
be collected within 30 minutes before dosing.
Table 5.5.1-1 and Table 5.5.1-2 list the sampling schedule to be followed for the assessment of 
PK, ECG, ADA and RO. Further details of blood collection and processing will be provided to the 
site in the procedure manual.
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Table 5.5.1-1:
Ulocuplumab PK and RO Sampling Schedule and ECG 
Measurements (Escalation Cohort and Expansion Cohort, 
Serial PK/ECG Subset)
Study Day
Time 
(Relative to 
Dosing)
Hour
Time 
(Relative to 
Dosing)
Hour: Min
PK 
Blood 
Sample
RO 
Sample
ADA 
Sample
ECGa
Cycle 1, Day 1
-1.0
-01:00
X
0 (pre-dose)
00:00
X
X
X
Xb
1.0 (end of 
infusion)c
01:00
X
X
1.5
01:30
X
Xb
2.0
02:00
X
3.0
03:00
X
Xb
5.0
05:00
X
Cycle 1, Day 2
24
24:00
X
Cycle 1, Day 3
48
48:00
X
Cycle 1, Day 4
72
72:00
X
Cycle 1, Day 8
0 (pre-dose)
00:00
X
X
1.0 (end of 
infusion)c
01:00
X
X
Cycle 1, Day 15
0 (pre-dose)
00:00
X
X
X
1.0 (end of 
infusion)c
01:00
X
X
Cycle 2, Day 1
0 (pre-dose) 
00:00
X
X
X
1.0 (end of 
infusion)c
01:00
X
X
Cycle 2, Day 8
0 (pre-dose)
00:00
X
X
1.0 (end of 
infusion)c
01:00
X
X
Cycle 2, Day 15
0 (pre-dose)
00:00
X
X
Xb
1.0 (end of 
infusion)c
01:00
X
X
1.5
01:30
X
Xb
3.0
03:00
X
Xb
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Table 5.5.1-1:
Ulocuplumab PK and RO Sampling Schedule and ECG 
Measurements (Escalation Cohort and Expansion Cohort, 
Serial PK/ECG Subset)
Study Day
Time 
(Relative to 
Dosing)
Hour
Time 
(Relative to 
Dosing)
Hour: Min
PK 
Blood 
Sample
RO 
Sample
ADA 
Sample
ECGa
Cycle 3-5, Day 1d
0 (pre-dose)
00:00
X
X
X
1.0 (end of 
infusion)c
01:00
X
X
Cycle 3-5, Day 8d
0 (pre-dose)
00:00
X
X
1.0 (end of 
infusion)c
01:00
X
X
Every 4 Cycles 
after 5, Day 1
0 (pre-dose)
00:00
X
X
End of Treatment 
X
X
Follow-upe
X
X
a ECG only for subjects in expansion cohort Serial PK/ECG Subset
b 12-lead ECGs will be extracted from the Holter recorded flashcards in triplicate within a 10-minute window ending 
prior to the nominal ECG collection time and before PK draws
c If infusion has not completed at 1 hour, then draw PK sample immediately after the infusion ends and record time 
accurately.
d The Day 1 and Day 8 pre-dose and end of infusion samples to be collected at Cycle 3 and every cycle thereafter 
until Cycle 5.
e Follow-up visit should occur no less than 30 days after the end of treatment visit
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Table 5.5.1-2:
Ulocuplumab PK and RO Sampling Schedule 
(Expansion Cohort, Sparse Sampling Subset)
Study Day
Time 
(Relative to Dosing)
Hour
Time 
(Relative to 
Dosing)
Hour: Min
PK Blood 
Sample
RO 
Sample
ADA 
Sample
Cycle 1, Day 1
0 (pre-dose)
00:00
X
X
X
1.0 (end of infusion)a
01:00
X
X
Cycle 1, Day 8
0 (pre-dose)
00:00
X
X
1.0 (end of infusion)a
01:00
X
X
Cycle 1, Day 15
0 (pre-dose)
00:00
X
X
X
1.0 (end of infusion)a
01:00
X
X
Cycle 2, Day 1
0 (pre-dose)
00:00
X
X
X
1.0 (end of infusion)a
01:00
X
X
Cycle 2, Day 8
0 (pre-dose)
00:00
X
X
1.0 (end of infusion)a
01:00
X
X
Cycle 2, Day 15
0 (pre-dose)
00:00
X
X
1.0 (end of infusion)a
01:00
X
X
Cycle 3-5, Day 1b
0 (pre-dose)
00:00
X
X
X
1.0 (end of infusion)a
01:00
X
X
Cycle 3-5, Day 8b
0 (pre-dose)
00:00
X
X
1.0 (end of infusion)a
01:00
X
X
Every 4 Cycles after 
Cycle 5, Day 1
0 (pre-dose)
00:00
X
X
End of Treatment 
X
X
Follow-upc
X
X
a If infusion has not completed at 1 hour, then draw PK sample immediately after the infusion ends and record time 
accurately.
b The Day 1 and Day 8 pre-dose and end of infusion samples to be collected at Cycle 3 and every cycle thereafter 
until Cycle 5.
c Follow-up visit should occur no less than 30 days after the end of treatment visit.
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5.5.2
Pharmacokinetic Sample Analysis
Serum samples will be analyzed for ulocuplumab by a validated immunoassay. 
The PK and potential covariate(s) data may be combined with data from other studies.
5.5.3
Labeling and Shipping of Biological Samples
Detailed instructions for the PK blood collection, labeling, processing, storage, and shipping will 
be provided to the site in the procedure manual.
5.6
ECG Assessments
Safety ECGs will be done for all subjects at screening, during the treatment period and during 
follow-up as indicated in Table 5.1-1, Table 5.1-2, and Table 5.1-3. All required safety ECGs will 
be performed on 12-lead ECG equipment used by the sites, per ECG central vendor guidelines.
Serial ECGs will be obtained only from a subset of subjects in the expansion cohort (a minimum 
of 15 subjects per dose level, Serial PK/ECG Subset) as indicated in Table 5.5.1-1 and should be
obtained at each time point listed.
The subjects must be placed in a supine position for 5 to 10 minutes prior to the start of the ECG 
recording for both safety and serial ECGs. The recorded QTc interval will be measured with 
Fridericia’s correction (QTcF).
All required serial ECGs will be collected on ECG holter monitor equipment provided by the ECG 
central vendor. The timing of the ECG data collected on the holter monitor is critical to the 
endpoint of the study and must be performed according the central vendor guidelines. The serial 
12-lead ECGs will be extracted from the Holter recorded flashcards in triplicate within a 10-minute 
window ending prior to the nominal ECG collection time and before PK draws. The serial ECGs 
will be assessed by the ECG vendor.
The investigative site should document any deviations from the protocol or procedures related to 
ECG collection or serum sampling. Accurate documentation will lead to proper accounting of the 
cumulative data and correct final analysis.
 
 
 
 
 
 
 
 
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5.8
Immunogenicity Assessments
Samples for the analysis of anti-drug antibodies (ADA) to ulocuplumab (immunogenicity) will be 
collected at pre-dose in all subjects according to the schedules in Table 5.5.1-1 and Table 5.5.1-2. 
Additional sample handling, labeling, and shipping details will be provided to the site in the 
procedure manual. Serum samples will be analyzed by a validated immunogenicity assay. Samples 
are always to be collected prior to the administration of study medication.
ADA samples are collected from subjects in the ulocuplumab/LDAC combination arms only.  
Subjects in the LDAC alone arm, who add ulocuplumab to their treatment regimen are not required 
to participate in ADA measurements.
5.9
Outcomes Research Assessments
Not applicable.
5.10
Other Assessments 
5.10.1
Additional Research
This protocol will include residual sample storage for additional research (AR).
For All US sites:
Additional research is mandatory for all study participants, except where prohibited by IRBs/ethics 
committees, or academic/institutional requirements. Where one or more of these exceptions occurs, 
participation in the additional research should be encouraged but will not be a condition of overall 
study participation.
•
If the IRB/ethics committees and site agree to the mandatory additional research retention 
and/or collection, then the study participant must agree to the mandatory additional research 
as a requirement for inclusion in the study.
•
If optional participation is permitted and approved, then the study participants may opt out of 
the additional research retention and/or collection.
For non-US Sites
Additional research is optional for all study participants, except where retention and/or collection 
is prohibited by local laws or regulations, ethics committees, or institutional requirements. 
This collection for additional research is intended to expand the translational R&D capability at 
Bristol-Myers Squibb, and will support as yet undefined research aims that will advance our 
understanding of disease and options for treatment. It may also be used to support health authority 
requests for analysis, and advancement of pharmacodiagnostic development to better target drugs 
to the right patients.  This may also include genetic/genomic exploration aimed at exploring disease 
pathways, progression and response to treatment etc. 
All requests for access to samples or data for additional research will be vetted through a diverse 
committee of the study sponsor’s senior leaders in Research and Development (or designee) to 
ensure the research supports appropriate and well-defined scientific research activities.
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Samples kept for future research will be stored at the BMS Biorepository in Hopewell, NJ, USA 
or an independent, BMS-approved storage vendor.
•
The manager of these samples will ensure they are properly used throughout their usable life 
and will destroy the samples at the end of the scheduled storage period, no longer than fifteen 
(15) years after the end of the study or the maximum allowed by applicable law.
•
Transfers of samples by research sponsor to third parties will be subject to the recipient’s 
agreement to establish similar storage procedures.
Samples will be stored in a coded fashion, and no researcher will have access to the key. The key 
is securely held by the Investigator at the clinical site, so there is no direct ability for a researcher 
to connect a sample to a specific individual.
Further details of sample collection and processing will be provided to the site in the procedure 
manual.
Table 5.10.1-1:
Residual Sample Retention for Additional Research 
Schedule 
Sample Type
Timepoints for which residual
samples will be retained
Serum for Pharmacokinetics
All samples
Bone Marrow Aspirate
All samples
Peripheral blood collections (including serum and plasma)
All samples
5.10.2
Cytogenetic and Molecular Assessments
A central laboratory will perform the following:
Baseline cytogenetic testing - bone marrow aspirate chromosome analysis and, if 
applicable, AML prognostic panel
5.11
Results of Central Assessments
Results of PK and immunogenicity assessments will be provided in aggregate after the end of the 
study as needed. All serial ECGs will be transmitted to a central laboratory for measurement of 
intervals and classification of ECG abnormalities.
6
ADVERSE EVENTS
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a 
preexisting medical condition in a clinical investigation subject administered study drug and that 
does not necessarily have a causal relationship with this treatment. An AE can therefore be any 
unfavorable and unintended sign (such as an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of study drug, whether or not considered related to the study 
drug.
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The causal relationship to study drug is determined by a physician and should be used to assess all 
adverse events (AE). The causal relationship can be one of the following:
Related: There is a reasonable causal relationship between study drug administration and 
the AE.
Not related: There is not a reasonable causal relationship between study drug 
administration and the AE. 
The term "reasonable causal relationship" means there is evidence to suggest a causal relationship. 
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a subject. (In order to prevent reporting bias, subjects should not be 
questioned regarding the specific occurrence of one or more AEs.)
Sponsor or designee will be reporting adverse events to regulatory authorities and ethics 
committees according to local applicable laws including European Directive 2001/20/EC and FDA 
Code of Federal Regulations 21 CFR Parts 312 and 320.
6.1
Serious Adverse Events
A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose: 
•
results in death
•
is life-threatening (defined as an event in which the subject was at risk of death at the time of 
the event; it does not refer to an event which hypothetically might have caused death if it were 
more severe)
•
requires inpatient hospitalization or causes prolongation of existing hospitalization (see NOTE
below)
•
results in persistent or significant disability/incapacity
•
is a congenital anomaly/birth defect 
•
is an important medical event (defined as a medical event(s) that may not be immediately 
life-threatening or result in death or hospitalization but, based upon appropriate medical and 
scientific judgment, may jeopardize the subject or may require intervention [eg, medical, 
surgical] to prevent one of the other serious outcomes listed in the definition above. Examples 
of such events include, but are not limited to, intensive treatment in an emergency room or at 
home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization.) Potential drug induced liver injury (DILI) is also considered an important 
medical event. (See Section 6.6 for the definition of potential DILI.)
Suspected transmission of an infectious agent (eg, pathogenic or nonpathogenic) via the study drug 
is an SAE.
Although pregnancy, overdose, cancer, and potential drug induced liver injury (DILI) are not 
always serious by regulatory definition, these events must be handled as SAEs. (See Section 6.1.1
for reporting pregnancies).
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Any component of a study endpoint that is considered related to study therapy (eg, death is an 
endpoint, if death occurred due to anaphylaxis, anaphylaxis must be reported) should be reported 
as SAE (see Section 6.1.1 for reporting details).
NOTE: 
The following hospitalizations are not considered SAEs in BMS clinical studies: 
−
a visit to the emergency room or other hospital department < 24 hours, that does not result 
in admission (unless considered an important medical or life-threatening event)
−
elective surgery, planned prior to signing consent
−
admissions as per protocol for a planned medical/surgical procedure
−
routine health assessment requiring admission for baseline/trending of health status (eg, 
routine colonoscopy)
−
medical/surgical admission other than to remedy ill health and planned prior to entry into 
the study. Appropriate documentation is required in these cases
−
admission encountered for another life circumstance that carries no bearing on health status 
and requires no medical/surgical intervention (eg, lack of housing, economic inadequacy, 
caregiver respite, family circumstances, administrative reason).
−
admission for administration of anticancer therapy in the absence of any other SAEs 
(applies to oncology protocols).
6.1.1
Serious Adverse Event Collection and Reporting
Sections 5.6.1 and 5.6.2 in the Investigator Brochure (IB) represent the Reference Safety 
Information to determine expectedness of serious adverse events for expedited reporting.
Following the subject’s written consent to participate in the study, all SAEs, whether related or not 
related to study drug, must be collected, including those thought to be associated with protocol-
specified procedures. All SAEs must be collected that occur during the screening period and within 
30 days of discontinuation of dosing.
The investigator should report any SAE that occurs after these time periods and that is believed to 
be related to study drug or protocol-specified procedure. 
An SAE report should be completed for any event where doubt exists regarding its seriousness. 
If the investigator believes that an SAE is not related to study drug, but is potentially related to the 
conditions of the study (such as withdrawal of previous therapy or a complication of a study 
procedure), the relationship should be specified in the narrative section of the SAE Report Form.
SAEs, whether related or not related to study drug, and pregnancies must be reported to Sponsor
or designee within 24 hours, and the head of the study site to comply with procedures of the study 
site. SAEs must be recorded on the SAE Report Form; pregnancies on a Pregnancy Surveillance 
Form (electronic or paper forms). The preferred method for SAE data reporting collection is 
through the eCRF. The paper SAE/pregnancy surveillance forms are only intended as a back-up 
option when the eCRF system is not functioning. In this case, the paper forms are to be transmitted 
via email or confirmed facsimile (fax) transmission to:
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SAE Email Address: Refer to Contact Information list.
SAE Facsimile Number: Refer to Contact Information list.
For studies capturing SAEs through electronic data capture (EDC), electronic submission is the 
required method for reporting. The paper forms should be used and submitted immediately, only 
in the event the electronic system is unavailable for transmission. When paper forms are used, the 
original paper forms are to remain on site.
6$( 7HOHSKRQH &RQWDFW (required for SAE and pregnancy reporting): Refer to Contact 
Information list.
If only limited information is initially available, follow-up reports are required. (Note: Follow-up 
SAE reports should include the same investigator term(s) initially reported.) 
If an ongoing SAE changes in its intensity or relationship to study drug or if new information 
becomes available, a follow-up SAE report should be sent within 24 hours to Sponsor or designee 
using the same procedure used for transmitting the initial SAE report.
All SAEs should be followed to resolution or stabilization.
BMS will be reporting adverse events to regulatory authorities and ethics committees according to 
local applicable laws including European Directive 2001/20/EC and FDA Code of Federal 
Regulations 21 CFR Parts 312 and 320. A SUSAR (Suspected, Unexpected Serious Adverse 
Reaction) is a subset of SAEs and will be reported to the appropriate regulatory authorities and 
investigators following local and global guidelines and requirements.
6.2
Nonserious Adverse Events
A nonserious adverse event is an AE not classified as serious.
6.2.1
Nonserious Adverse Event Collection and Reporting
The collection of nonserious AE information should begin at initiation of study drug. Nonserious 
AE information should also be collected from the start of a placebo lead-in period or other 
observational period intended to establish a baseline status for the subjects. 
Nonserious AEs should be followed to resolution or stabilization, or reported as SAEs if they 
become serious (see Section 6.1.1). Follow-up is also required for nonserious AEs that cause 
interruption or discontinuation of study drug and for those present at the end of study treatment as 
appropriate. All identified nonserious AEs must be recorded and described on the nonserious AE 
page of the CRF (paper or electronic). 
Completion of supplemental CRFs may be requested for AEs and/or laboratory abnormalities that 
are reported/identified during the course of the study.
6.3
Laboratory Test Result Abnormalities
The following laboratory test result abnormalities should be captured on the nonserious AE CRF 
page or SAE Report Form (paper or electronic) as appropriate:
•
Any laboratory test result that is clinically significant or meets the definition of an SAE 
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•
Any laboratory test result abnormality that required the subject to have study drug discontinued 
or interrupted
•
Any laboratory test result abnormality that required the subject to receive specific corrective 
therapy.
It is expected that wherever possible, the clinical rather than laboratory term would be used by the 
reporting investigator (eg, anemia versus low hemoglobin value).
6.4
Pregnancy
If, following initiation of the study drug, it is subsequently discovered that a study subject or a 
partner of a male subject is pregnant or may have been pregnant at the time of study exposure, 
including 78 days (5 half-live s of study drug plus duration of ovulatory cycle) for a female subject 
and 138 days (5 half-lives of study drug plus duration of sperm turnover) for a partner of a male 
subject after product administration, the investigator must immediately notify the Sponsor or 
designee of this event and complete and forward a Pregnancy Surveillance Form to BMS Designee 
within 24 hours and in accordance with SAE reporting procedures described in Section 6.1.1.
In most cases, the study drug will be permanently discontinued in an appropriate manner (eg, dose 
tapering if necessary for subject safety). Please call the Sponsor or designee within 24 hours of 
awareness of the pregnancy.
In the rare event that the benefit of continuing study drug is thought to outweigh the risk, after 
consultation with Sponsor/designee, the pregnant subject may continue study drug after a thorough 
discussion of benefits and risk with the subject.
Protocol-required procedures for study discontinuation and follow-up must be performed on the 
subject unless contraindicated by pregnancy (eg, x-ray studies). Other appropriate pregnancy 
follow-up procedures should be considered if indicated.
The investigator must immediately notify the Sponsor or designee of this event and complete and 
forward a Pregnancy Surveillance Form to Sponsor or designee within 24 hours and in accordance 
with SAE reporting procedures described in Section 6.1.1. 
Follow-up information regarding the course of the pregnancy, including perinatal and neonatal 
outcome and, where applicable, offspring information must be reported on the Pregnancy 
Surveillance Form.
Any pregnancy that occurs in a female partner of a male study participant should be reported to 
Sponsor or designee. In order for BMS to collect any pregnancy surveillance information from the 
female partner, the female partner must sign an informed consent form for disclosure of this 
information. Information on this pregnancy will be collected on the Pregnancy Surveillance Form.
6.5
Overdose
An overdose is defined as the accidental or intentional administration of any dose of a product that 
is considered both excessive and medically important. All occurrences of overdose must be 
reported as an SAE (see Section 6.1.1 for reporting details.).
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6.6
Potential Drug Induced Liver Injury (DILI)
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should 
occur prior to the reporting of a potential DILI event. All occurrences of potential DILIs, meeting 
the defined criteria, must be reported as SAEs (see Section 6.1.1 for reporting details).
The criteria for identifying p-DILI events depend on whether the subject’s baseline liver 
biochemistry is normal or abnormal (see Figure 6.6-1). 
Potential drug induced liver injury is defined as: 
Figure 6.6-1:
Algorithm for p-DILI identification and mandatory SAE reporting in 
subjects with (i) normal baseline liver biochemistry, and (ii) abnormal 
baseline liver biochemistry
6.7
Other Safety Considerations
Any significant worsening noted during interim or final physical examinations, electrocardiogram, 
x-ray filming, any other potential safety assessment required or not required by protocol should 
also be recorded as a nonserious or serious AE, as appropriate, and reported accordingly. 
Since ulocuplumab contains only human protein sequences, it is unlikely to be immunogenic and 
to induce infusion or hypersensitivity reactions. Since this antibody specifically binds to CXCR4, 
this makes it less likely that such a reaction would occur. However, if such a reaction were to occur, 
it might manifest with fever, chills, rigors, headache, rash, pruritus, arthralgias, hypo or 
hypertension, bronchospasm, or other symptoms.
Abnormal liver biochemistry suggestive of p-DILI or
signs/symptoms of liver disease (eg jaundice)
Repeat liver biochemistry within <3 days 
Normal baseline liver biochemistry
ALT or AST 䍹3 xULN
+
TB 䍹2 xULN
+
No cholestatic
or other apparent 
causes identified
Abnormal baseline liver biochemistry
ALT or AST 䍹3 xULN 
+ 
䍹2 xscreening baseline 
(or <2 xscreening 
baseline but 䍹8 xULN)
+
TB 䍹2 xULN
+
No cholestatic or other 
apparent 
causes identified
p-DILI
p-DILI
AND
AND
IF repeat liver biochemistry
abnormal
AND
IF repeat liver biochemistry
abnormal
AND
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As of the 17-Feb-2014 cut-off date, infusion reactions have been reported in 1 AML subject, 3 CLL 
subjects and 1 DLBCL subject out of the 86 treated subjects in the CA212001 study and 
2 myeloma subjects out of the 42 treated subjects in the CA212002 study.
Prophylactic premedication may be given any time after the first dose of Cycle 1. However, if a
subject experiences a Grade 2 infusion reaction, the subject will be required to receive prophylactic 
premedication for subsequent infusions of ulocuplumab (Section 3.4.1).
Infusion reactions should be graded according to the NCI CTCAE v4.03 guidelines. Treatment 
recommendations are provided below and may be modified based on local treatment standards and 
guidelines, as appropriate:
For Grade 1 symptoms: (Mild reaction; infusion interruption not indicated; intervention not 
indicated)
Remain at bedside and monitor subject until recovery from symptoms. Information on prophylactic 
premedications is provided in Section 3.4.1.
For Grade 2 symptoms: (Moderate reaction, requires therapy or infusion interruption but responds 
promptly to symptomatic treatment [eg, antihistamines, nonsteroidal anti inflammatory drugs 
(NSAIDs), narcotics, corticosteroids, IV fluids]; prophylactic medications indicated for 
≤24 hours).
Stop the ulocuplumab infusion, begin an IV infusion of normal saline, and treat the subject with 
diphenhydramine 50 mg IV (or equivalent) and/or acetaminophen; remain at bedside and monitor 
subject until resolution of symptoms. Corticosteroid therapy may also be administered as 
appropriate. If the infusion is interrupted, then restart the infusion at 50% of the original infusion 
rate when symptoms resolve; if no further complications ensue after 30 minutes, the rate may be 
increased to 100% of the original infusion rate. Monitor subject closely. If symptoms recur then 
no further ulocuplumab will be administered at that visit. The amount of study drug infused must 
be recorded on the case report form (CRF). The following prophylactic premedications are 
recommended for future infusions: diphenhydramine 50 mg (or equivalent), paracetamol 
(acetaminophen) and/or corticosteroids should be administered at least 30 minutes before 
additional ulocuplumab administration. Remain at bedside and monitor subject until recovery from 
symptoms.
For Grade 3 or Grade 4 symptoms: (Severe reaction, Grade 3: prolonged [ie, not rapidly responsive 
to symptomatic medication and/or brief interruption of infusion]; recurrence of symptoms 
following initial improvement; hospitalization indicated for other clinical sequelae [eg, renal 
impairment, pulmonary infiltrates]. Grade 4: life threatening; pressor or ventilatory support 
indicated).
Immediately discontinue infusion of ulocuplumab. Begin an IV infusion of normal saline, and treat 
the subject as follows: Recommend bronchodilators, epinephrine 0.2 to 1 mg of a 1:1,000 solution 
for subcutaneous administration, 0.3 mg of a 1:1,000 solution for intramuscular administration, or 
0.1 to 0.25 mg of a 1:10,000 solution injected slowly for IV administration, and/or
diphenhydramine 50 mg IV with methylprednisolone 100 mg IV (or equivalent), as needed. The 
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subject should be monitored until the investigator is comfortable that the symptoms will not recur. 
Ulocuplumab will be permanently discontinued. Investigators should follow their institutional 
guidelines for the treatment of anaphylaxis. Remain at bedside and monitor subject until recovery 
from symptoms.
In the case of late occurring hypersensitivity symptoms (eg, appearance of a localized or 
generalized pruritus within 1 week after treatment), symptomatic treatment may be given (eg, oral 
antihistamine, or corticosteroids).
7
DATA MONITORING COMMITTEE AND OTHER EXTERNAL 
COMMITTEES
An independent data monitoring committee (DMC) will be constituted for review of safety 
information and assessment of overall benefit/risk balance in this study. Specific data to be 
reviewed and timing of the reviews by the DMC will be described in a DMC Charter. 
8
STATISTICAL CONSIDERATIONS
8.1
Sample Size Determination
The size of the study is not based on testing a formal statistical hypothesis. The Escalation Cohort 
is a Phase 1 safety phase and the sample size cannot be precisely determined and depends on the 
observed toxicities; it is estimated that a total of 6 subjects will be treated in this cohort, assuming 
600 mg and 800 mg are explored. For the Expansion Cohort (Phase 2), a sample size of 40 subjects 
per treatment group will allow estimation of the response rate with the following degree of 
precision, where response is defined by complete remission (CR/CRi=CR+CRi). A response rate 
of 0.6 will be estimated with the following 95% exact confidence interval (CI): 0.43 - 0.75. If the 
response rate is 0.45, then the associated 95% CI will be 0.29 - 0.62.
8.2
Populations for Analyses
The following populations will be defined for each cohort.
−
All Enrolled Subjects: All subjects who signed an informed consent form. Subject 
disposition will be tabulated using this dataset.
−
All Randomized Subjects (Expansion Cohort only): All subjects who signed an informed 
consent form and were randomized to either ulocuplumab 800 mg or 1000 mg in 
combination with LDAC or to LDAC alone. This dataset will be used for baseline and 
efficacy analyses.
−
All Treated Subjects: All subjects who received at least one dose of study medication
(ulocuplumab in the combination arm and LDAC in the LDAC only arm). This dataset will 
be used for safety analyses (as well as some efficacy analyses).
−
PK Subjects: All treated subjects who received at least one dose of ulocuplumab and have 
evaluable PK data.
−
Immunogenicity Subjects: All subjects treated with ulocuplumab who have baseline and at 
least one post baseline immunogenicity assessment.
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8.3
Endpoints
8.3.1
Primary Endpoint(s)
•
Phase 1 (escalation cohort): DLTs in Cycle 1, and AEs, ≥ Grade 3 AEs, AEs leading to 
discontinuation, SAEs, deaths and laboratory abnormalities in combination therapy during the 
Treatment period plus 30 days of follow-up will be the primary endpoints for this study. AEs 
will be graded according to NCI CTCAE v4.03
•
Phase 2 (expansion cohort): Investigator will assess best overall response. The primary 
endpoint will be based on the rate of Complete Remission (CR/CRi) prior to the initiation of 
any alternative therapy (including any subsequent ulocuplumab 800 mg for subjects in the 
LDAC alone arm). The primary analysis will be conducted after all patients had an opportunity 
for 6 months of follow-up. Please refer to Appendix 1 for AML response criteria.
8.3.2
Secondary Endpoint(s)
•
Phase 1 (escalation cohort): Investigator assessed best overall response prior to the initiation 
of any alternative therapy. Please refer to Appendix 1 for AML response criteria.
•
Phase 2 (expansion cohort): Safety and tolerability will be assessed through AEs, AEs leading 
to discontinuation, SAEs, deaths and laboratory abnormalities in combination therapy during 
the Treatment period plus 30 days of follow-up will be the primary endpoints for this study. 
AEs will be graded according to NCI CTCAE v4.03.
•
ADA positive for ulocuplumab. 
•
PK parameters will be determined for subjects in both escalation and expansion cohorts, 
whenever data permit:
Cmax
Maximum observed serum concentration
Ctrough
Trough observed serum concentration
Tmax
Time of maximum observed ulocuplumab serum concentration
AUC(0-T)
Area under the ulocuplumab concentration-time curve from time zero to the 
last quantifiable concentration (calculated by log- and linear-trapezoidal 
summation)
AUC(TAU)
Area under the ulocuplumab concentration-time curve in one dosing interval  
AUC(INF) 
Area under the ulocuplumab concentration-time curve from time zero to 
infinity (calculated by summing AUC(0-T) and the extrapolated area, 
computed by the quotient Clast/λz)
T-HALF
Elimination half-life, determined as 0.693/λz
CLT
Total body clearance of ulocuplumab (calculated by dividing the total dose of 
ulocuplumab by its corresponding AUC(INF) value)
Vss
Volume of distribution at steady state
AUC from the time of dosing extrapolated to infinity (AUC(INF)) after first dosing and 
T-HALF will be calculated when feasible. Individual subject PK parameter values will be 
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derived by non-compartmental methods by a validated PK analysis program. Actual times will 
be used for the analyses.
•
In Phase 2 (expansion cohort): To assess rates of Overall Remission (OR=PR+CR +CRi) as 
well as duration of complete remission (CR/ CRi) in subjects treated with ulocuplumab at two 
different dose levels 800 mg and 1000 mg in combination with LDAC.
•
In Phase 2 (expansion cohort): To assess efficacy (in terms of rates of CR/CRi and OR and 
duration of remission, respectively, in subjects treated with LDAC alone, to compare with 
historical controls of LDAC in the same patient population. Overall survival will also be 
assessed in this group.
•
Duration of remission (DoR) is defined as the time from the date of first documented CR or 
CRi to the date of death or relapse. For subjects who remain alive and have not relapsed 
following remission, DoR will be censored on the date of last relapse-related assessment prior 
to the initiation of alternative anti-cancer therapy. 
•
The primary ECG endpoint is ΔQTcF, the change from baseline in QTcF, the QT interval 
normalized using Fridericia’s heart rate correction. Other endpoints include QTcF, QT, QRS, 
PR, HR (heart rate), and QTcB as well as ΔQT, ΔQRS, ΔPR, ΔHR (heart rate), ΔQTcB, the 
associated changes from baseline. (Note: QTcB is the QT interval normalized using Bazett’s
hear rate correction.) The schedule for ECGs is given in Table 5.5.1-1 (PK, RO, ADA, and 
ECG Sampling).
•
Overall survival (OS) will also be summarized. OS is defined as the time between the first date 
of treatment and the date of death due to any cause. A subject who has not died will be censored 
at the last known alive date.
 
 
 
8.4
Analyses
The following will be analyzed separately by cohort, and by treatment group within the expansion 
cohort.
8.4.1
Demographics and Baseline Characteristics
Frequency distributions of gender, race and ECOG status will be tabulated. Summary statistics for 
age, body weight, height and body mass index will be tabulated.
8.4.2
Efficacy Analyses
Individual tumor responses will be listed by treatment and study day. Bone marrow blast and its 
percent change from baseline will be listed. 
In addition, for the expansion cohort, best overall response prior to the initiation of any alternative 
therapy (including any subsequent ulocuplumab 800 mg for subjects in the LDAC alone arm) will 
be tabulated. The rate of subjects with complete remission (CR/CRi) will be summarized by a 
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binomial response rate and corresponding two-sided 95% exact CI using the Clopper and Pearson 
method. The combined rate of subjects with responses of either CR or CRi or PR will similarly be 
summarized.
OS and DoR will be summarized descriptively using Kaplan-Meier methodology. Median values 
of OS, along with two-sided 95% CIs using the Brookmeyer and Crowley method considering a 
log-log transformation, will be calculated.
8.4.3
Safety Analyses
All recorded adverse events will be listed and tabulated by system organ class, preferred term and 
treatment. Vital signs, clinical laboratory test results and any significant physical examination 
findings will be listed and summarized by treatment. ECG readings will be evaluated by the 
Investigator and abnormalities, if present, will be listed. To assess the effects of ulocuplumab on 
heart rate, PR, QRS, QT, QTcF, and ΔQTcF intervals the frequency distribution for maximum 
QTcF, PR, QRS and the maximum ΔQTcF will be tabulated. For QTcF a linear regression of 
ΔQTcF on drug concentration will be estimated. Summary statistics will be tabulated for all ECG 
parameters and changes from baseline. The plots of mean and mean changes from baseline versus 
time or ulocuplumab concentration may be provided. A two-sided 90% confidence interval will 
be constructed for the population mean of ΔQTcF at each time point.
8.4.4
Immunogenicity Analyses
Immunogenicity status will be reported relative to baseline as ADA negative, ADA positive, and 
positive baseline. Listings for ADA positive response will be provided by treatment.
8.4.5
Pharmacokinetic Analyses and Receptor Occupancy
Summary statistics will be tabulated for the PK parameters and RO (expansion cohort only) listed 
in Section 8.3.2 by treatment and study day. For PK, geometric means and coefficients of variation 
will be presented for Cmax, AUC and CL. Medians, minimum, and maximum will be presented 
for Tmax. Means and standard deviations will be provided for the remaining PK parameters. 
Individual as well as mean concentration-time plots will be depicted.
The distribution of Ctrough concentrations will be summarized using descriptive statistics by 
treatment and study day. To assess the attainment of steady state, geometric mean Ctrough values 
will be plotted by treatment and study day.
Changes of CXCR4 RO is related to the dose and exposure of ulocuplumab. The association 
between the percent of RO and ulocuplumab serum concentration in peripheral blood and, when 
possible, bone marrow will be explored.
8.4.6
ECG Analyses
Triplicate measurements of each serial ECG will be used to obtain an average value for each time 
point. These averages will be used in the listings and statistical analyses. Baseline will be defined 
as the time point prior to dosing on the first day of Cycle 1. Summary statistics (n, mean, standard 
deviation of the mean, minimum and maximum) will be provided for all ECG intervals (QT, QTcF, 
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QTcB, QRS, PR) and for heart rate and changes relative to baseline in ECG intervals and heart 
rate, per day and time point.
A two-sided 90% confidence interval will be constructed for the population mean of ΔQTcF at 
each time point. (Change from baseline in QTcF is assumed to follow a normal distribution.) The 
frequency distribution of QTcF and ΔQTcF will be calculated for each sampling point on Cycle 1 
Day 1 and Cycle 2 Day 15. The categories for the frequency distribution will be (≤450 msec, 
451- 480 msecs, 481- 500 msecs, > 500 msecs) for QTcF and (≤30 msec, 31- 60 msec, > 60 msec) 
for ΔQTcF. ECG analyses will be conducted on the ECG evaluable population. These analyses 
will be summarized separately for each cohort.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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8.4.8
Outcomes Research Analyses
Not applicable.
8.4.9
Other Analyses
HCT-CI scores will be summarized at baseline and at end of treatment.
Cytogenetic and molecular results will be summarized at baseline only.
8.5
Interim Analyses
For the dose expansion cohort, an interim assessment of safety will be assessed by Sponsor or 
designee on the first 6 patients treated on the 1000 mg ulocuplumab/LDAC combination arm.  
These must have had an opportunity for at least 28 days of follow-up. The review will be based all 
available safety data including DLTs reported during the first 28 days of follow-up. Randomization 
to the 1000 mg ulocuplumab combination arm will be suspended until the safety review is 
complete. Randomization to the other 2 arms will continue on a 1:1 basis until a decision is reached 
to resume randomization to all 3 arms.
In addition, an interim analysis of efficacy and safety will be conducted when 60 patients (i.e., 
50% of the sample size) will have had an opportunity for 2 months of treatment and follow-up.
9
STUDY MANAGEMENT
9.1
Compliance
9.1.1
Compliance with the Protocol and Protocol Revisions
The investigator should not implement any deviation or change to the protocol without prior 
review and documented approval/favorable opinion of an amendment from the IRB/IEC (and if 
applicable, also by local health authority) except where necessary to eliminate an immediate 
hazard(s) to study subjects. 
If a deviation or change to a protocol is implemented to eliminate an immediate hazard(s) prior to 
obtaining IRB/IEC relevant approval/favorable opinion(s), the deviation or change will be 
submitted as soon as possible to:
•
IRB/IEC
•
Regulatory Authority(ies), if applicable by local regulations per national requirements
Documentation of approval/favorable opinion signed by the chairperson or designee of the 
IRB(s)/IEC(s) and if applicable, also by local health authority, must be sent to BMS.
If an amendment substantially alters the study design or increases the potential risk to the subject: 
(1) the consent form must be revised and submitted to the IRB(s)/IEC(s) via the head of the study 
site for review and approval; (2) the revised form must be used to obtain consent from subjects 
currently enrolled in the study if they are affected by the amendment; and (3) the new form must 
be used to obtain consent from new subjects prior to enrollment.
If the revision is done via an administrative letter, BMS must inform the IRB(s)/IEC(s).
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9.1.2
Monitoring
Representatives of BMS must be allowed to visit all study site locations periodically to assess the 
data quality and study integrity. On site they will review study records and directly compare them 
with source documents, discuss the conduct of the study with the investigator, and verify that the 
facilities remain acceptable. Source documents are defined as follows: screening log, subject 
identification code sheet, medical records, written informed consent, and study drug management 
sheets. Certain CRF pages and/or electronic files may serve as the source documents: such as the 
investigator assessment of efficacy.
In addition, the study may be evaluated by BMS or designee, internal auditors and government 
inspectors who must be allowed access to CRFs, source documents, other study files, and study 
facilities. BMS audit reports will be kept confidential.
The investigator must notify BMS promptly of any inspections scheduled by regulatory authorities, 
and promptly forward copies of inspection reports to BMS or designee.
9.1.2.1
Source Documentation
The Investigator is responsible for ensuring that the source data are accurate, legible, 
contemporaneous, original and attributable, whether the data are hand-written on paper or entered 
electronically. If source data are created (first entered), modified, maintained, archived, retrieved, 
or transmitted electronically via computerized systems (and/or any other kind of electronic 
devices) as part of regulated clinical trial activities, such systems must be compliant with all 
applicable laws and regulations governing use of electronic records and/or electronic signatures. 
Such systems may include, but are not limited to, electronic medical/health records (EMRs/EHRs), 
adverse event tracking/reporting, protocol required assessments, and/or drug accountability 
records.
When paper records from such systems are used in place of electronic format to perform regulated 
activities, such paper records should be certified copies. A certified copy consists of a copy of 
original information that has been verified, as indicated by a dated signature, as an exact copy 
having all of the same attributes and information as the original. 
9.2
Records
9.2.1
Records Retention
The investigator (or head of the study site in Japan) must retain all study records and source 
documents for the maximum period required by applicable regulations and guidelines, or 
institution procedures, or for the period specified by BMS or designee, whichever is longer. The 
investigator (or head of the study site in Japan) must contact BMS or designee prior to destroying 
any records associated with the study.
BMS or designee will notify the investigator (or head of the study site in Japan) when the study 
records are no longer needed.
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If the investigator withdraws from the study (eg, relocation, retirement), the records shall be 
transferred to a mutually agreed upon designee (eg, another investigator, study site, IRB/IEC). 
Notice of such transfer will be given in writing to BMS or designee.
9.2.2
Study Drug Records
Records for IP must substantiate IP integrity and traceability from receipt, preparation, 
administration, and through destruction or return. Records must be made available for review at 
the request of BMS/designee or a Health Authority.
If...
Then...
Supplied by BMS (or its vendors):
•
and guidelines and should include:
•
amount received and placed in storage area
•
amount currently in storage area
•
label identification number or batch number
•
amount dispensed to and returned by each subject, 
including unique subject identifiers
•
amount transferred to another area/site for  dispensing or 
storage
•
nonstudy disposition (eg, lost, wasted)
•
amount destroyed at study site, if applicable
•
amount returned to BMS
•
retain samples for  bioavailability/bioequivalence, if 
applicable
•
dates and initials of person responsible for 
Investigational Product dispensing/accountability, as 
per the Delegation of Authority Form.
Sourced by site, and not supplied by BMS 
or its vendors (examples include IP sourced 
from the sites stock or commercial supply, 
or a specialty pharmacy)
The investigator or designee accepts responsibility for 
documenting traceability and study drug integrity in 
accordance with requirements applicable under law and the 
SOPs/standards of the sourcing pharmacy.
These records should include:
•
label identification number or batch number
•
amount dispensed to and returned by each subject, 
including unique subject identifiers
•
dates 
and 
initials 
of 
person 
responsible 
for  
Investigational Product dispensing/accountability, as per 
the Delegation of Authority Form.
BMS or designee will provide forms to facilitate inventory control if the investigational site does 
not have an established system that meets these requirements.
9.2.3
Case Report Forms
An investigator is required to prepare and maintain adequate and accurate case histories designed 
to record all observations and other data pertinent to the investigation on each individual treated 
or entered as a control in the investigation. Data that are derived from source documents and 
reported on the CRF must be consistent with the source documents or the discrepancies must be 
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explained. Additional clinical information may be collected and analyzed in an effort to enhance 
understanding of product safety. CRFs may be requested for AEs and/or laboratory abnormalities 
that are reported or identified during the course of the study.
For sites using the Sponsor or designee electronic data capture tool, electronic CRFs will be 
prepared for all data collection fields except for fields specific to SAEs and pregnancy, which will 
be reported on the paper or electronic SAE form and Pregnancy Surveillance form, respectively. 
Spaces may be left blank only in those circumstances permitted by study-specific CRF completion 
guidelines provided by Sponsor or designee. 
The confidentiality of records that could identify subjects must be protected, respecting the privacy 
and confidentiality rules in accordance with the applicable regulatory requirement(s).
BMS and the investigator will maintain an original and a copy of the signature sheet to document 
signatures and initials of all persons authorized to make entries and/or corrections on CRFs. 
The completed CRF, including any paper or electronic SAE/pregnancy CRFs, must be promptly 
reviewed, signed, and dated by the investigator or a qualified physician who is a subinvestigator 
and who is delegated this task on the Delegation of Authority Form. Subinvestigators in Japan may 
not be delegated the CRF approval task. For electronic CRFs, review and approval/signature is 
completed electronically through the BMS electronic data capture tool. The investigator must 
retain a copy of the CRFs including records of the changes and corrections.
Each individual electronically signing electronic CRFs must meet Sponsor or designee training 
requirements and must only access the BMS electronic data capture tool using the unique user 
account provided by Sponsor or designee. User accounts are not to be shared or reassigned to other 
individuals.
9.3
Clinical Study Report and Publications
A Signatory Investigator must be selected to sign the clinical study report. 
For this protocol, the Signatory Investigator will be selected as appropriate based on the following 
criteria:
•
Subject recruitment (eg, among the top quartile of enrollers)
•
Other criteria (as determined by the study team)
The data collected during this study are confidential and proprietary to BMS or designee. Any 
publications or abstracts arising from this study must adhere to BMS’s publication requirements 
set forth in the clinical trial agreement (CTA) governing Investigator participation in the study. 
These requirements include, but are not limited to, submitting proposed publications to BMS or 
designee at the earliest practicable time prior to submission or presentation and otherwise within
the time period set forth in the CTA.
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10
GLOSSARY OF TERMS
Term
Definition
Complete Abstinence
If one form of contraception is required, Complete Abstinence is defined 
as complete avoidance of heterosexual intercourse and is an acceptable 
form of contraception for all study drugs. Female subjects must continue 
to have pregnancy tests. Acceptable alternate methods of highly effective 
contraception must be discussed in the event that the subject chooses to 
forego complete abstinence.
If two forms of contraception is required, Complete abstinence is defined 
as complete avoidance of heterosexual intercourse and is an acceptable 
form of contraception for all study drugs. Subjects who choose complete 
abstinence are not required to use a second method of contraception, but 
female subjects must continue to have pregnancy tests. Acceptable 
alternate methods of highly effective contraception must be discussed in 
the event that the subject chooses to forego complete abstinence.
Expanded definition Complete abstinence as defined as complete 
avoidance of heterosexual intercourse is an acceptable form of 
contraception for all study drugs. This also means that abstinence is the 
preferred and usual lifestyle of the patient. This does not mean periodic 
abstinence (eg, calendar, ovulation, symptothermal, profession of 
abstinence for entry into a clinical trial, post-ovulation methods) and 
withdrawal, which are not acceptable methods of contraception. Subjects 
who choose complete abstinence are not required to use a second method 
of contraception, but female subjects must continue to have pregnancy 
tests. Acceptable alternate methods of highly effective contraception must 
be discussed in the event that the subject chooses to forego complete 
abstinence
Serious Adverse Event
Serious adverse event defined as any untoward medical occurrence that at 
any dose: results in death; is life threatening (defined as an event in which 
the subject was at risk of death at the time of the event; it does not refer to 
an event which hypothetically might have caused death if it were more 
severe), requires inpatient hospitalization or causes prolongation of 
existing hospitalization, results in persistent or significant 
disability/incapacity, is a congenital anomaly/birth defect, is an important 
medical event (defined as a medical event(s) that may not be immediately 
life threatening or result in death or hospitalization but, based upon 
appropriate medical and scientific judgment, may jeopardize the subject 
or may require intervention [eg, medical, surgical] to prevent one of the 
other serious outcomes listed in the definition above). Examples of such 
events include, but are not limited to, intensive treatment in an emergency 
room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization). For reporting purposes 
only, BMS also considers the occurrence of pregnancy, overdose 
(regardless of association with an AE), and cancer as important medical 
events.
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11
LIST OF ABBREVIATIONS
Term
Definition
ADA
anti-drug antibody
ADCC
antibody-dependent cell-mediated cytotoxicity
AE
adverse event
ALT
alanine aminotransferase
AML
acute myeloid leukemia
AML IWG 2003
2003 International Working Group Response Criteria for AML
ANC
absolute neutrophil count
AST
aspartate aminotransferase
AUC(INF)
area under the concentration-time curve from time zero extrapolated to 
infinite time
AUC(0-T)
area under the concentration-time curve from time zero to the time of the 
last quantifiable concentration
AUC(TAU)
area under the concentration-time curve in one dosing interval
BID
twice daily
BMI
body mass index
BMS
Bristol-Myers Squibb
CDC
complement-dependent cytotoxicity activity
CLL
chronic lymphocytic leukemia
CLT
total body clearance
Cmax
maximum observed concentration
Cmin
trough observed concentration
CR
complete remission
CRi
complete remission with incomplete blood count recovery
CRF
case report form
CRP
C-reactive protein
Ctrough
Trough observed plasma concentration
CXCL12
C-X-C motif ligand 12
CXCR4
C-X-C chemokine receptor type 4
DILI
drug induced liver injury
DLBCL
diffuse large B-cell lymphoma
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Term
Definition
DLCO
diffusing capacity of the lungs for carbon monoxide 
DLT
dose limiting toxicity
DoR
duration of response
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EDC
electronic data capture
FL
follicular lymphoma
FSH
follicle stimulating hormone
GCP
good clinical practice
HCT-CI
hematopoietic cell transplant-comorbidity index
HIV
human immunodeficiency virus
HRT
hormone replacement therapy
ICH
International Conference on Harmonisation 
IEC
Independent Ethics Committee
IFN
interferon
IgG4
immunoglobulin G4
IL
interleukin
IMP
investigational medicinal products
IP
investigational products
IRB
Institutional Review Board
IV
intravenous
IWRS
Interactive Web Response System
LDAC
low dose cytarabine
MEC
mitoxantrone, etoposide and cytarabine
MM
multiple myeloma
MTD
maximum tolerated dose
mTPI
modified Toxicity Probability Interval
N/A
not applicable
NCI CTCAE 
v4.03
National Cancer Institute Common Terminology Criteria for Adverse 
Events Version 4.03
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Term
Definition
OR
overall remission
OS
overall survival
PD
pharmacodynamics
PD
progressive disease
PK
pharmacokinetics
PR
partial remission
RBC
red blood cell
RO
receptor occupancy
SAE
serious adverse event
SC
subcutaneously
SOP
standard operating procedures
T-HALF
half life
Tmax
time of maximum observed concentration
TNF
tumor necrosis factor
Vss
apparent volume of distribution at steady state
WBC
white blood cell
WHO
World Health Organization
WOCBP
women of childbearing potential
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APPENDIX 1
2003 IWG RESPONSE CRITERIA FOR AML
Table 1:
2003 IWG Response Criteria for AML
Response
Definition
Criteria
CR
Morphologic
leukemia-free state
Bone Marrow: < 5% blasts with normal maturation of cell lines.
Peripheral blood:
- Absolute neutrophil count > 1000/μL
- Platelets ≥100,000/μL
- Blasts 0%
No residual evidence of extramedullary disease.
Independent of RBC transfusions.
No Auer rods present in bone marrow blasts.
CRi
Morphologic
leukemia –free state 
with incomplete
blood count
recovery
Same criteria as CR except:
platelet count < 100,000/μL and/or absolute neutrophil count < 1000/μL
PR
Regression of
leukemia
≥50% decrease (from baseline) in the percentage of blasts to 5% to 25%
in the bone marrow aspirate and all the hematologic values for CR. Bone
marrow blasts <5% but with Auer rods present.
Treatment 
Failure (TF)
Failing to achieve a
complete or partial 
remission
Failure to achieve a CR, CRi, or PR during the treatment period. Last 
posttreatment peripheral blood smear and/or bone marrow aspirate/biopsy 
show persistent leukemia.
Relapse 
(after 
CR/CRi)
Morphologic
recurrence of
leukemia
Reappearance of leukemic blasts in the peripheral blood or ≥5% blasts in 
the bone marrow not attributed to any other cause. Reappearance or 
development of cytologically proven extramedullary disease.
PD 
(after PR)
Morphologic
increase in leukemia
50% increase (from nadir) in either leukemia peripheral blood
involvement (absolute count), bone marrow leukemia infiltrate, or
extramedullary site of disease, if applicable.
Abbreviations: CR = complete remission; CRi = complete remission with incomplete blood count recovery; 
PR = partial remission; PD = progressive disease; RBC = red blood cells.
Source: Cheson BD, Bennett JM, Kopecky KJ et al. Revised Recommendations of the International Working Group 
for diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic 
Trials in Acute Myeloid Leukemia. J Clin Oncol 2003: 21: 4642-4649.
Leukemia responses will be assessed after each cycle as follows: CR, CRi, PR, TF, PD, or 
Relapse as described above. Local laboratory reports supporting assessments will be sent to 
BMS. Subjects without local laboratory reports will be recorded as not done.
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APPENDIX 2
SIMULATION TO EXAMINE MTPI VS. TRADITIONAL 3+3 
DESIGN FOR DOSE ESCALATION STUDY WITH 2 DOSE 
LEVELS
The dose escalation part of the study utilizes the mTPI method. The mTPI uses a set of decision 
rules guided by simple Bayesian models and requires a definition of an equivalence interval (EI), 
in which any dose is considered close to the true maximum tolerated dose (MTD). For this study, 
the EI is defined as [15%, 25%] with the target toxicity rate of 20%. With this method, there are 
3 intervals in the toxicity probability scale: (0, 15%) that is considered lower than the target 
toxicity rate, [15, 25%] that is considered within the toxicity target range, and (25, 100%) that is 
considered toxic. 
Using this mTPI design, initially 3 eligible subjects will be treated at the dose level of 600 mg. 
Any additional subjects will not be added to the same dose level, ie a total number of 3 subjects 
will be treated for a given dose level. A decision to stop the enrollment or to consider the next 
higher dose level (800 mg), will be guided by the number of subjects with dose-limiting 
toxicities (DLTs) observed (see Table 1).
Table 1: 
Guidance for Safety Monitoring Based on Observed DLTs
Number of Subjects Treated at given dose level
3
Number of Subjects with DLTs
0
E
1
E
2
DU
3
DU
At Starting Dose (600 mg):
E: Escalate and enroll subjects to the next higher dose level
DU: The current dose is too toxic. Discuss of proceeding with the next lower dose level
At Maximum Dose (800 mg):
E: Current dose level is safe and stop enrollment
DU: The current dose is too toxic.
Simulations were conducted to examine the performances of the mTPI design and the traditional 
escalation 3+3 design for this study. The 3+3 design starts from the lower dose level (600 mg); 
adapts every cohort of 3 patients; considers the next dose level if unacceptable toxicity rate 
observed. The “1/3” rule has been used in the design, in the way below:
Initially, 3 subjects per level will be treated. If 0 out of 3 subjects experiences DLT, 3 subjects 
will be treated at the next higher dose level. If 1 out of 3 subjects experiences DLT, an additional 
3 subjects at the same dose level will be treated. If 1 out of 6 subjects experiences DLT at a level, 
3 subjects will be treated at the next higher dose level. If ≥2 out of 6 subjects, or ≥2 out of 
initial 3 subjects experience DLT at a dose level, then the MTD is considered to have been 
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exceeded, and 3 more subjects will be treated at the previous dose unless 6 subjects have already 
been treated at that dose. The MTD is defined as the highest dose at which not more than 1out of 
6 subjects experience DLT.
The mTPI design is knowledge-driven, which assumes a target toxicity rate. On the contrary, the 
traditional 3+3 design is algorithm-driven, which uses the "1/3" rule.
Simulation Implementation:
•
10,000 simulated trials
•
Target toxicity rate for the mTPI design: 20% with EI = [15, 25%]
•
mTPI design and traditional 3+3 design as described above
Toxicity Scenarios for Each Dose Level:
Dose levels
1
2
3
4
5
6
600 mg
0.10
0.10
0.15
0.10
0.15
0.20
800 mg
0.15
0.20
0.20
0.25
0.25
0.25
Table 2: 
Simulation Results Summary
Scenario 1
% Selected
Average
Toxicity rate
Average
Total number
of Subjects
Under 600 mg
600 mg
800 mg
0.1
0.15
mTPI
3.0 
5.9 
91.1 
12.4 
5.9 
Traditional 3+3
9.6 
19.5 
70.9 
12.8 
9.5 
Note: mTPI design selects the correct dose (800 mg) more frequently than the traditional designs (91% vs 71%);  
the Traditional design selects sub-optimal dose (600 mg and under 600 mg) more frequently (9% vs 29%); the 
average toxicity rates for mTPI is slightly less than the traditional design; the average total number of subjects 
for mTPI is less than the traditional design.
Scenario 2
% Selected
Average
Toxicity rate
Average
Total number
of Subjects
Under 600 mg
600 mg
800 mg
0.1
0.2
mTPI
3.0 
10.2 
86.9 
14.9 
5.9 
Traditional 3+3
10.0 
30.3 
59.7 
15.3 
9.6 
Note: mTPI design selects the correct dose (800 mg) more frequently than the traditional designs (87% vs 60%);  
the Traditional design selects sub-optimal dose (600 mg and under 600 mg) more frequently (13% vs 40%); the 
average toxicity rates for mTPI is slightly less than the traditional design; the average total number of subjects 
for mTPI is less than the traditional design.
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Scenario 3
% Selected
Average
Toxicity rate
Average
Total number
of Subjects
Under 600 mg
600 mg
800 mg
0.15
0.2
mTPI
6.1 
9.8 
84.1 
17.4 
5.9 
Traditional 3+3
20.0 
26.6 
53.3 
17.5 
9.2 
Note: mTPI design selects the correct dose (800 mg) more frequently than the traditional designs (84% vs 53%);  
the Traditional design selects sub-optimal dose (600 mg and under 600 mg) more frequently (16% vs 47%); the 
average toxicity rates for mTPI is slightly less than the traditional design; the average total number of subjects for 
mTPI is less than the traditional design.
Scenario 4
% Selected
Average
Toxicity rate
Average
Total number
of Subjects
Under 600 mg
600 mg
800 mg
0.1
0.25
mTPI
2.2 
15.3 
82.5 
17.4 
5.9 
Traditional 3+3
9.7 
41.7 
48.6 
17.7 
9.8 
Note: mTPI design selects the correct dose (800 mg) more frequently than the traditional designs (83% vs 49%);  
the Traditional design selects sub-optimal dose (600 mg and under 600 mg) more frequently (18% vs 51%); the 
average toxicity rates for mTPI is slightly less than the traditional design; the average total number of subjects for 
mTPI is less than the traditional design.
Scenario 5
% Selected
Average
Toxicity rate
Average
Total number
of Subjects
Under 600 mg
600 mg
800 mg
0.15
0.25
mTPI
5.8 
14.8 
79.4 
19.8 
5.8 
Traditional 3+3
20.3 
36.9 
42.8 
19.8 
9.4 
Note: mTPI design selects the correct dose (800 mg) more frequently than the traditional designs (80% vs 43%);  
the Traditional design selects sub-optimal dose (600 mg and under 600 mg) more frequently (21% vs 57%); the 
average toxicity rates for mTPI is the same as the traditional design; the average total number of subjects for 
mTPI is less than the traditional design.
Scenario 6
% Selected
Average
Toxicity rate
Average
Total number
of Subjects
Under 600 mg
600 mg
800 mg
0.2
0.25
mTPI
11.3 
13.9 
74.8 
22.3 
5.7 
Traditional 3+3
31.9 
30.2 
37.9 
22.3 
8.7 
Note: mTPI design selects the correct dose (800 mg) more frequently than the traditional designs (75% vs 38%);  
the Traditional design selects sub-optimal dose (600 mg and under 600 mg) more frequently (25% vs 62%); the 
average toxicity rates for mTPI is the same as the traditional design; the average total number of subjects for 
mTPI is less than the traditional design.
In summary, the mTPI design selects the correct dose (800 mg) more frequently than the 
traditional 3+3 design for all the scenarios under the true toxicity rate within EI evaluated. The 
average toxicity rates for mTPI design are similar to the rates of the traditional designs and closer 
to the target toxicity rate of 20% in most cases. The average of total number of subjects for mTPI 
design is less than the traditional designs in all cases. The traditional 3+3 design is more 
conservative and may select sub-optimal dose frequently.
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APPENDIX 3
WHO CLASSIFICATION OF AML
Table 1:
WHO Classification of AML
Acute myeloid leukemia
Acute myeloid leukemia with recurrent genetic abnormalities
AML with t(8;21)(q22;q22); RUNX1-RUNX1T1
AML with inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11
AML with t(9;11)(p22;q23); MLLT3-MLL
AML with t(6;9)(p23;q34); DEK-NUP214
AML with inv(3)(q21q26.2) or t(3;3)(q21;q26.2); RPN1-EVI1
AML (megakaryoblastic) with t(1;22)(p13;q13); RBM15-MKL1
AML with mutated NPM1
Provisional entity: AML with BCR-ABL1
AML with biallelic mutations CEBPA
Provisional entity: AML with mutated RUNX1
Acute myeloid leukemia with myelodysplasia-related changes
Therapy-related myeloid neoplasms
Acute myeloid leukemia, not otherwise specified
AML with minimal differentiation
AML without maturation
AML with maturation
Acute myelomonocytic leukemia
Acute monoblastic/monocytic leukemia
Pure erythroid leukemia
Acute megakaryoblastic leukemia
Acute basophilic leukemia
Acute panmyelosis with myelofibrosis
Myeloid sarcoma
Note: Subjects with APL will be excluded from this study.
Source(s): Swerdlow SH, Campo E, Harris NI et al. WHO Classification of Tumours of Haematopoietic and 
Lymphoid Tissues, Fourth Edition. Lyon: IARC press; 2008.
Arber DA, Orazi A, Hasserjian R et al. The 2016 revision to the World Health Organization classification of 
myeloid neoplasms and acute leukemia. Blood 2016: 127: 2391-2405.
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APPENDIX 4
ECOG PERFORMANCE STATUS
Grade
ECOG
0
Fully active, able to carry on all pre-disease performance without 
restriction
1
Restricted in physically strenuous activity but ambulatory and able to 
carry out work of a light or sedentary nature, e.g., light house work, 
office work
2
Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than 50% of waking hours
3
Capable of only limited self-care, confined to bed or chair more than 
50% of waking hours
4
Completely disabled. Cannot carry on any self-care. Totally confined to 
bed or chair
5
Dead
Source: Oken MM, Creech RH, Tormey DC et al. Toxicity and Response Criteria of the Eastern Cooperative 
Oncology Group. Am J Clin Oncol 1982;5:649-655.
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APPENDIX 5
WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND 
METHODS OF CONTRACEPTION
DEFINITIONS
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile. Permanent sterilization methods include hysterectomy, bilateral 
salpingectomy, and bilateral oophorectomy.
Women in the following categories are not considered WOCBP
•
Premenarchal
•
Premenopausal female with 1 of the following:
−
Documented hysterectomy
−
Documented bilateral salpingectomy
−
Documented bilateral oophorectomy
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview.
•
Postmenopausal female
−
A postmenopausal state is defined as 12 months of amenorrhea in a woman over age 45 
years in the absence of other biological, physiological or medical causes. In addition, 
females under the age of 55 years must have a serum follicle stimulating hormone, (FSH) 
level > 40 mIU/mL to confirm menopause.
Note: Females treated with hormone replacement therapy, (HRT) are likely to have artificially 
suppressed FSH levels and may require a washout period in order to obtain a physiologic FSH 
level. The duration of the washout period is a function of the type of HRT used. The duration of 
the washout period below are suggested guidelines and the investigators should use their 
judgement in checking serum FSH levels. 
•
1 week minimum for vaginal hormonal products (rings, creams, gels)
•
4 week minimum for transdermal products
•
8 week minimum for oral products
Other parenteral products may require washout periods as long as 6 months. If the serum FSH 
level is > 40 mIU/ml at any time during the washout period, the woman can be considered 
postmenopausal.
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CONTRACEPTION GUIDANCE FOR FEMALE PARTICIPANTS OF CHILD BEARING 
POTENTIAL
Women  must follow instructions for methods of contraception for the duration of treatment with 
study drugs, ulocuplumab and cytarabine (LDAC), plus 5 half-lives of the study drug (48 days) 
plus 30 days (duration of ovulatory cycle) for a total of 78 days post-treatment completion. 
Local laws and regulations may require use of alternative and/or additional contraception 
methods.
Highly Effective Contraceptive Methods That Are User Dependent 
Failure rate of <1% per year when used consistently and correctly.a
•
Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulationb 
−
oral 
−
intravaginalc
−
transdermalc
•
Progestogen-only hormonal contraception associated with inhibition of ovulationb 
−
oral 
−
injectablec
Highly Effective Methods That Are User Independent
•
Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulation b,c
•
Intrauterine device (IUD)d
•
Intrauterine hormone-releasing system (IUS)d
•
Bilateral tubal occlusion
•
Vasectomized partner 
A vasectomized partner is a highly effective contraception method provided that the partner 
is the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. 
If not, an additional highly effective method of contraception should be used. 
•
Sexual abstinence
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study drug. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study 
and the preferred and usual lifestyle of the participant.
•
It is not necessary to use any other method of contraception when complete abstinence is 
elected. 
•
WOCBP participants who choose complete abstinence must continue to have pregnancy 
tests, as specified in Section 2. 
•
Acceptable alternate methods of highly effective contraception must be discussed between 
the subject and the investigator in the event that the WOCBP participants chooses to 
forego complete abstinence 
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NOTES: 
a Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent 
with local regulations regarding the use of contraceptive methods for participants participating in clinical 
studies. 
b Hormonal contraception may be susceptible to interaction with the study drug, which may reduce the efficacy 
of the contraceptive method.  Hormonal contraception is permissible only when there is sufficient evidence 
that the IMP and other study medications will not alter hormonal exposures such that contraception would be 
ineffective or result in increased exposures that could be potentially hazardous.  In this case, alternative 
methods of contraception should be utilized. 
c These methods are not approved nor certified in Japan.
d
Intrauterine devices and intrauterine hormone releasing systems are acceptable methods of contraception in 
the absence of definitive drug interaction studies when hormone exposures from intrauterine devices do not 
alter contraception effectiveness
Less Than Highly Effective Contraceptive Methods That Are User Dependent 
Failure rate of >1% per year when used consistently and correctly.
•
Male or femalec condom with or without spermicide.  Male and female condoms cannot be 
used simultaneously
•
Diaphragm with spermicidec
•
Cervical cap with spermicidec
•
Vaginal Sponge with spermicidec
•
Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the 
primary mechanism of action
Unacceptable Methods of Contraception
•
Periodic abstinence (calendar, symptothermal, post-ovulation methods)
•
Withdrawal (coitus interruptus).
•
Spermicide only c
•
Lactation amenorrhea method (LAM)
These methods are not approved nor certified in Japan.
CONTRACEPTION GUIDANCE FOR MALE PARTICIPANTS WITH PARTNER(S) OF 
CHILD BEARING POTENTIAL.
Male participants with female partners of childbearing potential are eligible to participate if they 
agree to the following during the treatment and until the end of relevant systemic exposure.
•
Inform any and all partner(s) of their participation in a clinical drug study and the need to 
comply with contraception instructions as directed by the investigator.
Males who are sexually active with WOCBP must agree to follow instructions for methods of 
contraception for the duration of treatment with study drugs, ulocuplumab and cytarabine
(LDAC), plus 5 half-lives of the study drug (48 days) plus 90 days (duration of sperm turnover) 
for a total of 138 days post-treatment completion.
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COLLECTION OF PREGNANCY INFORMATION
Guidance for collection of Pregnancy Information and outcome of pregnancy on the Pregnancy 
Surveillance Form is provided in Section 9.2.3 and the Appendix for Adverse Events and Serious 
Adverse Events Definitions and procedures for Evaluating, Follow-up and Reporting
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APPENDIX 6
HEMATOPOIETIC CELL TRANSPLANTATION (HCT) –
SPECIFIC COMORBIDITY INDEX
Comorbidity
Definition of Comorbidity
Score
Arrhythmia
Atrial fibrillation or flutter, sick sinus syndrome, or ventricular 
arrhythmias
1
Cardiac
Coronary artery disease (one or more vessel-coronary artery stenosis 
requiring medical treatment, stent, or bypass graft); congestive heart 
failure, myocardial infarction,
or EF ≤50%
1
Inflammatory bowel disease
Crohn disease or ulcerative colitis
1
Diabetes 
Requiring treatment with insulin or oral hypoglycemics but not diet 
alone
1
Cerebrovascular disease
Transient ischemic attack or cerebrovascular accident
1
Psychiatric disturbance
Depression or anxiety requiring psychiatric consult or treatment
1
Hepatic, mild
Chronic hepatitis, bilirubin > ULN to 1.5 x ULN, or AST/ALT 
> ULN to 2.5 x ULN
1
Obesity
Patients with a body mass index > 35 kg/m2
1
Infection
Requiring continuation of antimicrobial treatment after day 0
1
Rheumatologic
SLE, RA, polymyositis, mixed CTD, or polymyalgia rheumatica
2
Peptic ulcer
Requiring treatment
2
Moderate/severe renal
Serum creatinine > 2 mg/dL, on dialysis, or prior renal 
transplantation
2
Moderate pulmonary
DLco and/or FEV1 66%-80% or dyspnea on slight activity
2
Prior solid tumor
Treated at any time point in the patient’s past history, excluding
nonmelanoma skin cancer
3
Heart valve disease
Except mitral valve prolapse
3
Severe pulmonary
DLco and/or FEV1 ≤65% or dyspnea at rest or requiring oxygen
3
Moderate/severe hepatic‡
Liver cirrhosis, bilirubin > 1.5 x ULN, or AST/ALT > 2.5 x ULN
3
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