Clinical trial NCT01829711
Conditions: Leukemia, Hairy Cell
Keywords: Moxetumomab Pasudotox CAT-8015 Anti-cd22 recombinant immunotoxin Biologic Therapy Monoclonal Antibody Pseudomonas Exotoxin Targeted Therapy
Sponsor: MedImmune LLC
Start date: 2013-04-29; Completion date: 2019-04-29
Enrollment: 80 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Background:

\- Moxetumomab pasudotox is an experimental non-chemotherapy cancer treatment drug. It targets CD22, a molecule on the surface of essentially all hairy cell leukemia cells. Moxetumomab pasudotox binds to CD22, goes into the cell, and releases a toxin which kills the cell. In a phase I trial it had activity in relapsed/refractory hairy cell leukemia with safety profile supporting further clinical study (http://ncbi.nlm.nih.gov/pubmed/22355053). This is a phase III multicenter trial designed to confirm these results.

Detailed description:
Background:

* Hairy cell leukemia (HCL) is an indolent B-cell leukemia comprising 2% of all leukemias, or approximately 900 of the 44,000 new cases of leukemia/year in the US
* Over the last two decades, immunotoxin research has accumulated to support a role for CD22-targeted therapy in the treatment of HCL.
* Moxetumomab pasudotox is a recombinant immunotoxin containing an Fv fragment of an anti-CD22 monoclonal antibody and truncated Pseudomonas exotoxin.
* Moxetumomab pasudotox has demonstrated a high complete response (CR) rate in patients with chemoresistant HCL and has shown activity in pediatric acute lymphoblastic leukemia as well.
* Modification of the structure of moxetumomab pasudotox has greatly improved binding and cytotoxicity toward CD22 expressing malignant cells compared to the precursor molecule. Preclinical and clinical studies have demonstrated that this increase in binding affinity results in improved antitumor activity and tolerability
* Currently there are no approved agents with significant efficacy for HCL patients after failure of standard therapy

Design:

* This is a multicenter, single-arm study of moxetumomab pasudotox in patients with relapsed/refractory hairy cell leukemia.
* 77 patients will be enrolled to receive moxetumomab pasudotox intravenously (IV) on days 1, 3 and 5 of each 28 day cycle for a maximum of 6 cycles or until disease progression, unacceptable toxicity occurs, the subject begins alternate therapy, or documented CR (for subjects who have no assessable minimal residual disease and not to exceed 6 cycles). If less than or equal to 2 of the first 25 patients do not achieve durable CR, no additional patients will be accrued.
* The overall IRB accrual ceiling is currently set at 80 to allow for a small number of patients that cannot be assessed for response.

Arms: arm 1: Patients will receive Moxetumomab Pasudotox intravenously (IV) over 30 minutes on days 1, 3, 5 of each 28 day cycle for a maximum of 6 cycles or until disease progression, unacceptable toxivity, initiation of alternate therapy or documented CR.
Interventions: intervention 1: Moxetumomab pasudotox intervention 2: IV Bag Protectant for Moxetumomab pasudotox
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_001.pdf: 
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A Pivotal Multicenter Trial of Moxetumomab Pasudotox
in Relapsed/Refractory Hairy Cell Leukemia
Sponsor Protocol Number: CD-ON-CAT-8015-1053
Application Number:
 EudraCT number 2014-003233-26
Investigational Product:
Moxetumomab pasudotox
Sponsor:
MedImmune, LLC, a wholly owned subsidiary of AstraZeneca, 
One MedImmune Way, Gaithersburg, Maryland, 20878, USA
Medical Monitor:
 
 
Contract
Research Organization:
Protocol History, Date
Original Protocol, 14Feb2013
Amendment 1, 26Mar2013
Amendment 2, 20Feb2014
Amendment 3, 09Jun2014
Amendment 4, 12Aug2014
Amendment 5, 02Oct2014
Amendment 6, 22Jan2015
Administrative Change 1, 11Mar2015
Amendment 7, 23Apr2015
Amendment 8, 06Jan2017
Amendment 9, 29Mar2017


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PRÉCIS
Background:
•
Hairy cell leukemia (HCL) is an indolent B-cell leukemia comprising 2% of all 
leukemias (Bouroncle, 1994; Kreitman and Cheson, 1999), or approximately 900 of the 
44,000 new cases of leukemia/year in the US (Jemal et al, 2007).
•
Over the last two decades, immunotoxin research has accumulated to support a role for 
CD22-targeted therapy in the treatment of HCL.
•
Moxetumomab pasudotox is a recombinant immunotoxin containing a variable domain
(Fv) fragment of an anti-CD22 monoclonal antibody and truncated Pseudomonas 
exotoxin.
•
Moxetumomab pasudotox has demonstrated a high complete response (CR) rate in 
patients with chemoresistant HCL and has shown activity in pediatric acute 
lymphoblastic leukemia as well.
•
Modification of the structure of moxetumomab pasudotox has greatly improved binding 
and cytotoxicity toward CD22 expressing malignant cells compared to the precursor 
molecule.  Preclinical and clinical studies have demonstrated that this increase in binding 
affinity results in improved antitumor activity and tolerability.
•
At the time of study start, 114 patients have been treated with moxetumomab pasudotox, 
including 48 with HCL. Moxetumomab pasudotox was generally well tolerated in HCL 
patients with no maximum tolerated dose (MTD) defined and some patients treated for 
over a year.
•
Currently there are no approved agents with significant efficacy for HCL patients after 
failure of standard therapy.
Objectives:
•
The primary objective of this study is to determine the rate of durable complete response 
(CR) in multiply relapsed HCL with moxetumomab pasudotox.  To meet the primary 
endpoint, patients will need to meet standard criteria for CR by analysis of blood, bone 
marrow and imaging, and maintain a hematologic remission (HR), namely the blood 
counts needed for CR, for >180 days.
•
Secondary objectives include determining the overall response rate (ORR), progression-
free survival (PFS), time to treatment failure (TTF), duration of responses (CR and partial 
response [PR]), confirming tolerability and safety, and evaluating immunogenicity and 
pharmacokinetics of moxetumomab pasudotox.


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Eligibility:
•
Histologically confirmed, immunotoxin-naïve HCL or HCL variant with a need for 
therapy based on at least one of the following criteria:
◦
neutrophils < 1.0 x 109/L
◦
platelets < 100 x 109/L
◦
hemoglobin < 10 g/dL
◦
symptomatic splenomegaly.
•
Have had at least 2 prior systemic therapies, including 2 courses of a purine nucleoside 
analog (PNA), or 1 course of either rituximab or BRAF inhibitor following a single prior 
course of PNA.
•
Age ≥ 18 years.
Design:
•
This is a multicenter, single-arm study of moxetumomab pasudotox in patients with 
relapsed or refractory HCL.
•
Seventy- seven patients will be enrolled to receive 40 μg/kg moxetumomab pasudotox, 
intravenous (IV) on Days 1, 3 and 5 of each 28 day cycle for a maximum of 6 cycles or 
until disease progression, unacceptable toxicity occurs, the subject begins alternate 
therapy, or documented CR (for subjects who have no assessable minimal residual 
disease and not to exceed 6 cycles). If ≤ 2 of the first 25 patients do not achieve durable 
CR, no additional patients will be accrued.
•
The primary endpoint is to determine the durable complete response (CR) rate of 
moxetumomab pasudotox with a minimum duration of >180 days. A durable CR will be 
defined as one in which HR, namely the blood counts required for CR, are maintained for 
>180 days. Disease assessments for determining CR include bone marrow examination, 
cross-sectional imaging, and peripheral blood evaluation. Recurrent sustained (non-
transient) cytopenias, particularly during the first 6 months of CR, will prompt a repeat 
bone marrow study to confirm relapse. The durable CR rate and its 95% confidence 
interval (CI) will be constructed using the exact probability method (Clopper-Pearson 
exact interval) in the Intent-to-Treat population. With 77 patients enrolled, there will be 
90% power to detect a difference between 28% and 13% (expected CR rate from best 
alternative non-chemotherapy treatment, rituximab) durable CR rates using a 2-sided 
significance level of 0.05.
•
The overall estimated accrual is 80 to allow for a small screen-failure rate.


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TABLE OF CONTENTS
1
OBJECTIVES ...............................................................................................................10
1.1
Primary Objectives .............................................................................................10
1.2
Secondary Objectives .........................................................................................10
2
BACKGROUND...........................................................................................................10
2.1
Hairy Cell Leukemia...........................................................................................10
2.2
IND Agent - Moxetumomab pasudotox .............................................................11
2.3
Rationale.............................................................................................................13
3
PATIENT SELECTION................................................................................................18
3.1
Eligibility Criteria...............................................................................................18
3.1.1Inclusion Criteria ........................................................................................18
3.1.2Exclusion Criteria .......................................................................................19
3.2
Inclusion of Women and Minorities...................................................................21
3.3
Protocol Evaluation.............................................................................................21
3.3.1Performed Within 4 Weeks Prior to Treatment..........................................21
3.3.2Pre-Cycle before Subsequent Cycles (Day -3 to Day 1) ............................22
3.3.3During Cycle...............................................................................................23
3.3.4Tests in Follow-up After Treatment Ends: .................................................24
3.3.4.1
All patients 28-42 days after the first day of dosing of prior 
cycle (end of treatment assessment)...........................24
3.3.4.2
Follow-up for those in Complete Response..............................25
3.3.4.3
For those not in Complete Response ........................................25
3.3.4.4
For all patients in follow-up......................................................25
4
REGISTRATION PROCEDURES...............................................................................26
5
TREATMENT PLAN ...................................................................................................26
5.1
Agent Administration .........................................................................................26
5.1.1Moxetumomab pasudotox...........................................................................26
5.1.2Reporting Product Complaints ...................................................................28
5.2
General Concomitant Medication and Supportive Care Guidelines...................29
5.2.1Concomitant Medications...........................................................................29
5.2.2Supportive Care ..........................................................................................30
5.2.2.1
Infections/Fever and Neutropenia.............................................30
5.2.2.2
Blood Product Support..............................................................30
5.2.2.3
Cytokine Support ......................................................................30
5.2.2.4
Capillary Leak Syndrome .........................................................30
5.2.2.5
Hemolytic Uremic Syndrome ...................................................31
5.2.2.6
Ocular Events............................................................................31
5.3
Duration of Therapy............................................................................................32


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5.4
Duration of Follow Up........................................................................................33
5.5
Off Study Criteria ...............................................................................................33
5.5.1Study Timetable and End of Study.............................................................34
6
DOSING DELAYS/DOSE MODIFICATIONS...........................................................34
7
ASSESSMENT OF SAFETY .......................................................................................35
7.1
Definition of Adverse Events .............................................................................35
7.2
Definition of Serious Adverse Events ................................................................36
7.3
Definition of Adverse Events of Special Interest ...............................................36
7.3.1Capillary Leak Syndrome...........................................................................37
7.3.2Thrombotic Microangiopathy/Hemolytic Uremic Syndrome.....................38
7.3.3Ocular Events..............................................................................................40
7.4
Recording of Adverse Events .............................................................................41
7.4.1Time Period for Collection of Adverse Events...........................................41
7.4.2Follow-up of Unresolved Adverse Events..................................................42
7.4.3Recording of Adverse Events of Special Interest.......................................42
7.4.3.1
Hepatic Function Abnormality .................................................42
7.4.3.2
Capillary Leak Syndrome .........................................................42
7.4.3.3
Thrombotic Microangiopathy/Hemolytic Uremic Syndrome...42
7.4.3.4
Ocular Events............................................................................42
7.5
Reporting of Serious Adverse Events.................................................................43
7.6
Other Events Requiring Immediate Reporting ...................................................43
7.6.1Overdose……….........................................................................................43
7.6.2Hepatic Function Abnormality ...................................................................44
7.6.3Pregnancy………........................................................................................45
7.6.4Other Adverse Events of Special Interest...................................................45
7.7
Safety Management During the Study................................................................45
8
PHARMACEUTICAL INFORMATION.....................................................................45
8.1
Additional Study Medications ............................................................................49
8.2
Labeling ..............................................................................................................49
8.3
Treatment Compliance........................................................................................49
8.4
Accountability.....................................................................................................50
9
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES....................................50
9.1
Pharmacokinetic Studies.....................................................................................50
9.1.1Moxetumomab Pasudotox PKs...................................................................50
9.2
Laboratory Correlative Studies...........................................................................51
9.2.1Evaluation of Immunogenicity ...................................................................51
9.2.2Bone Marrow Aspirate Minimal Residual Disease Analysis .....................51
9.2.3Peripheral Blood Flow Cytometry..............................................................52


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9.2.4Lymphocyte Enumeration...........................................................................52
9.2.5Peripheral Blood Disease B-cell Clone Detection......................................52
9.3
Sample Storage, Tracking, and Disposition........................................................52
10
STUDY CALENDAR...................................................................................................54
11
MEASUREMENT OF EFFECT...................................................................................59
11.1
Response Criteria................................................................................................59
11.2
Data Collection ...................................................................................................61
12
STUDY AND DATA MANAGEMENT......................................................................62
12.1
IRB/IEC Approvals.............................................................................................62
12.2
Study Agreements...............................................................................................62
12.3
Archiving of Study Documents ..........................................................................62
12.4
Training of Study Site Personnel........................................................................62
12.5
Monitoring of the Study......................................................................................63
12.5.1Protocol Deviation....................................................................................63
13
STATISTICAL CONSIDERATIONS..........................................................................64
13.1
General Considerations.......................................................................................64
13.2
Analysis Populations...........................................................................................64
13.3
Primary Endpoint................................................................................................64
13.4
Secondary Endpoints ..........................................................................................65
13.4.1Other Antitumor Activities.......................................................................65
13.4.1.1
CR Rate, Duration of CR (Disease-Free Survival), 
and Duration of Hematologic Remission...................65
13.4.1.2
Objective Response Rate............................................66
13.4.1.3
Time to Response.......................................................66
13.4.1.4
Duration of Objective Response ................................66
13.4.1.5
Progression-Free Survival..........................................66
13.4.1.6
Time to Treatment Failure..........................................67
13.4.2Safety Assessment ....................................................................................67
13.4.3Pharmacokinetic Assessment....................................................................67
13.4.4Immunogenic Potential of Moxetumomab Pasudotox..............................67
13.5
Sample Size and Power Calculations..................................................................68
13.6
Early stopping Rule Due to Lack of Efficacy.....................................................68
13.7
Data Monitoring Committee...............................................................................68
14
HUMAN SUBJECTS PROTECTIONS........................................................................69
14.1
Ethical Conduct of the Study..............................................................................69
14.2
Rationale for Subject Selection...........................................................................69
14.3
Evaluation of Benefits and Risks/Discomforts...................................................69
14.3.1Benefits……….........................................................................................69


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14.3.2Risks………..............................................................................................69
14.3.2.1
Important Potential Risks...........................................69
14.3.2.2
Identified Risks ..........................................................71
14.4
Risks/Benefits Analysis......................................................................................71
14.5
Consent Process and Documentation..................................................................71
14.6
Ethics and Regulatory Review............................................................................71
14.7
Changes to the Protocol and Informed Consent Form........................................72
14.8
Audits and Inspections........................................................................................73
15
REFERENCES..............................................................................................................74
16
CHANGES TO THE PROTOCOL...............................................................................81
LIST OF IN-TEXT TABLES
Table 3.1.1-1
Effective Methods of Contraception....................................................19
...........................................................47
Table 10-1
Study Calendar for Cycle 1 and Subsequent Cycles............................54
Table 10-2
Study Calendar for End of Treatment and Follow-up .........................57
LIST OF IN-TEXT FIGURES
Figure 2.3-1
Relative Bioactivity of Process 2, Process 3 (Unadjusted), Process 3 
(Adjusted) ............................................................................................16
LIST OF APPENDICES
Appendix 1
Signatures...........................................................................................103
Appendix 2
Performance Status Criteria...............................................................106
Appendix 3
Cockcroft-Gault Equation..................................................................107
Appendix 4
Additional Safety Guidance...............................................................108
Appendix 5
National Institute of Allergy and Infectious Diseases (NIAID) and 
Food and Allergy Anaphylaxis Network (FAAN) Guidance for 
Anaphylaxis Diagnosis ......................................................................111


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LIST OF ABBREVIATIONS
Abbreviation or 
Specialized Term
Definition
ADA
antidrug antibody(ies)
AE
adverse event
AESI
adverse event of special interest
ALT
alanine transaminase
ANC
absolute neutrophil count
AST
aspartate aminotransferase
BP
blood pressure
BUN
blood urea nitrogen
CBC
complete blood count
CD
cluster of differentiation
CI
confidence interval
CK
creatinine kinase
CLS
capillary leak syndrome
CR
complete response
eCRF
electronic case report form
CRP
C reactive protein
CT
computed tomography
DMC
Data Monitoring Committee
DNA
deoxyribonucleic acid
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
fT4
free thyroxine
Fv
variable domain
GGT
gamma-glutamyl transferase
GMP
Good Manufacturing Practice
HBcAg
hepatitis B core antigen
HBsAg
hepatitis B surface antigen 
HCG
human chorionic gonadotropin
HCL
hairy cell leukemia
HIV
human immunodeficiency virus
HLA 
human leukocyte antigen
HPF
high power field
HR
hematologic remission
HUS
hemolytic uremic syndrome
INR
international normalized ratio 
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
Ig
immunoglobulin


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Abbreviation or 
Specialized Term
Definition
IRB
Institutional Review Board
IV
Intravenous(ly)
LDH
lactate dehydrogenase
MRD
minimal residual disease
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
NAb
neutralizing antidrug antibodies
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events 
NK
natural killer
NSAIDs
non-steroidal anti-inflammatory medications
ORR
overall response rate
PD
progressive disease
PFS
progression-free survival
PFT
pulmonary function test
PI
principal investigator
PK
pharmacokinetics
PNA
purine nucleoside analog
PR
partial response 
PT
prothrombin time
PTT
partial thromboplastin time
RBC
red blood cell
SAE
serious adverse event
SD
stable disease
SID
subject identification
sIg
surface immunoglobulin
TLS
tumor lysis syndrome
TSH
thyroid stimulating hormone
TTF
time to treatment failure
ULN
upper limit of normal
US
United States


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1
OBJECTIVES
1.1
Primary Objectives
•
The primary objective of this study is to determine the rate of durable complete response 
(CR) in multiply relapsed hairy cell leukemia (HCL) with moxetumomab pasudotox. To 
meet the primary endpoint, patients will need to meet standard criteria for CR by analysis 
of blood, bone marrow and imaging, and maintain a hematologic remission (HR), the 
blood counts needed for CR, for >180 days.
1.2
Secondary Objectives
•
Determine the overall response rate (ORR), progression-free survival (PFS), time to 
treatment failure (TTF), and duration of responses (CR and partial response [PR]).
•
Confirm the tolerability and safety of moxetumomab pasudotox in patients with HCL.
•
Evaluate immunogenicity and pharmacokinetics (PK) of moxetumomab pasudotox.
2
BACKGROUND
2.1
Hairy Cell Leukemia
HCL is an indolent B-cell leukemia comprising 2% of all leukemias (Bouroncle, 1994; 
Kreitman and Cheson, 1999), or approximately 900 of the 44,000 new cases of leukemia/year 
in the United States (US) (Jemal et al, 2007). Patients present with pancytopenia and 
splenomegaly, and the malignant cells have cytoplasmic projections resembling hairs (Sharpe
and Bethel, 2006; Cawley, 2006).  By flow cytometry, B-cell antigens FMC7, cluster of 
differentiation (CD) 11c, CD20, CD22 and surface immunoglobulin (sIg) are strongly 
positive, and in the typical or classic form, CD103, CD25 and CD123 are also positive
(Robbins et al, 1993; Matutes, 2006; Matutes et al, 2008).The median survival of HCL 
without effective treatment is about 4 years (Golomb et al, 1978), and early treatments 
including splenectomy and interferon were of modest benefit (Habermann, 2006). Treatment 
of HCL was revolutionized with the advent of purine nucleoside analog (PNA) therapy in the 
late 1980s. Response rates for PNA averaged 70% in the primary setting and ranged from 70-
90% among patients that relapsed (Cheson et al, 1998; Piro et al, 1990; Quesada et al, 1984; 
Rai et al, 1995; Ratain et al, 1995; Saven et al, 1998; Tallman et al, 1996). However, the 
responses were less durable in the relapse setting.  Furthermore, side effects 
including bone marrow aplasia, persistent CD4 lymphopenia, infections and 
neurotoxicity (Cheson et al, 1998; Betticher et al, 1994; Cheson, 1995; Legrand et al, 1997; 
Seymour et al, 1994) associated with the repetitive administration of PNA signify a need for 


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the development of new treatments for patients who have relapsed following PNA therapy or
who are refractory to PNA treatment.
2.2
IND Agent - Moxetumomab pasudotox
Over the last two decades, developments in immunotoxin research have accumulated to 
support a role for CD22-targeted therapy in the treatment of HCL. An initial construct, BL22 
(CAT-3888), is a recombinant immunotoxin containing a variable domain (Fv) fragment of 
an anti-CD22 monoclonal antibody and truncated Pseudomonas exotoxin. In Phase 1 
and 2 trials, BL22 had 47-61% CR rates and 72-81% ORR in chemoresistant HCL        
(Kreitman et al 2001; Kreitman et al, 2005; Kreitman et al, 2009).
Moxetumomab pasudotox (HA22, CAT-8015), is a high affinity (14-fold improved) mutant 
of BL22, differing by 3 amino acids (Salvatore et al, 2002). 
 
 In HCL, the agent was tested in a Phase 1 trial in multiply relapsed patients. The 
results of the Phase 1 trial in the first 28 patients were published in the Journal of Clinical 
Oncology (Kreitman et al, 2012). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Benefit in HCL therapy is not limited to CR. Patients with advanced HCL are at risk of dying 
of cytopenias due to bleeding or infection, due to thrombocytopenia or neutropenia. 
Symptoms may include abdominal pain and weight loss due to splenomegaly, and fatigue 
from anemia. Lymphocytosis and adenopathy are associated with more advanced 
disease and worse outcome (Mercieca et al, 1992; Mercieca et al, 1994; Mercieca et al, 1996; 
Robak et al, 1999). Therefore achievement of durable PR, which requires improvement or 
resolution of cytopenias, lymphocytosis, splenomegaly and adenopathy, is considered 
beneficial in HCL. Conversely, the difference between achievement of PR and CR is limited 
to the presence and absence of marrow disease assessed by bone marrow biopsy, and the 
achievement of CR may be associated with a longer TTF than achievement of PR. 
 
 
 
 
 
 
 
 
 
 
 


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Given the efficacy and safety profile associated with moxetumomab pasudotox, this pivotal 
trial will determine the durable CR rate of the experimental agent in the setting of multiply-
relapsed or PNA refractory HCL.
2.3
Rationale
Standard first- and second-line treatment for HCL. Starting at the time HCL was initially 
described 54 years ago up until the 1980s, the outcome for patients with the disease was poor 
with a median survival of 4 years (Golomb et al, 1978). In the early 1980s, splenectomy and 
alpha interferon were noted to have efficacy in inducing remissions, mostly partial, in a 
significant percent of patients (Habermann, 2006). However these treatments are now mainly 
of historical interest because of the effectiveness of PNA, demonstrated in the late 1980s and 
early 1990s. Purine analogs cladribine and pentostatin each showed durable CR rates of 
72-89% in first line therapy (Cheson et al, 1998), with most of these patients remaining in 
CR after 4-8 years of follow-up. In a randomized trial, pentostatin was found to be far 
superior to interferon, with CR rates of 79% vs 11%, and no patient responded after crossing 
over from pentostatin to interferon (Grever et al, 1995). Today, PNA remains the accepted 
standard HCL treatment not only in 1st line, but also in 2nd line, since 62-69% of patients 
achieve CR with PNA in second line (Saven et al, 1998).
 
 
 
 
Purine analogs for multiply relapsed HCL.
 
 Data from 
small groups of patients suggest 50% or less of patients may achieve CR from repeated 
courses of PNA in > 2second line (Else, et al, 2009; Saven et al, 1998), and these 
retrospective data contains a strong selection bias because patients having more durable 
remissions in second line are more likely to receive PNA in third or later lines. Anecdotally, 
responses to 1 PNA are reported after failure of the other (Saven and Piro, 1993;           
Chadha et al, 2005), but overall, the lower response rate observed in repeated courses of PNA 
is not improved if a different PNA is used (Else, et al, 2009). 
 
 
 Moreover, the toxicity 
of multiple courses of PNA can be both substantial and long-lasting.  Even 1 course of either 
cladribine or pentostatin is reported to result in decreases in CD4+ lymphocytes lasting up to 
4 years (Seymour et al, 1994; Seymour et al, 1997), and damage to stem cells may be 
irreversible and lead to myelodysplasia (Kroft et al, 1997; Leleu et al, 2009;                          


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Todd et al, 2002). Still further, PNA cause neuropathy in about 15% of patients after a single 
course (Cheson et al, 1994). These long-lasting toxicities of PNA accumulate with multiple 
courses and thus, decreasing efficacy combined with increased toxicity, argue against their 
repeated use in most situations. Rather, multiply relapsed HCL patients are in particular need 
of effective non-chemotherapy options.
Rituximab for HCL depending on extent of cytopenias and prior therapy. Though 
not approved for HCL by the US Food and Drug Administration, the most widely used non-
chemotherapy option at this time for HCL is rituximab, which binds to and kills CD20+ cells 
by inducing apoptosis or by mediating complement and antibody dependent cytotoxicity 
(CDC and ADCC, respectively) (Villamor et al, 2003). CR rates among the 6 reported 
rituximab studies in HCL (10-25 patients each, total 97) vary from 10 to 54% (Hagberg and 
Lundholm, 2001; Lauria et al, 2001; Nieva et al, 2003; Thomas et al, 2003; Angelopoulou et 
al, 2008; Zenhausern et al, 2008).
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Treatment of HCL with BRAF inhibition. Recurrent somatic mutation of BRAF (V600E)
has been reported in 100% of classic HCL patients (Tiacci et al, 2011; Tiacci et al, 2012) The 
V600E inhibitor vemurafenib achieves a 4-month overall survival advantage in melanoma 
patients with the same mutation (Chapman et al, 2011). However, it has recently been 
reported that 21% of HCL patients, most of whom had multiply relapsed HCL, do not have 
this mutation (Xi et al, 2012), indicating that mutation may be lost during PNA resistance, or 
that multiply-relapsed HCL populations may be enriched in BRAF wild-type patients. 
 
A single case report in which 
minimal residual disease (MRD) was not eliminated and durability of response was not yet 
assessed has been reported (Dietrich et al, 2012)
 
 
 
 
 
Primary endpoint for moxetumomab pasudotox. The minimum prior treatment required 
for this study, 2 courses of PNA or 1 purine analog plus one course of either rituximab or 
BRAF inhibitor, is appropriate because repeat courses of purine analog are now used 
less frequently due to their cumulative toxicity and decreasing benefit (Cheson, 1995; 
Cheson et al, 1994).
 
 
 
 
 
 
 
 
 
 
 
 
 




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Subjects will be treated for up to a total of 6 cycles in the study.
 
 
 
 


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 The 
study design also allows subjects maintaining blood counts needed for CR for at least 4 
weeks to have an interim disease assessment. If this assessment shows CR without detectable 
MRD, therapy will stop. 
 
 
3
PATIENT SELECTION
3.1
Eligibility Criteria 
3.1.1
Inclusion Criteria
1. Patients must have histologically confirmed HCL or HCL variant with a need for therapy 
based on at least one of the following criteria:
a.
neutrophils < 1.0x 109/L
b. platelets < 100 x 109/L
c.
hemoglobin < 10 g/dL
d. symptomatic splenomegaly
2. Patients must be Pseudomonas-immunotoxin naïve
3. Patients must have received at least 2 prior systemic therapies, including 2 courses of
courses of a PNA, or 1 course of either rituximab or BRAF inhibitor following a single 
prior course of PNA.
4. Men or women age > 18 years. Because this disease does not generally occur in children,
children are excluded from this study.
5. Eastern Cooperative Oncology Group (ECOG) performance status ≤2 (Appendix 2).
6. Patients must have adequate organ function as defined below:
a.
total bilirubin ≤1.5 mg/dL, unless consistent with Gilbert’s (ratio between total and 
direct bilirubin > 5)
b. AST and ALT ≤3x upper limit of normal (ULN)
c.
alkaline phosphatase < 2.5 ULN
d. serum creatinine ≤1.5 mg/dL or creatinine clearance ≥ 60 mL/min as estimated by 
the Cockcroft-Gault equation (Appendix 3)
7. Prothrombin time (PT)/international normalized ratio (INR) or partial thromboplastin 
time (PTT) < 2.5 ULN, fibrinogen ≥ 0.5 lower limit of normal; if on warfarin, INR < 3.5, 
if on any other anticoagulation, PT < 2.5 x baseline 
8. Ability to understand and the willingness to sign a written informed consent document.
9. Life expectancy ≥ 6 months.
10. Females of childbearing potential who are sexually active with a nonsterilized male 
partner must use a highly effective method of contraception prior to study entry and or 
the duration of study participation, and must agree to continue using such precautions for 
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contraception after this point should be discussed with a responsible physician. Periodic 
abstinence, the rhythm method, and the withdrawal method are not acceptable methods of 
contraception.
a.
Females of childbearing potential are defined as those who are not surgically sterile 
(ie, bilateral tubal ligation, bilateral oophorectomy, or complete hysterectomy) or 
those who are premenarchal or postmenopausal (defined as 12 months with no 
menses without an alternative medical cause).
b. A highly effective method of contraception is defined as one that results in a low 
failure rate (ie, less than 1% per year) when used consistently and correctly. Effective
methods of contraception are described in Table 3.1.1-1. Not all methods of 
contraception are highly effective. Female subjects must use a hormonal method in 
addition to a barrier method alone, to minimize the chance of pregnancy.
c.
Should a woman become pregnant or suspect she is pregnant while she or her partner 
is participating in this study, she should inform her treating physician immediately.
11. Nonsterilized males who are sexually active with a female partner of childbearing 
potential must use an effective method of contraception (Table 3.1.1-1) from Day 1 for 
90 days after receipt of the final dose of investigational product. It is required that a 
female partner of a male subject also use an effective method of contraception throughout 
this period.
Table 3.1.1-1
Effective Methods of Contraception
Barrier Methods
Hormonal Methods
•
Male condom plus spermicide a, b
•
Copper T intrauterine device
•
Levonorgesterel-releasing intrauterine system) 
(eg, Mirena®) c
•
Implants
•
Hormone shot or injection
•
Combined pill
•
Minipill b
•
Patch
a
Female partners of male subjects must use an effective method of birth control.
b
Not highly effective (< 1% pregnancy rate per year) when used as the only method of birth control.
c
This is also considered a hormonal method.
3.1.2
Exclusion Criteria
1. Patients who have had chemotherapy, immunotherapy or radiotherapy within 4 weeks 
prior to initiation of treatment.
2. Patients who are receiving any other investigational agents.
3. Patients with known brain metastases should be excluded from this clinical trial because 
of their poor prognosis and because they often develop progressive neurologic 
dysfunction that would confound the evaluation of neurologic and other adverse events
(AEs).
4. Patients with retinal or choroidal detachment identified during the screening 
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3.2
Inclusion of Women and Minorities
Both men and women of all races and ethnic groups are eligible for this trial. No clinically 
important sex/gender and/or race/ethnicity differences are expected from the intervention 
effect.
3.3
Protocol Evaluation
3.3.1
Performed Within 4 Weeks Prior to Treatment 
•
Informed consent
•
Demographics
•
Performance status (ECOG)
•
Vital signs including temperature, blood pressure (BP), pulse rate, respiratory rate, and 
pulse oximetry
•
Orthostatic BP
•
Height
•
Weight
•
Baseline AEs and concurrent medications, then monitored continuously after enrollment
•
History and physical examination, query for visual symptoms
•
Complete blood count (CBC) with differential and peripheral blood smear
•
Chem7 (sodium, potassium, chloride, bicarbonate, creatinine, glucose, blood urea 
nitrogen [BUN]), albumin, calcium, magnesium, phosphorus, AST (SGPT), ALT 
(SGOT), total bilirubin, direct bilirubin, lactate dehydrogenase (LDH), total protein, 
alkaline phosphatase, and uric acid
•
Creatine kinase (CK)
•
Triglycerides
•
Cholesterol
•
GGT
•
Serum human chorionic gonadotropin (HCG) (in females of childbearing potential only)
•
Urinalysis
•
PT/PTT/Fibrinogen
•
Serum ferritin
•
•
Computed tomography (CT) scan or magnetic resonance imaging (MRI) to evaluate 
organomegaly and/or lymph nodes (does not need to be repeated if performed within 


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8 weeks prior to treatment). Note: Subjects enrolled in Germany will utilize MRI for all 
radiographic assessments (CT not permissible).
•
Bone marrow biopsy and aspirate (does not need to be repeated if performed within 
8 weeks prior to treatment) for analysis by flow cytometry/sequencing.
•
12-lead electrocardiogram (ECG) (analyzed by central vendor, ERT
◦
The ERT-ECG machine, training on the proper usage of the ERT-ECG machine, and 
methods of submission of reports will be provided by ERT. Submission of ECG 
reports will be transmitted via fax or via FedEx to MedImmune in accordance with 
the instructions provided in the ERT training session and outlined in the ERT user 
manual.
•
Thyroid stimulating hormone (TSH)
•
Free thyroxine (fT4)
•
C reactive protein (CRP)
•
Haptoglobin
•
Serum amylase
•
Serum lipase
•
•
•
Immunoglobulin G (IgG), IgA and IgM
•
For patients with prior history of pulmonary illness; FEV1 and DLCO ≥ 50% of predicted 
are required for enrollment 
•
Ophthalmologic Exam (slit lamp and fundus)
•
Serum and urine protein electrophoresis
•
Hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (HBcAb)
•
Hepatitis B Viral DNA load (if HBsAg is positive)
•
Hepatitis C antibody
•
Human leukocyte antigen (HLA) typing (central lab analysis)
•
Complement C3, C4, CH50
3.3.2
Pre-Cycle before Subsequent Cycles (Day -3 to Day 1)
•
Physical exam, query for visual symptoms
•
Performance status (ECOG)
•
Weight (can be obtained on Day -4 to Day 1) - do not change dose during a cycle; dose 
should be adjusted for weight change ≥10% from screening in subsequent cycles.


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•
AEs and concurrent medications
•
•
•
Uric acid, creatine kinase (CK or creatinine phosphokinase), GGT, PT, Haptoglobin 
•
12-lead ECG analyzed by central vendor, ERT.
3.3.3
During Cycle
•
Day 1 (Prior to dosing)
◦
Patients should be asked about visual symptoms and reminded to report any visual 
symptoms during the cycle. New visual symptoms of Grade 2 or greater should be 
evaluated with a full ophthalmologic assessment.
◦
•
Days 1, 3, and 5
◦
AEs and concurrent medications
◦
CBC with differential and peripheral blood smear
◦
Chem7 ( sodium, potassium, chloride, bicarbonate, glucose, BUN, creatinine)
◦
mineral panel (calcium, magnesium, phosphorus, albumin)
◦
hepatic panel (AST-SGPT, ALT-SGOT, total bilirubin, direct bilirubin, alkaline 
phosphatase )
◦
LDH
◦
Urinalysis (Day 1 only)
◦
Vital signs including pulse oximetry
◦
Physical exam, query for visual symptoms
◦
Orthostatic BP 
◦
Moxetumomab pasudotox dosing
•
Days 1 and 5
◦
12-lead ECG (analyzed by central vendor, ERT), 30-60 minutes post end of infusion 
(Cycle 1 only)
◦
PK (EDTA) 
▪
Day 1 pre (Odd cycles and Cycle 2)
▪
Day 1 immediately post (Odd cycles and Cycle 2)
▪
Day 1, 3 hours post (Cycles 1 and 2)
▪
Day 5 pre, immediately post, 1 hour, 3 hours, 6 hours post (Cycle 1 only)
•
Day 8 (±1 day):  CBC with differential and peripheral blood smear , Chem7, mineral 
panel, hepatic panel, LDH, vital signs, orthostatic BP, weight, AEs, concurrent 
medications 


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•
Recommended on Days 15 and 21 (each ±2 days): CBC with differential and peripheral 
blood smear, Chem 7 (sodium, potassium, chloride, bicarbonate, glucose, BUN, 
creatinine), mineral panel (calcium, magnesium, phosphorus, albumin), hepatic panel 
(AST-SGPT, ALT-SGOT, total bilirubin, direct bilirubin, alkaline phosphatase), LDH, 
AEs, concurrent medications  and vital signs 
•
IgA, IgG, IgM, C3, C4, and CH50 should be repeated upon both 
diagnosis and resolution of HUS and > Grade 2 CLS. Measurement of tumor burden is 
also recommended, but not required, in the event of HUS
Interim Disease Assessment (Optional)
•
During treatment and prior to completion of 6 cycles of therapy, if blood counts are 
consistent with CR for at least 4 weeks, an interim disease assessment may be performed 
at the discretion of the investigator. All assessments listed in Section 3.3.4.1 are required 
if an optional interim disease assessment is performed. Imaging (CT or MRI) and 
ophthalmologic examination may be deferred for up to 7 days until after the bone marrow 
aspirate and biopsy if CR without MRD is confirmed. For a response less than CR 
without MRD, therapy should resume and imaging and ophthalmologic examination may 
be deferred (if not performed concurrently with the bone marrow examination) until the 
end of treatment assessment.
3.3.4
Tests in Follow-up After Treatment Ends:
3.3.4.1
All patients 28-42 days after the first day of dosing of prior cycle (end of 
treatment assessment)
•
History and physical exam, concurrent medications, AEs, performance status (ECOG)
•
Pulse Oximetry with vital signs and weight 
•
Ophthalmologic exam (slit lamp and fundus)
•
12-lead ECG (analyzed by central vendor, ERT)
•
Imaging with CT or MRI for lymphadenopathy and organomegaly
•
Bone marrow biopsy and aspirate with flow cytometry/sequencing
•
CBC with differential (no peripheral blood smear)
•
Chem 7 (sodium, potassium, chloride, bicarbonate, glucose, BUN, creatinine)
•
mineral panel (calcium, magnesium, phosphorus, albumin)
•
Hepatic panel (AST-SGPT, ALT-SGOT, total bilirubin, direct bilirubin, alkaline 
phosphatase)
•
Uric acid, total protein, triglycerides, cholesterol, GGT 
•
PT, PTT, LDH, fibrinogen, quantitative immunoglobulins, CK, CRP, serum ferritin


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•
TSH, fT4, serum amylase, serum lipase, haptoglobin, and urinalysis
•
•
•
•
Patients with SD, PR or CR are then followed until relapse from baseline
3.3.4.2
Follow-up for those in Complete Response
•
CBC with differential (no peripheral blood smear) performed monthly until 181 days
after documentation of CR/end of treatment assessment, then every 3 months for 2 years, 
and then every 6 months thereafter
3.3.4.3
For those not in Complete Response
•
CBC with differential (no peripheral blood smear) performed every 3 months for 2 years 
after end of treatment, then every 6 months thereafter
3.3.4.4
For all patients in follow-up
The Day 181 post-end of treatment assessment may not be performed prior to Day 181. This 
assessment may be performed between Day 181 and Day 195 post-end of treatment.
Refer to Table 10-2:
•
History and physical exam, concurrent medications, pulse oximetry with vital signs and 
weight, performance status 
•
•
•
For subjects with CR or PR, disease assessment by CT or MRI at Day 181 and 18-month 
time points after the end of treatment.
•
Bone marrow biopsy and aspirate with flow cytometry/sequencing is required 
 
•
Peripheral blood for disease B-cell clone detection 
 
•
Chem 7/Acute Care Panel (sodium, potassium, chloride, bicarbonate, glucose, BUN, 
creatinine)
•
Mineral panel (calcium, magnesium, phosphorus, albumin)
•
Hepatic panel (AST-SGPT, ALT-SGOT, total bilirubin, direct bilirubin, alkaline
phosphatase)


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•
Uric acid, total protein, triglycerides, cholesterol, GGT, PT, PTT, LDH, quantitative 
immunoglobulins, CK, CRP, serum ferritin, TSH, fT4, serum amylase, serum lipase 
•
Haptoglobin (end of treatment and Day 181 post-end of treatment only)
•
Urinalysis (end of treatment and Day 181 post-end of treatment only)
4
REGISTRATION PROCEDURES
Study participation begins (ie, a subject is “enrolled”) once written informed consent is 
obtained. Once informed consent is obtained, a subject identification (SID) number will be 
assigned by a central system (eg, an interactive voice response system), and the screening 
evaluations may begin to assess study eligibility (inclusion/exclusion) criteria. The SID 
number will be used to identify the subject during the screening process and throughout study 
participation, if applicable.
A master log of all consented subjects will be maintained at the site and will document all 
screening failures (ie, subjects who are consented but do not meet study eligibility criteria), 
including the reason(s) for screening failure. Subjects who fail to meet the 
inclusion/exclusion criteria and are rescreened will receive a new SID number. 
5
TREATMENT PLAN
5.1
Agent Administration
Treatment may be administered on either an inpatient or outpatient basis. Appropriate dose 
modifications are described in Section 6. No investigational or commercial agents or 
therapies other than those described below may be administered with the intent to treat the 
patient's malignancy. Seventy-seven evaluable patients will be enrolled to 
receive moxetumomab pasudotox.  Unevaluable patients may be replaced as discussed in 
Section 13.5.
5.1.1
Moxetumomab pasudotox
Moxetumomab pasudotox (40 μg/kg) will be administered by IV infusion over 30
(± 10) minutes on Days 1, 3 and 5 of each 28-day cycle until documentation of CR or for up 
to 6 cycles, progressive disease (PD), initiation of alternate therapy or unacceptable toxicity.
The cycle interval can be decreased by up to 2 days. For a dosing delay, refer to Section 6.
Subjects will receive up to 6 cycles of therapy.  
In an attempt to prevent renal insufficiency, patients will receive fluid and aspirin 
prophylaxis. Patients will receive low-dose aspirin orally (81 mg daily or local standard dose) 


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on Days 1-8 of those cycles with platelet counts ≥100 x 109/L. Aspirin will be held on days 
where the platelet count is below 75 x 109/L. Patients will receive 1 L of 5% dextrose 0.45% 
NaCl, (recommended over 2-4 hours) prior to the beginning and after the end of each 
moxetumomab pasudotox infusion. Patients under 50 kg may receive 0.5 L instead of 1 L of 
fluid before the beginning and after the end of moxetumomab pasudotox infusion. On Days 
0-8 of the cycle, patients are expected to drink at least 3 liters of fluid/day.
To mitigate risk for allergic reaction and fever, patients will be premedicated with 10- 25 mg 
hydroxyzine (dose to be determined by the investigator), 650 mg of acetaminophen, and 
150 mg ranitidine orally 30-90 minutes prior to every moxetumomab pasudotox infusion. 
After the end of infusion, patients are recommended to receive acetaminophen 650 mg orally 
every 6 hours x 4 doses and hydroxyzine 10-25 mg orally every 8 hours for 2 doses.
Substitutions of diphenhydramine for hydroxyzine and famotidine or cimetidine for 
ranitidine are permitted. In subjects experiencing infusion-related reactions, including, but 
not limited to pyrexia, nausea, or dyspnea, premedication with dexamethasone 4 mg 
intravenous (IV) or oral may be administered at the investigator’s discretion as secondary 
prophylaxis.
Moxetumomab pasudotox will be infused in 50 mL of 0.9% NaCl containing IV Bag 
Protectant over 30 (±10) minutes. Vital signs will be obtained every 15 (±5) minutes during 
the infusion, then every hour (±30 minutes) for an additional 4 hours during Cycle 1. During 
subsequent cycles, vital signs will be obtained every 15 (±5) minutes during the infusion, 
then every hour (±30 minutes) for an additional 2 hours. Vital signs will also be obtained on 
Day 8 ± 1 day for the first 3 dosing cycles. Patients will be monitored for orthostatic 
hypotension on Days 1, 3 and 5 of each cycle prior to moxetumomab pasudotox. Medications 
and equipment will be available at the patient's unit for treatment of an allergic reaction 
(including epinephrine, oxygen, corticosteroids, diphenhydramine). These procedures will be 
followed for all cycles of moxetumomab pasudotox.
Additional recommended safety monitoring includes weekly serum creatinine/albumin 
monitoring on Days 8, 15 and 21 (± 1 day) of Cycle 1 with additional attention to fluid status 
and weight. Investigator should consider establishing a maximum fluid intake of 6000
mL/day during the first cycle of drug administration with consideration of diuresis with a
5-10% increase in weight above baseline. The investigator may elect to have subjects 
measure their weight daily with further evaluation indicated if weight gain (> 5%) is noted. 
Subjects with hyperuricemia of > 10 mg/dL (> 0.59 mmol/L) prior to administration of 
moxetumomab pasudotox will receive allopurinol 300 mg once daily for tumor lysis 


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syndrome (TLS) prophylaxis. Treatment of TLS will be based on institutional guidelines. 
Adequate Pneumocystis carinii pneumonia (PCP) prophylaxis will be provided for patients 
receiving corticosteroids ≥ 10 mg of prednisone daily or equivalent, CD4 lymphocyte count 
< 0.2 x 109/L, or at the discretion of the investigator. Viral prophylaxis is also required for 
subjects receiving chronic corticosteroids or with lymphopenia.
Patients should not receive non-steroidal anti-inflammatory medications (NSAIDS), other 
than aspirin for prophylaxis of renal insufficiency, during the course of the study through 
7 days after the last dose of moxetumomab pasudotox.
An event of ≥ Grade 2 hypercalcemia with calcium level corrected for serum albumin will 
require a delay in dosing until resolution to < Grade 2.
If visual symptoms ≥ Grade 2 are reported, an ophthalmologic examination including slit-
lamp and fundoscopic evaluation is required.
If a ≥ 10% increase in body weight due to fluid overload occurs, it is recommended that 
imaging of the chest is obtained for any evidence of pulmonary edema so appropriate 
treatment may be instituted promptly.
5.1.2
Reporting Product Complaints
Any defects with the investigational product must be reported immediately to the 
MedImmune Product Complaint Department by the site with further notification to the site 
monitor. All defects will be communicated to MedImmune and investigated further with the 
Product Complaint Department. During the investigation of the product complaint, all 
investigational product must be stored at labeled conditions unless otherwise instructed.
Product defects may be related to component, product, or packaging and labeling issues. The 
list below includes, but is not limited to, descriptions of product complaints that should be 
reported.
•
Component Issue: Defect in container or dosing mechanism of the investigational 
product. The component defect may be damaged, missing, or broken. Component 
examples include vials, stoppers, caps, spray barrels, spray nozzles, or plungers.
•
Product Issue: Defect in the product itself. The product appearance has visual 
imperfections such as foreign particles, crystallization, discoloration, turbidity, 
insufficient volume, or anything that does not apply to the product description.
•
Packaging/Labeling Issue: Defect in the packaging or labeling of the product. The 
packaging or labeling defects may be damaged or unreadable, or the label may be 
missing.


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When reporting a product complaint, site staff must be prepared to provide the following 
information:
1. Customer information: reporter name, address, contact number, and date of complaint.
2. Product information: product name, packaging kit number or lot number, expiry date, and 
clinical protocol number.
3. Complaint information: complaint issue category and description.
MedImmune contact information for reporting product complaints:
5.2
General Concomitant Medication and Supportive Care Guidelines
5.2.1
Concomitant Medications
Subjects may receive medications as supportive care or to treat AEs as deemed necessary by 
the investigator or the subject’s physician.
All concomitant medications given to the subject from the time the subject signs the 
informed consent form through 181 days after end of treatment of moxetumomab pasudotox
will be recorded on the source document. Beyond 181 days after the end of treatment of 
moxetumomab pasudotox until end of study, only administrations of blood component 
transfusions and hematopoietic growth factors will be recorded. 
Subjects should continue to take their usual chronic maintenance medications (such as 
antihypertensives, thyroid replacement therapy, vitamin or mineral supplements) during the 
course of the study other than those contraindicated by the inclusion/exclusion criteria.
Instructions for specific medications are listed below:


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1. Prophylactic use of hematopoietic growth factors, such as filgrastim, sargramostim, or 
pegfilgrastim, is permitted when IV antibiotics are given for fever (> 38.0ºC) and 
neutropenia (< 0.5 x 109/L). Use at the discretion of the study principal investigator (PI)
for Grade 4 neutropenia without fever is permitted but discouraged.
2. Concurrent chemotherapy, radiotherapy, immunotherapy, biologic, and hormonal therapy 
for treatment of cancer during the study are not permitted.
3. Use of steroids is not routinely recommended to prevent CLS or fever from 
moxetumomab pasudotox; however, secondary prophylaxis for infusion-related reactions 
with dexamethasone 4 mg IV or oral may be administered at the investigator’s discretion. 
4. Use of NSAIDs is not permitted from the first dose of the cycle through 7 days after the 
last dose of the cycle.
5.2.2
Supportive Care
5.2.2.1
Infections/Fever and Neutropenia
Fever 
 may be treated symptomatically.
5.2.2.2
Blood Product Support
Symptomatic anemia should be treated with appropriate red blood cell (RBC) support.  
Transfusion is generally recommended if the hemoglobin falls below 8g/dL, but lower levels 
are acceptable particularly for younger patients. Platelets are generally given when the 
platelet count is <10 x 109/Lor when there is bleeding.
5.2.2.3
Cytokine Support
Prophylactic filgrastim (G-CSF) or sargramostim (GM-CSF) is not indicated for
chemotherapy in HCL but may be used in special situations, for example, when patients have 
serious neutropenic infections.
5.2.2.4
Capillary Leak Syndrome
Any subject with any Grade 2 weight gain, albumin, hypotension, edema, hypoxia, or 
pulmonary AEs will be evaluated by thorough clinical examination including vital signs and 
pulse oximetry, assessment of albumin, CBC, electrolytes, BUN, and creatinine. A chest 
x-ray will be obtained if clinically indicated. These subjects will be prospectively monitored 
for the potential worsening of the above symptoms. Subjects who develop CLS will be 
managed according to the respective institutional standards.  It is important to recognize that 
weight gain during CLS is often associated with intravascular volume depletion rather than 
overload. Thus, use of diuretics should be avoided unless patients are experiencing AEs
related to weight gain, particularly when associated with dyspnea. Albumin infusions may be 
used to permit diuresis with or without diuretics by transiently raising oncotic pressure, but 


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the need for albumin infusions is generally limited to situations where the serum albumin is 
below 2.5 g/dL.
The potential for developing CLS will be evaluated prior to each dose within a cycle by 
monitoring the subject’s weight, orthostatic BP, and pulse. If any subject experiences an 
increase in weight of 5.5 lb (2.5 kg) or 5% (whichever is greater) of the Day 1 weight of that 
cycle, or orthostatic BP and pulse changes which are deemed clinically significant, the 
subject will be thoroughly evaluated for incipient CLS prior to administration of the next 
dose. Evaluation will include careful physical examination and evaluation of laboratory 
parameters, including serum albumin, which may indicate CLS.
5.2.2.5
Hemolytic Uremic Syndrome
Any subject with suspected Grade 1-4 HUS will be evaluated as for CLS and in addition will 
be followed with serial haptoglobin, LDH, CBCs, and urinalyses to detect urine free 
hemoglobin. Subjects with an unexplained drop in hemoglobin ≥ 1.5 g/dL during any 
treatment cycle should be evaluated for possible HUS. Peripheral blood will be assessed for 
schistocytes. Patients need not be managed with plasmapheresis, and rather may be managed 
with fluid repletion and/or diuretics at the discretion of the institution PI, with consultation of 
the sponsor. If HUS of any grade develops, treatment should be suspended until resolution of 
all laboratory abnormalities, and should only be resumed if the maximum grade was ≤ 2, and 
after consultation and agreement with the sponsor. 
 
 
Diuresis early on may worsen the creatinine by causing 
dehydration, and should only be used to treat symptoms of fluid overload. Patients may have 
creatinine elevations and/or microscopic hematuria without evidence of HUS, but such 
patients may be managed similarly with attention to adequate hydration. Patients should be 
observed carefully for evidence of severe HUS, including mental status abnormalities, renal 
failure, and bleeding from severe thrombocytopenia.
5.2.2.6
Ocular Events
In the event of visual symptoms of Grade 2 or greater, an ophthalmologic evaluation is 
required. Subjects must be queried for and encouraged to report any ocular symptoms on 
dosing days prior to the administration of moxetumomab. 
 
 
  Due to the potential association of HUS with retinal damage, 
subjects with visual symptoms and new finding(s) on ophthalmologic examination should be 


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hospitalized with daily monitoring of renal function with serum creatinine and close 
observation. 
If the subject displays any retinal abnormalities, dosing with the investigational agent must 
be discontinued. In the event that an ocular event or symptom occurs without any evidence of 
retinal abnormalities, dosing must be interrupted and may not resume until there is full
resolution of ocular symptoms.
5.3
Duration of Therapy
Treatment may continue until one of the following criteria applies:
•
Completion of 6 cycles of therapy.
•
Disease progression
•
Documented CR without assessable MRD
•
Treatment delay of > 2 weeks beyond scheduled start of subsequent cycle
•
Intercurrent illness that prevents further administration of treatment
•
Unacceptable AEs as defined in Section 6
•
General or specific changes in the patient's condition render the patient unacceptable for 
further treatment in the judgment of the investigator.
•
Severe or life-threatening anaphylaxis or hypersensitivity reaction
•
Withdrawal of consent from further treatment with investigational product or lost to 
follow-up
•
Subject is determined to have met one or more of the exclusion criteria or failed to meet 
all of the inclusion criteria for study participation
•
Pregnancy
•
Any of the following liver function abnormalities:
◦
ALT or AST > 5 x ULN for more than 2 weeks
◦
ALT or AST > 3 x ULN and (total bilirubin > 2 x ULN or INR > 1.5); see 
Section 7.6.2 for additional details regarding reporting of subjects with ALT or 
AST > 3 x ULN and total bilirubin > 2 x ULN with unknown etiology (ie, Hy’s law 
cases)
◦
ALT or AST > 3 x ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (> 5%)
◦
Corrected QT interval (Fridericia) > 500 msec confirmed (persistent for at least 
5 minutes; based on manual over-read by medically qualified person) and determined 
post dose either during continuous 12-lead ECG monitoring or on a repeat 12-lead 
ECG


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Subjects who are permanently discontinued from receiving investigational product will be 
followed for protocol-specified assessments (Table 10-2) including follow-up of any AEs 
unless consent is withdrawn specifically from further study participation, the subject is lost to 
follow-up, the subject starts alternative treatment, or the subject is enrolled in another clinical 
study.
5.4
Duration of Follow Up
Patients will be followed according to the follow-up timepoints in Table 10-2. Patients who 
are in CR will be followed until clinical relapse (defined as loss of HR, development of 
disease related symptoms, or organomegaly), subsequent therapy, death, or withdrawal of 
consent. Patients in CR should not receive any anti-cancer therapies for remission 
maintenance. Patients removed from study for unacceptable AEs will be followed until 
resolution or stabilization of the AE. The sponsor may, in the future, request that subjects be 
transitioned to a long-term follow-up study to allow for closure of the study database and 
final reporting of the primary outcome, while allowing for additional follow-up under a 
separate study to facilitate assessment of secondary endpoints.
5.5
Off Study Criteria
•
Unexpected illness or other comorbid condition, by PI discretion after consultation with 
the sponsor
•
Manufacturer no longer able to supply study agent
•
Participant requests to be withdrawn from study
•
Patient has completed study intervention and follow-up period
•
Death
•
Subject non-compliance that, in the opinion of the investigator or sponsor, warrant 
withdrawal (eg, refusal to adhere to scheduled visits)
•
Initiation of alternative anticancer therapy including another investigational agent
•
Confirmation of disease progression or relapse
•
Lost to follow-up
The reason for study removal and the date the patient was removed must be documented in 
the electronic case report form (eCRF).


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5.5.1
Study Timetable and End of Study
An individual subject will be considered to have completed the study if the subject was 
followed through the Day 181 post-end of treatment visit, regardless of the number of doses 
of investigational product that was received. Subjects are encouraged to continue study 
follow-up detailed in Table 10-2 so that duration of response to moxetumomab pasudotox 
can be determined.
Subjects will be considered not to have completed the study if consent was withdrawn or the 
subject was lost to follow-up if prior to completion of the Day 181 post-end of treatment 
visit.
The end of the study (“study completion”) is defined as the date of the last protocol-specified 
visit/assessment (including telephone contact) for the last subject in the study. This date will 
be 3 years after the final subject is entered into the study.
6
DOSING DELAYS/DOSE MODIFICATIONS
•
There will be no dose reductions for moxetumomab pasudotox.
•
Dosing may be delayed up to 2 weeks for toxicity or logistical reasons. Patients should 
not begin a subsequent treatment cycle of moxetumomab if there is active, ongoing 
infection requiring treatment.  Patients with excessive delay (delay > 2 weeks) are 
permanently discontinued from treatment and should be followed but not retreated.
•
Moxetumomab pasudotox infusion should be interrupted for Grade 2 or Grade 3 infusion 
related reactions (eg, rapid tumor lysis) and should be permanently discontinued for 
Grade 4 (life-threatening) anaphylaxis or hypersensitivity reaction
•
Patients with ≥ Grade 3 CLS or ≥Grade 3 HUS should be permanently discontinued 
from treatment.
•
If the ANC is < 1.0 x 109/L, dosing should be held during Grade 1 or higher fever
(≥38.0°C).
•
Dosing should be delayed until Grade 3 or Grade 4 AEs attributed to the study drug 
decrease to at least Grade 2 or below EXCEPT for the following (ie, dosing delay not 
required if any of the following are present):
◦
Grade 3 hematologic toxicity.
◦
Grade 4 hematologic toxicity resolving within < 4 weeks (lymphopenia, leukopenia 
and lymphocyte subsets will not be considered as grounds for a dosing delay).
◦
Hematologic toxicity managed with transfusion and/or other support.
◦
Grade 3 transaminase elevations.
◦
Grade 3 electrolyte and mineral levels, hyperlipidemia, lipase, proteinuria and fever
not associated with ANC < 1.0 × 109/L.  


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▪
Hypocalcemia is graded after correction for the albumin, which increases the 
measured calcium level by 0.2 mmol/L or 0.8 mg/dL for each 1 g/dL of albumin 
less than 4 g/dL.
▪
An event of ≥ Grade 2 hypercalcemia with calcium level corrected for serum 
albumin will require a delay in dosing until resolution to < Grade 2.
◦
Worsening of the coagulation profile of patients on anticoagulation.
◦
Grade 4 hyperlipidemia if pre-existing at Grade 2-4 levels or resolved to < Grade 4 by 
< 2 months.
◦
Grade 3 hypoalbuminemia unless related to CLS.
•
After dosing delays and re-challenge: 
◦
Patients who redevelop ≥ Grade 3 non-hematologic toxicities, which are not covered 
by the exclusions in this section, with at least possible attribution to the study drug, 
will result in the patient discontinuing treatment but not off-study. 
7
ASSESSMENT OF SAFETY
7.1
Definition of Adverse Events
The International Conference on Harmonisation (ICH) Guideline for Good Clinical Practice
(GCP) E6(R1) defines an AE as:
Any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended 
sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product.
An AE includes but is not limited to any clinically significant worsening of a subject’s pre-
existing condition. An abnormal laboratory finding (including ECG finding) that requires 
medical intervention by the investigator, or a finding judged by the investigator as medically 
significant should be reported as an AE. If clinical sequelae are associated with a laboratory 
abnormality, the diagnosis or medical condition should be reported (eg, renal failure, 
hematuria) not the laboratory abnormality (eg, elevated creatinine, urine RBC increased).  
Abnormal laboratory values that are not, in the investigator's opinion, medically significant 
and do not require intervention should not be reported as AEs.
AEs may be treatment emergent (ie, occurring after initial receipt of investigational product) 
or nontreatment emergent. A nontreatment-emergent AE is any new sign or symptom, 


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disease, or other untoward medical event that begins after written informed consent has been 
obtained but before the subject has received investigational product. 
Elective treatment or surgery or preplanned treatment or surgery (that was scheduled prior to 
the subject being enrolled into the study) for a documented pre-existing condition that did not 
worsen from baseline is not considered an AE (serious or nonserious). An untoward medical 
event occurring during the prescheduled elective procedure or routinely scheduled treatment 
should be recorded as an AE or serious adverse event (SAE).
7.2
Definition of Serious Adverse Events
An SAE is any AE that:
•
Results in death
•
Is immediately life-threatening
•
Requires inpatient hospitalization or prolongation of existing hospitalization 
•
Results in persistent or significant disability/incapacity 
•
Is a congenital anomaly/birth defect in offspring of the subject
•
Is an important medical event that may jeopardize the subject or may require medical 
intervention to prevent one of the outcomes listed above
Medical or scientific judgment should be exercised in deciding whether expedited 
reporting is appropriate in this situation. Examples of medically important events are 
intensive treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias, or convulsions that do not result in hospitalizations; or development of drug 
dependency or drug abuse.
7.3
Definition of Adverse Events of Special Interest
An AESI is one of scientific and medical interest specific to understanding of the 
Investigational Product and may require close monitoring and rapid communication by the 
investigator to the sponsor. An AESI may be serious or non-serious. The rapid reporting of 
AESIs allows ongoing surveillance of these events in order to characterize and understand 
them in association with the use of this investigational product.
Hepatic function abnormality meeting the definition of Hy’s law is considered an AESI. See 
Section 7.6.2 for the definition and reporting of AESIs of hepatic function abnormality.


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7.3.1
Capillary Leak Syndrome 
CLS is a rare and life-threatening condition that can be characterized by capillary 
hyperpermeability resulting in a shift of intravascular fluid and protein to the interstitial 
space resulting in transient shock and generalized or segmental edema accompanied by 
hypotension, elevated hematocrit, and hypoalbuminemia. The systemic CLS may be difficult 
to recognize and diagnose on initial presentation. A characteristic triad of hypotension, 
hemoconcentration (elevated hematocrit, leukocytosis, and thrombocytosis), and 
hypoalbuminemia in the absence of secondary causes of shock is typical. Although CLS has 
no pathognomonic marker, it should be considered in any patient with acute, severe 
hypotension, without obvious cardiac dysfunction - particularly if it is unresponsive to or 
worsens despite aggressive IV fluid resuscitation or vasopressor support and is accompanied 
by an elevated hematocrit. Treatment of the acute phase is generally supportive, focusing on 
adequate but not overzealous fluid resuscitation (Druey and Greipp, 2010). The references 
are provided as guidance only. Management of the subjects is ultimately at the PI’s or 
designee’s discretion.
The sponsor recommends that any subject with any Grade 2 weight change, decrease in 
albumin (> 1 mg/dL), hypotension, peripheral edema, hypoxia or pulmonary AEs be 
thoroughly evaluated for other signs and symptoms consistent with CLS. Monitoring for the 
development of CLS, as well as instructions for supportive care in the event of CLS are 
outlined in Section 5.2.2.4.
CLS should be suspected if any of the following are observed:
1. A requirement for fluids in excess of 20 mL/kg/hour to treat hypotension.
2. Grade 3 hypotension in temporal association with CLS.
3. Symptomatic pulmonary edema requiring supplemental oxygen or > 10% (absolute) 
decrease in oxygen saturation in the absence of another clinical explanation.
 
Any changes in body weight must be reported by the subject or caregiver to the staff at the 
site so the subject can be monitored closely for any other signs/symptoms suggestive of CLS 
or HUS. PIs should consider inpatient hospitalization for subjects who show signs or have 
symptoms of CLS.


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If subjects develop any grade of CLS during study treatment, 
 
 
 
 
 a disease assessment including bone marrow examination is 
encouraged, but not mandatory.
Instructions to the site on how to record (in the eCRF) and report these events (to 
MedImmune Patient Safety) are provided in Section 7.4.3 and Section 7.6.4, respectively.
7.3.2
Thrombotic Microangiopathy/Hemolytic Uremic Syndrome
Thrombotic microangiopathy/HUS is characterized by the triad of microangiopathic 
hemolytic anemia, thrombocytopenia, and progressive renal failure. Patients also 
may develop various combinations of pulmonary edema, systemic arterial hypertension, 
neurologic dysfunction, and cardiac abnormalities (Corrigan and Boineau, 2001;
Banerjee et al, 2009).
If HUS is suspected, the PI or designee will monitor the subject to confirm or rule out a 
diagnosis of HUS. Subjects with Grade 2 or higher HUS will be admitted for inpatient 
management.
HUS will be graded using the following expanded guidelines:
Grade 1: Evidence of RBC destruction, without clinical consequences:
◦
The appearance of schistocytosis (≥ 5/high power field [HPF]) in a subject with no 
schistocytosis at baseline, or an increase in the frequency of schistocytes (≥5/HPF)
over baseline.
Grade 2: Laboratory findings without clinical consequences:
◦
Microangiopathic anemia (schistocytosis as defined for Grade 1, and decreased Hgb 
by 1 g/dL), and
◦
Mild renal insufficiency (increased creatinine, Grade 1).
Grade 3: Laboratory findings with clinical consequences (eg, renal insufficiency, petechiae):
◦
Microangiopathic anemia (schistocytosis as defined for Grade 1, and decreased Hgb 
by 1 g/dL), and/either:
◦
Grade 4 Thrombocytopenia if platelets were normal at baseline; or


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◦
Moderate renal insufficiency (increased creatinine, Grade 2 if normal at baseline or 
1 grade worse than baseline).
Grade 4: Laboratory findings with life-threatening or disabling consequences (eg, CNS 
hemorrhage/bleeding, or thrombosis/embolism, or renal failure) laboratory findings:
◦
Microangiopathic anemia (schistocytosis as defined for Grade 1, and decreased Hgb 
by 1 g/dL), and/either:
◦
Thrombocytopenia (Grade 4, if platelets were normal at baseline), or
◦
Moderate renal insufficiency (increased creatinine, Grade 3 if normal at baseline or 
2 grades worse than baseline).
Subjects meeting all of the above criteria for Grade 2-4 HUS except for the requirement ≥5 
schistoscytes/HPF will be defined as having an “HUS-like event”. Subjects experiencing an 
HUS-like event should be managed and reported using the same guidelines as for subjects 
meeting all criteria for HUS.
Any subject with Grade 1-4 HUS or Grade 2-4 HUS-like event will be evaluated with serial 
haptoglobin, LDH, CBCs, peripheral smear, and urinalyses. Peripheral blood smears will be 
used to assess for schistocytes. Subjects need not be managed with plasmapheresis, and 
rather may be managed with fluid repletion and/or diuretics and other supportive measures at 
the discretion of the PI or designee. Diuresis early on may worsen the creatinine by causing 
dehydration, and should only be used to treat symptoms of fluid overload. Subjects should be 
observed carefully for evidence of severe HUS, including mental status abnormalities, renal 
failure, and bleeding from severe thrombocytopenia. For additional management, PIs or 
designee may refer to the following publications: Ariceta et al, 2009 and Michael et al, 2009.
If subjects develop any grade of HUS during study treatment, 
 
 
 
 
 a disease assessment including bone marrow examination is 
encouraged, but not mandatory.
 
 
Instructions to the site on how to record (in the eCRF) and report this event (to MedImmune 
Patient Safety) are provided in Section 7.4.3 and Section 7.6.4, respectively. Each reported 


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event of thrombotic microangiopathy/HUS of Grade 3 or greater will be followed by the PIs
or designees and evaluated by the sponsor. 
 
 
 
 
 
 
7.3.3
Ocular Events
Ocular events of special interest to the sponsor are defined as any clinically significant 
change in vision, retinal abnormalities, or choroidal disturbance that occurs during the course 
of the study. Subjects will be queried for ocular symptoms at screening, prior to initiation of 
a new treatment cycle, prior to administration of each moxetumomab dose, and at the end of 
treatment. 
In the event of visual symptoms ≥ Grade 2, ophthalmologic evaluation is required. If a 
subject has an ocular event with new abnormality by ophthalmologic examination during 
study treatment, PK and immunogenicity samples, and serum complement factors and serum 
Ig levels will be collected within 24 hours of diagnosis, during the event as clinically 
indicated (eg, in order to capture peak intensity of event as well as at least one time point 
during period of improvement), and after resolution of the event. 
Due to the potential association of HUS with retinal damage, subjects should be hospitalized 
with daily monitoring of renal function with serum creatinine and close observation. If the 
subject displays any retinal abnormalities, dosing with the investigational agent must be 
permanently discontinued. 
In the event of an ocular event or symptoms occur without any evidence of retinal 
abnormalities, dosing must be interrupted and may not resume until there is full resolution of 
ocular symptoms. 
In the event of an ocular event where the etiology is unknown, timely follow-up 
investigations and inquiries must be initiated by the investigational site, based on medical 
judgment, to make an informed decision regarding the etiology of the event. Ocular events 
will be followed to resolution until the end of subject participation in the study. Prompt 
notification of the sponsor is required as with other AESIs.


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Instructions to the site on how to record (in the eCRF) and report these events (to 
MedImmune Patient Safety) are provided in Section 7.4.3 and Section 7.6.4, respectively.
7.4
Recording of Adverse Events
AEs will be recorded on the eCRF using a recognized medical term or diagnosis that 
accurately reflects the event. AEs will be assessed by the investigator for severity, 
relationship to the investigational product, possible etiologies, and whether the event meets 
criteria of an SAE and therefore requires immediate notification to MedImmune Patient 
Safety. See Section 7.2 for the definition of SAEs and Appendix 4 for guidelines for 
assessment of severity and relationship. If an AE evolves into a condition that meets the 
regulatory definition of “serious,” it will be reported on the SAE Report Form.
Infusion of biological products is commonly associated with infusion related reactions. 
Anaphylaxis and infusion related reactions have some common manifestations and may be 
difficult to distinguish from each other. Infusion related reactions are commonly observed 
during or shortly after the first time exposure to therapeutic monoclonal antibodies delivered 
through IV infusion. These reactions are less common following subsequent exposures. 
Unlike infusion related reactions, anaphylaxis is a rare event, usually occurring after 
subsequent exposure to an antigen, and it is most commonly accompanied by severe systemic 
skin and or mucosal reactions. The Investigator is advised to carefully examine symptoms of 
adverse reactions observed during or shortly after exposure to moxetumomab pasudotox, and 
consider the above mentioned facts prior to making a final diagnosis. Reactions occurring at 
the time of or shortly after subsequent infusions of investigational product are to be judged 
by the investigator at his/her own discretion. For the Investigator’s convenience and in order 
to facilitate consistency in judgments a copy of the National Institute of Allergy and 
Infectious Diseases (NIAID) and Food and Allergy Anaphylaxis Network (FAAN) guidance 
for anaphylaxis diagnosis is provided in Appendix 5.
7.4.1
Time Period for Collection of Adverse Events
All AEs and SAEs will be recorded from the time of informed consent. AEs will be collected 
within 4 weeks prior to treatment enrollment, throughout the treatment period, and 4-6 weeks 
after the last dose (end of treatment).


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7.4.2
Follow-up of Unresolved Adverse Events
Any AEs that are unresolved at the subject’s last AE assessment or other assessment/visit as 
appropriate in the study are followed up by the investigator for as long as medically 
indicated, but without further recording in the eCRF. MedImmune retains the right to request 
additional information for any subject with ongoing AE(s)/SAE(s) at the end of the study, if 
judged necessary.
7.4.3
Recording of Adverse Events of Special Interest 
7.4.3.1
Hepatic Function Abnormality
Events of hepatic function abnormality (as defined in Section 7.6.2) should be recorded in the 
eCRF according to the definitions of AE and SAE (Section 7.1 and Section 7.2, 
respectively):
•
If the underlying diagnosis for the hepatic function abnormality is known (including 
progression of pre-existing disease such as primary or metastatic malignancy), the 
diagnosis should be recorded as an AE/SAE per Section 7.4.
If the underlying diagnosis for the hepatic function abnormality remains unknown, the term 
“hepatic function abnormal” should be used to report the AE/SAE per Section 7.4.
7.4.3.2
Capillary Leak Syndrome
Events of CLS (as defined in Section 7.3.1) should be recorded in the eCRF according to the 
definitions of AE and SAE (Section 7.1 and Section 7.2, respectively).
7.4.3.3
Thrombotic Microangiopathy/Hemolytic Uremic Syndrome
Events of thrombotic microangiopathy/HUS (as defined in Section 7.3.2) and HUS-like 
events should be recorded in the eCRF according to the definitions of AE and SAE 
(Section 7.1 and Section 7.2, respectively).
7.4.3.4
Ocular Events
Ocular events (as defined in Section 7.3.3) should be recorded in the eCRF according to the 
definitions of AE and SAE (Section 7.1 and Section 7.2, respectively).




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consequences of the overdose are serious, for example death or hospitalization, the event is 
serious and must be reported as an SAE (Section 7.4 and Section 7.5). MedImmune does not 
recommend specific treatment for an overdose. The investigator will use clinical judgment to 
treat any overdose.
7.6.2
Hepatic Function Abnormality
AEs of hepatic function abnormality of special interest to the sponsor are defined as any 
increase in ALT or AST to greater than 3 × ULN and concurrent increase in bilirubin to 
greater than 2 × ULN (ie, Hy’s law cases). Concurrent findings are those that derive from a 
single blood draw or from separate blood draws taken within 8 days of each other. In the 
event of hepatic function abnormality where the etiology is unknown, timely follow-up 
investigations and inquiries should be initiated by the investigational site, based on medical 
judgment, to make an informed decision regarding the etiology of the event. 
If the underlying diagnosis for the hepatic function abnormality is known (including 
progression of pre-existing disease such as primary or metastatic malignancy), the diagnosis 
should be recorded as an AE/SAE.
If the underlying diagnosis for the hepatic function abnormality remains unknown, the term 
“hepatic function abnormal” should be used to report the AE/SAE.
 
 
 
 
The investigator will review the data with the medical monitor. The investigator should then 
use clinical judgment to establish the cause based on local standard of care and follow the 
subject by conducting testing as clinically indicated.
•
If, after appropriate workup, in the opinion of the investigator, the underlying diagnosis 
for the abnormality remains unexplained, or is considered attributable to investigational 
product, permanent discontinuation of dosing for the study subject should be considered.
Each reported event of hepatic function abnormality will be followed by the investigator and 
evaluated by the sponsor. 


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7.6.3
Pregnancy
Pregnancy in a female subject who has received investigational product is required to be 
reported within 24 hours of knowledge of the event to MedImmune Patient Safety or 
designee using the Safety Fax Notification Form (see Section 7.5 for contact information).
Subjects who become pregnant during the study period must not receive additional doses of 
investigational product and will be withdrawn from the study. The pregnancy will be 
followed for outcome of the mother and child (including any premature terminations) and 
should be reported to MedImmune Patient Safety or designee after outcome.
Should the investigator become aware of a pregnancy in the partner of a male study subject 
who has received investigational product this should be reported within 24 hours of 
knowledge of the event to MedImmune Patient Safety or designee using the Safety Fax 
Notification Form (see Section 7.5 for contact information). The sponsor will endeavor to 
collect follow-up information on such pregnancies provided the partner of the study subject 
provides consent.
7.6.4
Other Adverse Events of Special Interest 
If any AESIs defined in Section 7.3 require immediate reporting to Patient Safety, including 
the following: Events of CLS, HUS and ocular events (as defined in Section 7.3) are 
required to be reported within 24 hours of knowledge of the event to MedImmune Patient 
Safety using the SAE Report Form, even if the event is considered to be non-serious (see 
Section 7.5 for contact information). 
7.7
Safety Management During the Study
The MedImmune medical monitor has primary responsibility for the ongoing medical review 
of safety data throughout the study. This includes review of SAEs and timely review of AEs 
and “other events” reported during the study. MedImmune Patient Safety is responsible for 
the receipt, immediate review, investigation, and follow-up of SAEs and other immediately 
reportable events (eg, overdose and pregnancies) reported from the clinical study sites.
A DMC will be convened to review the study data after the first 15 subjects have been 
treated at a dose level of 40 μg/kg. The DMC will continue to evaluate safety at a frequency 
of at least every 6 months during the study to identify any safety signals (Section 13.7). 
8
PHARMACEUTICAL INFORMATION
Other Names: CAT-8015, HA22


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Classification: Recombinant anti-CD22 MAb Conjugated Immunotoxin
Molecular Weight: 63.5 kDa
Mode of Action: Moxetumomab pasudotox specifically binds to CD22 on the cell surface of 
B cells. Following binding, the complex is endocytosed and then processed to release the 
exotoxin. The exotoxin domain is translocated to the cytosol, where it catalyzes the 
adenosine diphosphate ribosylation of elongation factor 2, causing inhibition of protein 
translation and subsequent cell death.
Description: Moxetumomab pasudotox is a recombinant conjugated immunotoxin composed 
of a disulfide-stabilized anti-CD22 Ig Fv genetically fused to a truncated form of 
Pseudomonas exotoxin, PE38.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




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Route of Administration: IV infusion
 
 
 
 
 
 
8.1
Additional Study Medications
No other study medications are specified for use in this clinical protocol.
8.2
Labeling
Labels for the investigational product will be prepared in accordance with Good 
Manufacturing Practice (GMP) and local regulatory guidelines. Label text will be translated 
into local languages, as required.
8.3
Treatment Compliance
Investigational product is administered by study site personnel, who will monitor 
compliance.




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9.2
Laboratory Correlative Studies
A laboratory manual will be provided to the sites that specifies the procedures for collection, 
processing, storage, and shipment of samples, as well as laboratory contact information, 
specific to this clinical research study.
9.2.1
Evaluation of Immunogenicity 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9.2.2
Bone Marrow Aspirate Minimal Residual Disease Analysis
 
 
 
 
 
 
 


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9.2.3
Peripheral Blood Flow Cytometry
 
 
 
 
 
 
 
 
 
9.2.4
Lymphocyte Enumeration 
 
 
 
9.2.5
Peripheral Blood Disease B-cell Clone Detection
 
 
 
 
 
 
9.3
Sample Storage, Tracking, and Disposition
All research samples will be used for the assays specified in this protocol. The assays will be 
performed using the entire sample designated for the particular study. 


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The PI would be notified upon discovery of sample loss or unplanned destruction associated 
with unforeseen problems such as, but not limited to, natural disasters, laboratory or 
equipment malfunctions and human error. The PI (or designee) would in turn notify the IRB. 
All patient samples that are shipped to 
 and stored must have patient identifying 
information removed to maintain patient anonymity. These samples will be used only for 
purposes described in the protocol and informed consent form and remaining samples will be 
destroyed at the end of the study. Assay results will be kept in a secure database prior to 
disclosure in the final study report and any public disclosure (manuscripts, presentations,
etc).


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10 STUDY CALENDAR
Table 10-1
Study Calendar for Cycle 1 and Subsequent Cycles
Evaluation/Intervention
Screening a
Pre-cycle b
Day 1
Day 3
Day 5
Day 8
(±1D)
Day 15
(±2D) c
Day 21 
(±2D) c
Informed consent, demographics, medical history, 
height, β-HCG
X
Adverse events and concurrent medications
X
X
X
X
X
X
X
X
Physical exam, pulse oximetry, query for visual symptoms
X
X
X
X
X
Ophthalmologic exam
X
12-lead ECG (analyzed by central vendor ERT)
X
X
X d
X d
CBC with differential ([peripheral blood smear with schistocyte 
count (selected timepoints]) e
X e
X e
X
X
X
X e
X
X
Urinalysis
X
X
HBsAg, HBcAB, HepC, Hepatitis B Viral DNA load (if needed), 
HLA, C3, C4, CH50, serum and urine protein electrophoresis, PFTs 
(if needed)
X
Sodium, potassium, chloride, bicarbonate, glucose, BUN, creatinine, 
calcium, magnesium, phosphorous, AST, ALT, total bilirubin, direct 
bilirubin, LDH, albumin, AlkPhos, 
X
X
X
X
X
X
X
X
Total protein, triglycerides, cholesterol, GGT, PT, PTT, fibrinogen, 
serum amylase, serum lipase, uric acid, fT4, TSH, CK, IgG, IgA, 
and IgM, CRP, serum ferritin, Haptoglobin 
X
X
 
CT or MRI abdomen for lymph nodes and organomegaly g
X
BM biopsy & aspirate (flow cytometry/sequencing)
X
Clinical response assessment
X




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Table 10-1
Study Calendar for Cycle 1 and Subsequent Cycles
Evaluation/Intervention
Screening a
Pre-cycle b
Day 1
Day 3
Day 5
Day 8
(±1D)
Day 15
(±2D) c
Day 21 
(±2D) c


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Table 10-2
Study Calendar for End of Treatment and Follow-up
Evaluation/Intervention
EOT a
From end of treatment assessment
Yearly 
Thereafter
(± 1M)
Every month
for 6 months
(if in CR)
(± 1W)
Every 3 months 
for 24 months
(± 2W)
181D
(+ 2W)
12 months
(± 1M)
18 months
(± 1M)
History and Physical exam
X
X
X
X
X
Vital signs including pulse oximetry and weight
X
X
X
X
X
Performance Status
X
X
X
X
X
Concurrent medications
X
X
X b
X b
X b
Adverse events
X
Ophthalmologic exam
X
12-lead ECG (analyzed by central vendor ERT)
X
Imaging with CT or MRI of abdomen c
X
X
X
BM biopsy and aspirate (flow 
cytometry/sequencing)
X
X d
Clinical response assessment
X
X
X
X
CBC with differential (no peripheral blood smear) 
X
X e
X e
X
X
X
X
Chem 7 (sodium, potassium, chloride, bicarbonate, 
glucose, BUN, creatinine)
X
X
X
X
X
Mineral panel (calcium, magnesium, phosphorous, 
albumin) 
X
X
X
X
X
Hepatic panel (AST, ALT, total  bilirubin, direct 
bilirubin, AlkPhos)
X
X
X
X
X
Uric acid, LDH, total protein, triglycerides, 
cholesterol, GGT, PT, PTT, fibrinogen, quantitative 
immunoglobulins, CK, CRP, serum ferritin
X
X
TSH, fT4, serum amylase, serum lipase, 
haptoglobin, urinalysis
X
X




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11 MEASUREMENT OF EFFECT
For the purposes of this study, patients will receive up to 6 cycles of therapy as described in 
Section 5.3.  Bone marrow examination and radiographic disease assessment will be 
performed at screening, the end of treatment, and 6 months post-end of treatment.  If during 
treatment and prior to completion of 6 cycles of therapy, blood counts are consistent with CR 
for at least 4 weeks, an interim disease assessment may be performed at the discretion of the 
investigator.  If a CR without MRD is documented, treatment will be discontinued.  For any 
other response, treatment should be continued to complete 6 cycles of therapy, with the full 
disease assessment repeated at EOT (Table 10-2).
11.1
Response Criteria
Following the end of treatment, 6 month post-end of treatment, and interim (during 
treatment; if applicable) disease assessment, the Principal or Associate Investigator will 
record the tumor response. Responses include: CR with or without MRD, PR, stable disease
(SD), PD, and relapse. The Principal or Associate Investigator will also record the clinical 
response prior to each treatment cycle, and at each follow-up visit after the 6 month post-end 
of treatment assessment. PD may only be used during therapy. Once a subject has ended 
therapy, worsening of disease no longer meeting criteria for best response will be 
designated as disease relapse.  Response criteria will be based on previous HCL studies
(Cheson et al, 1998; Grever et al, 1995; Hoffman et al, 1997; Catovsky et al, 1987). Although 
the requirements varied slightly among these trials, certain requirements are well accepted 
and considered standard. Isolated laboratory values not consistent with a response may be 
ignored in the assessment of a response, at the discretion of the investigator, if preceded and 
followed by the values for the same laboratory that are consistent with the identified 
response, or if they occur within the first 12 days of the cycle. The CBC used as a baseline 
for determining improvement is generally the last one prior to drug, unless that CBC is not 
representative of others immediately preceding it and is thought to contain lab errors.  
Response is verified independently through a central disease response assessment vendor to 
be determined.
Complete Response with or without Minimal Residual Disease 
CR ± MRD requires all of the following to be present: 
•
No evidence of leukemic cells in the peripheral blood and/or by routine H/E staining of 
bone marrow. Minimal Residual Disease: CR with HCL evident in blood or marrow by 
flow cytometry or in bone marrow biopsy by immunohistochemistry (NOTE: A second 
confirmatory bone marrow examination is not required).


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•
Resolution of any hepatomegaly, splenomegaly, and abnormal (≥2 cm minimum length) 
lymphadenopathy by CT or MRI. Although a normal spleen size is not defined, the 
maximum diameter of the spleen should be either < 17 cm or have decreased by >25%
from its baseline.
•
Normal CBC as exhibited by: Neutrophils ≥ 1.5 x 109/L, Platelets ≥ 100 x 109/L, and 
Hemoglobin ≥ 11.0 g/dL without transfusions or growth factors for at least 4 weeks.
Definition of Hematologic Remission
HR is defined as the blood counts required for CR. The primary endpoint requires that CRs 
maintain HR for >180 days after first achieving CR. Once a CR is achieved, the HR duration 
is not interrupted by transient decreases in normal blood counts. 
Complete Response Duration
The duration of complete remission is calculated from the time of achievement of all criteria 
of CR to the time of relapse from CR. Relapse from CR will be defined as any CR criteria 
(blood counts, imaging or bone marrow) no longer consistent with CR. However, to meet the 
primary endpoint, patients will need to achieve CR and then maintain a HR for >180 days.
Partial Response
PR requires all of the following for a period of at least 4 weeks (NOTE: PR does not require 
bone marrow examination): 
The patient must have the following (if abnormal prior to treatment): 
•
≥ 50% decrease or normalization (<5.0 x 109/L) in peripheral blood lymphocyte count 
from the pretreatment baseline value, 
•
≥ 50% reduction in lymphadenopathy by CT or MRI, based on sum of products of 
perpendicular diameters, or resolution to size consistent with CR,
•
≥ 50% reduction in abnormal hepatosplenomegaly by CT or MRI, or resolution to size 
consistent with CR,
•
Neutrophils ≥ 1.5x 109/L or 50% improvement over baseline without growth factors for 
at least 4 weeks, 
•
Platelets ≥ 100 x 109/L or 50% improvement over baseline, and 
•
Hemoglobin ≥ 11.0 g/dL or 50% improvement over baseline without transfusions or 
growth factors for at least 4 weeks. For patients who are transfusion-dependent at 
baseline, a hemoglobin of ≥ 9.0 g/dL without transfusions or growth factors for at least 
4 weeks. 


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•
The beginning of PR will be considered the beginning of the 4-week duration of required 
blood counts meeting PR criteria.
Progressive Disease
PD is defined by at least one of the following compared to pretreatment: 
•
≥ 25% increase in the sum of the products of the greatest perpendicular dimensions of at 
least two lymph nodes by CT or MRI on two consecutive examinations at least 2 weeks 
apart (at least 1 node must be ≥ 2 cm in minimum length) or appearance of new palpable 
lymph nodes
•
≥ 50% increase in the absolute number of circulating lymphocytes, on two consecutive 
examinations showing abnormal lymphocytosis at least 2 weeks apart
•
≥ 25% decrease in hemoglobin (must be < 11g/dL), platelets (must be < 100 x 109/L), or 
ANC (must be < 1.5 x109/L) unless these are judged to be effects of treatment.
Stable Disease 
SD will be characterized by not meeting the criteria for CR, PR, or PD as outlined above. 
Relapse 
•
Relapse from CR:  Loss of criteria needed for CR, excluding transient decrease in lab 
values below criteria for CR.
•
Relapse from PR:  Loss of criteria needed for PR, excluding transient decrease in lab 
values below criteria for PR.
•
Relapse from SD:  Patients who meet above criteria for PD when compared to
measurements after end of therapy.
11.2
Data Collection
Data will be collected prospectively and entered into
according to the data 
management plan. The PI is responsible for the collection, maintenance and quality control 
of study data.
Quality assurance complete records must be maintained on each patient treated on the 
protocol. These records should include primary documentation (eg, laboratory report slips, 
X-ray reports, scan reports, pathology reports, physician notes, etc) which confirm that:
•
The patient met all eligibility criteria


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•
Signed informed consent was obtained prior to treatment
•
Treatment was given according to protocol (dated notes about doses given, 
complications, and clinical outcomes)
•
Toxicity was assessed according to protocol (laboratory report slips, etc)
•
Response was assessed according to protocol (X-ray, scan, lab reports, date noted on 
clinical assessment, as appropriate)
All data will be kept secure. Personal identifiers will not be used when collecting and storing 
data. An enrollment log will be maintained in the regulatory binder/file which is the only 
location of personal identifiers with unique SID number.
12 STUDY AND DATA MANAGEMENT
12.1
IRB/IEC Approvals 
The PI will provide the sponsor with a copy of the participating institution’s approved 
continuing review. Registration will be halted at any participating institution in which a 
current continuing approval is not on file at the IRB/IEC.
12.2
Study Agreements
The PI at each center should comply with all the terms, conditions, and obligations of the 
Clinical Study Agreement, or equivalent, for this study. In the event of any inconsistency 
between this Clinical Study Protocol and the Clinical Study Agreement, the terms of Clinical 
Study Protocol shall prevail with respect to the conduct of the study and the treatment of 
subjects and in all other respects, not relating to study conduct or treatment of subjects, the 
terms of the Clinical Study Agreement shall prevail.
Agreements between the sponsor and the PI must be in place before any study-related 
procedures can take place, or subjects are enrolled.
12.3
Archiving of Study Documents
The Investigator follows the principles outlined in the Clinical Study Agreement.
12.4
Training of Study Site Personnel
A sponsor representative will review and discuss the requirements of the Clinical Study 
Protocol and related documents with the investigational staff and also train them in any 
study-specific procedures and system(s) utilized.


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The PI will ensure that appropriate training relevant to the study is given to all of these staff, 
and that any new information relevant to the performance of this study is forwarded to the 
staff involved.
The PI will maintain a record of all individuals involved in the study (medical, nursing and 
other staff).
12.5
Monitoring of the Study
During the study, a sponsor representative will have regular contacts with the study site, 
including visits to:
•
Provide information and support to the investigator(s)
•
Confirm that facilities remain acceptable
•
Confirm that the investigational team is adhering to the protocol, that data are being 
accurately and timely recorded in the eCRFs, that biological samples are handled in 
accordance with the Laboratory Manual and that study drug accountability checks are 
being performed
•
Perform source data verification (a comparison of the data in the eCRFs with the 
subject’s medical records at the hospital or practice, and other records relevant to the 
study) including verification of informed consent of participating subjects. This will 
require direct access to all original records for each subject (eg, clinic charts)
•
Ensure withdrawal of informed consent to the use of the subject’s biological samples is 
reported and biological samples are identified and disposed of/destroyed accordingly, and 
the action is documented, and reported to the subject.
The sponsor representative will be available between visits if the investigator(s) or other staff 
at the center needs information and advice about the study conduct.
12.5.1
Protocol Deviation
A protocol deviation is generally an unplanned excursion from the protocol that is not 
implemented or intended as a systematic change. A protocol deviation may be categorized as 
major or minor depending on its effect on the risk/benefit; subject's rights, safety, or welfare; 
and/or on the integrity of the data. 
A major protocol deviation generally increases risk or decreases benefit; affects the subject's 
rights, safety, or welfare; or affects the integrity of the data. Examples include failure to 
obtain informed consent, obtaining informed consent after initiation of study procedures, 
failure to report SAE to the IRB or sponsor, and failure to document drug administration. A 
minor protocol deviation does not increase risk or decrease benefit; does not have a 


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significant effect on the subject's rights, safety, or welfare; and/or does not have a significant 
effect on the integrity of the data. Examples include receiving prior radioimmunotherapy 
between 6 months to 2 years prior to enrollment in study and missing optional visits.
The investigator(s) should document any deviation from the protocol regardless of the reason 
for the deviation. Only when the protocol was not followed in order to avoid an immediate 
hazard to the subjects or for other medically compelling reason, the investigator should 
prepare and submit the records explaining the reasons thereof to MedImmune and the head of 
study site and retain a copy of the records.
13 STATISTICAL CONSIDERATIONS
13.1
General Considerations
Data will be provided in data listings sorted by subject number and in tabular summaries.
Categorical data will be summarized by the number and percentage of subjects in each 
category. Continuous variables will be summarized by descriptive statistics, including mean, 
standard deviation, median, minimum, and maximum. Confidence intervals (CIs) will be 
two-sided, unless otherwise stated. Details of endpoint analyses will be described in the 
statistical analysis plan.
13.2
Analysis Populations
The intent-to-treat (ITT) subject population will include all subjects who have been entered 
into the study and treated by moxetumomab pasudotox. The ITT population is the primary 
population for the efficacy analyses and the summary of baseline characteristics. 
The efficacy evaluable subject population will include all subjects who have received at least 
1 dose of moxetumomab pasudotox and have a baseline and at least one post baseline disease 
assessment including bone marrow examination and cross sectional imaging. The evaluable 
subject population will be identified prior to database lock and will be the secondary 
population for efficacy analysis.
The safety subject population will include all subjects who receive at least 1 dose of 
moxetumomab pasudotox.
13.3
Primary Endpoint
The primary objective of this study of moxetumomab pasudotox in relapsed HCL is to 
determine the rate of durable CR, defined as the proportion of subjects who meet blood, bone 
marrow, and imaging criteria for CR, followed by a > 180 day duration of HR, with HR 


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being defined as the blood counts needed for CR. The durable CR rate and its 95% CI will be 
constructed using the exact probability method (Clopper-Pearson exact interval) in the Intent-
to-Treat population.
 
 
 Seventy-seven subjects will 
provide 90% power to detect a difference between 28% and 13% durable CR rates using 
2-sided significance level of 0.05. As a supportive analysis, the durable CR rate and its 95% 
CI will be estimated based on the evaluable population. 
 
 
The central independent review of disease response and disease progression will be the basis 
for primary analyses. Blinded independent review of response to treatment will be 
performed by a central vendor. An imaging manual will be distributed to provide guidance to 
both imaging and study personnel regarding review of scanning parameters and associated 
activities required for study image collection. Bone marrow slides will be used for response 
assessment. Images, pathology slides from bone marrow biopsies/aspirates, reports of CBC,
and associated documentation must be acquired as instructed in this manual and submitted to 
the central vendor. 
13.4
Secondary Endpoints
The secondary objectives of this study are to evaluate the safety of moxetumomab pasudotox
in this subject population, other antitumor activities, PK, and immunogenicity.
13.4.1
Other Antitumor Activities
Other assessments of antitumor activity include rate of CR, objective response (OR), time to 
response (TTR), duration of CR and OR, and PFS.
13.4.1.1
CR Rate, Duration of CR (Disease-Free Survival), and Duration of 
Hematologic Remission
The CR rate is defined as the proportion of subjects that have achieved CR. The 95% CI of 
the CR rate will be constructed using the exact probability method (Clopper-Pearson exact 
interval). Duration of CR (also called disease-free survival) will be measured from the first 
documentation of CR (by imaging, bone marrow biopsy and blood counts) to the time of 
relapse as defined in Section 11.1. Duration of HR will be measured from the first 
documentation of CR (by imaging, bone marrow biopsy and blood counts) to the time of loss 
of HR. Duration of CR will be censored on the date of the last disease assessment or clinical 


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response assessment for subjects who have no documented relapse prior to data cutoff, 
dropout, or the initiation of alternative anticancer therapy. Duration of HR will be censored 
on the date of the last evaluable hematologic assessment for subjects who have no 
documented loss of HR prior to data cutoff, dropout, or the initiation of alternative anticancer 
therapy. The proportion of subjects with a CR and HR at certain time points (eg, 6 month, 1 
year, or 2 year) and the median duration of CR and HR may be estimated, if feasible, for the 
subgroup of subjects with CR using the Kaplan-Meier method. It should be noted that CR 
duration, which may be shorter than HR duration, is a secondary endpoint and will be 
summarized separately.
13.4.1.2
Objective Response Rate
Objective response rate is defined as the proportion of subjects with CR or PR. The 95% CIs 
of ORR will be estimated using the exact probability method.
13.4.1.3
Time to Response
Time to response will be measured from the start of moxetumomab pasudotox administration 
to the first documentation of response (CR or PR). Descriptive statistics of time to response 
(median, minimum, and maximum) will only be summarized for subjects who have achieved 
objective response. 
13.4.1.4
Duration of Objective Response
Duration of objective response will be measured from the first documentation of objective
response to the event of relapse as defined in Section 11.1. Duration of objective response 
will be censored on the date of last disease assessment for subjects who have no documented 
relapse prior to data cutoff, dropout, or the initiation of alternative anticancer therapy. 
Duration of objective response will be summarized descriptively by using minimum and 
maximum of duration of objective response observed at a certain follow-up period. The 
proportion of subjects with response at certain time points (eg, 6 month, 1 year, or 2 year) 
and the median duration of response may be estimated, if feasible, for the subgroup of 
subjects with objective response using the Kaplan-Meier method.
13.4.1.5
Progression-Free Survival
PFS is measured from the start of moxetumomab pasudotox administration to relapse, PD, or 
death from any cause. Relapse is considered post-end of treatment when patients no longer 
meet criteria required for their best response (Section 11.1). PFS will be censored on the last 
hematologic assessment for subjects without relapse, PD, or death. PFS will be evaluated 
using the Kaplan-Meier method.


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13.4.1.6
Time to Treatment Failure
TTF will be measured from the start of moxetumomab pasudotox administration until 
relapse, PD, initiation of alternate cancer therapy, or death due to disease or disease-related 
complication. (Else et al, 2009). TTF will be censored as in PFS but will also be censored for 
death not accompanied by relapse, and will also be evaluated using the Kaplan-Meier 
method.
13.4.2
Safety Assessment
Safety endpoints include assessment of AEs, SAEs, changes in clinical laboratory 
evaluations and vital signs. The occurrence of AEs, abnormal laboratory values, and SAEs 
reported from the first administration of moxetumomab pasudotox through 30 days after last 
dose of moxetumomab pasudotox will be summarized for all subjects who received any 
moxetumomab pasudotox. AEs and SAEs will be graded according to the NCI CTCAE V4.0
and described by system organ class and by Medical Dictionary for Regulatory Activities 
(MedDRA) preferred term, severity, and relationship to moxetumomab pasudotox. 
Frequency rates will be calculated for each system organ class and MedDRA preferred term.  
13.4.3
Pharmacokinetic Assessment
Individual moxetumomab pasudotox serum concentrations will be tabulated by treatment 
cycles along with descriptive statistics. Noncompartmental PK data analysis will be 
performed for Cycle 1 and 2 concentration data using scheduled or actual PK sample 
collection times.
If data allows, descriptive statistics of noncompartmental PK parameters will be provided. 
 
13.4.4
Immunogenic Potential of Moxetumomab Pasudotox 
Immunogenicity results will be listed for each subject. The number and percentage of 
subjects who develop detectable ADA and NAb will be summarized. Titers and specificity 
will be reported for NAb-positive subjects. The impact of ADA on PK, safety and efficacy 
will be evaluated if data allow. Summaries of ADAs and NAbs will be provided at the 
completion of the study and will not be performed on a real-time basis.


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13.5
Sample Size and Power Calculations
The sample size estimation in this study is based on the assumption that the historical durable 
CR rate in this population is ≤ 13% (null hypothesis). 
 
, a total 
of 77 subjects will provide 90% power to detect a difference between 28% and 13% durable 
CR rates at a 2-sided significance level of 0.05.
 
 
 
13.6
Early stopping Rule Due to Lack of Efficacy
 
 
 
13.7
Data Monitoring Committee 
An external DMC composed of individuals with no involvement in the study will be 
employed. The committee will review safety data, including AEs, SAEs, treatment-related 
mortality, and laboratory data. The planned DMC analysis will occur after the first 15 
subjects are treated and followed for at least one treatment cycle and every 6 months 
thereafter until the end of the study. 
 
 The committee will report its 
findings to an internal MedImmune safety review committee. In addition, the DMC may be 
asked by the medical monitor or a MedImmune safety review committee to independently 
review data on an ad hoc basis. At each review, the DMC will make a recommendation to 
continue the study with or without modification, or to halt enrollment for safety concerns. 
This recommendation will be relayed to a MedImmune safety review committee and 
appropriate action will be taken. Where applicable, regulatory authorities and IRBs/IECs will 
be notified of any actions taken with the study.


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14 HUMAN SUBJECTS PROTECTIONS
14.1
Ethical Conduct of the Study
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH/Good Clinical Practice, and applicable 
regulatory requirements.
14.2
Rationale for Subject Selection
Subjects with histologically confirmed HCL will be eligible for participation in this study. 
Individuals of any race or ethnic group will be eligible for this study. Eligibility assessment 
will be based solely on the patient’s medical status.  
14.3
Evaluation of Benefits and Risks/Discomforts
14.3.1
Benefits
The potential benefits to patients on this study, based on the results of a completed Phase 1 
study in subjects with multiply relapsed HCL, include a high ORR and CR rate that is 
durable (Section 2.2). This may lead to improved disease-free survival and overall survival
compared to available salvage therapies.
14.3.2
Risks
The primary risks of participation in this study include the possible occurrence of any of a 
range of side effects from moxetumomab pasudotox which are described in Section 2.2 and 
in the consent document. Frequent monitoring for adverse effects and exclusion of subjects at 
risk for these adverse effects will help to minimize the risks associated with administration.
14.3.2.1
Important Potential Risks
 
 
 
 
 
 


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Potential Risks Common to Any Immunoglobulin
Potentially severe or fatal infusion-related reactions and acute IgE-mediated allergic 
reactions may occur following the administration of any Ig. 
Administration of polyclonal Ig preparations and mAbs has been associated with infusion-
related reactions that occur during or shortly after dosing such as fever, chills, myalgia, 
nausea, vomiting, pruritus, rash, headache, flushing, sweating, tachycardia, dyspnea, 
bronchospasm, hypotension, dizziness or lightheadedness, and hemodynamic instability. 
These reactions are more common with higher doses, higher rates of infusion, and in subjects 
with a history of allergies. 
IgE-mediated allergic reactions may include hypotension, dyspnea, cyanosis, respiratory 
failure, urticaria, pruritus, angioedema, hypotonia, and unresponsiveness. Acute severe 
allergic reactions (anaphylaxis) usually occur soon after exposure, usually within 10 minutes. 
Subjects may experience paresthesia, hypotension, laryngeal edema, mental status changes, 
facial or pharyngeal angioedema, airway obstruction, bronchospasm, urticaria and pruritus, 
serum sickness, arthritis, allergic nephritis, glomerulonephritis, temporal arteritis, and death.
Potential Risks Associated with Immune Reactivity
 
 
 
 
 
 
 
 
Potential Risks Associated with Administration
Moxetumomab pasudotox is administered IV. Possible risks associated with IV 
administration of moxetumomab pasudotox are infection, redness, swelling, pain, and 
induration at the administration site.


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14.3.2.2
Identified Risks
 
 
 
 
 
 
 
14.4
Risks/Benefits Analysis
For patients with HCL without effective therapy, median survival is about 4 years. 
Moxetumomab pasudotox has shown activity
 in patients with
multiply relapsed HCL in an early phase clinical trial.
 
 
 
 For these reasons, the risk/benefit ratio of this protocol 
is favorable; 
 
14.5
Consent Process and Documentation
The investigational nature and objectives of this trial, the procedures and treatments involved 
and their attendant risks and discomforts, and the potential benefits will be carefully 
explained to the patient or the patient’s advocate. This process will include a general 
description of the disease process, as well as a description of the patient’s expected clinical 
course. Alternative therapies will be carefully explained, and outlined in the consent 
document. The patient will be asked to read the consent at his/her convenience and will be 
encouraged to ask questions. Enrollment on this study will only occur if the patient meets all 
eligibility criteria, is judged by the Investigator to potentially benefit from the therapy, is able 
and willing to provide full consent, and has signed the consent document. The PI or an 
associate investigator on the trial will obtain consent.
14.6
Ethics and Regulatory Review
An IRB/IEC should approve the final study protocol, including the final version of the 
Informed Consent Form and any other written information and/or materials to be provided to 


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the subjects. The investigator will ensure the distribution of these documents to the 
applicable IRB/IEC, and to the study site staff.
The opinion of the IRB/IEC should be given in writing. The investigator should submit the 
written approval to the sponsor before enrollment of any subject into the study. 
The IRB/IEC should approve all advertising used to recruit subjects for the study.
The sponsor should approve any modifications to the Informed Consent Form that are needed 
to meet local requirements.
If required by local regulations, the protocol should be re-approved by the IRB/IEC annually.
Before enrollment of subjects, the final study protocol, including the final version of the 
Informed Consent Form, should be approved by or notified to the national regulatory 
authority, according to local regulations.
The sponsor or sponsor’s designee will provide regulatory authorities and PIs with safety 
updates/reports according to local requirements, including suspected unexpected serious 
adverse reactions (SUSARs), where relevant.
Each PI is responsible for providing IRB/IECs with reports of SUSARs with the 
investigational product. The sponsor will provide this information to the PI so that he/she can 
meet these reporting requirements.
14.7
Changes to the Protocol and Informed Consent Form
If there are any substantial changes to the study protocol, then these changes will be 
documented in a study protocol amendment and where required in a new version of the study 
protocol.
The amendment is to be approved by the relevant IRB/IEC and if applicable, also the 
national regulatory authority, before implementation. Local requirements are to be followed 
for revised protocols.
MedImmune will distribute any subsequent amendments and new versions of the protocol to 
each PI. For distribution to IRB/IEC see Section 14.6.
If a protocol amendment requires a change to a site’s Informed Consent Form, MedImmune 
and the site’s IRB/IEC are to approve the revised Informed Consent Form before the revised 
form is used. 


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If local regulations require, any administrative change will be communicated to or approved 
by each IRB/IEC.
14.8
Audits and Inspections
Authorized representatives of MedImmune, a regulatory authority, or an IRB/IEC may 
perform audits or inspections at the center, including source data verification. The purpose of 
an audit or inspection is to systematically and independently examine all study-related 
activities and documents, to determine whether these activities were conducted, and data 
were recorded, analyzed, and accurately reported according to the protocol, GCP, guidelines 
of the ICH, and any applicable regulatory requirements. The investigator will contact 
MedImmune immediately if contacted by a regulatory agency about an inspection at the site.


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the peripheral blood and bone marrow” to “No evidence of leukemic cells in the 
peripheral blood and/or by routine H/E staining of bone marrow.” 
 
 
 In addition, the replacement of “and” with “and/or” was done 
to align with both ESMO and NCCN guideline regarding the definition of CR. See 
reference: Grever MR. How I treat hairy cell leukemia. Blood. 2010;115(1):21-28.
4. Section 12.5 (Clinical Monitoring) – A new subsection 12.5.1 (Protocol Deviation) 
was added. 
 
 
 
 
 
 
5. Section 13.3 (Primary Endpoint) –
 
 
 
 
6. Section 13.3 (Primary Endpoint) – A sentence was added after the sentence 
“…review of scanning parameters and associated activities required for study image 
collection.” The new text is “Bone marrow slides will be used for response 
assessment.” 
 
7. Section 13.3 (Primary Endpoint) – The text “from bone marrow biopsies/aspirates, 
reports of CBC” was added to the sentence “Images, pathology slides from bone 
marrow…” The revised sentence is “Images, pathology slides from bone marrow 
biopsies/aspirates, reports of CBC, and associated documentation must be acquired
as instructed in this manual and submitted to the central vendor.”
 
 
8. Section 13.4.1.1 (CR Rate, Duration of CR (Disease-Free Survival), and Duration of 
Hematologic Remission) – The text “as defined in Section 11.1” was added at the end 
of to the sentence “Duration of CR (also called disease-free survival) will be 


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measured …” The revised sentence is “Duration of CR (also called disease-free 
survival) will be measured from the first documentation of CR (by imaging, bone 
marrow biopsy and blood counts) to the time of relapse as defined in Section 11.1.”
9. Section 13.4.1.1 (CR Rate, Duration of CR [Disease-Free Survival], and Duration of 
Hematologic Remission) – The sentence “Duration of CR and HR will be 
censored…” was revised to “Duration of CR will be censored on the date of the last 
disease assessment or clinical response assessment for subjects who have no 
documented relapse prior to data cutoff, dropout, or the initiation of alternative 
anticancer therapy.” A new sentence explaining how the duration of HR will be 
censored was added as follows: “Duration of HR will be censored on the date of the 
last evaluable hematologic assessment for subjects who have no documented loss of 
HR prior to data cutoff, dropout, or the initiation of alternative anticancer therapy.”
 
10. Section 13.4.1.4 (Duration of Objective Response) – The text “as defined in 
Section 11.1” was added at the end of the sentence “Duration of objective response 
will be measured...” The revised text is “Duration of objective response will be 
measured from the first documentation of objective response to the event of relapse as 
defined in Section 11.1.” 
11. Section 13.4.1.5 (Progression-Free Survival) – The text “PFS is measured from the 
start of moxetumomab pasudotox administration to relapse, PD, initiation of 
alternative anticancer therapy, or death from any cause (Saven et al, 1998; Else et al, 
2009)” was changed to “PFS is measured from the start of moxetumomab pasudotox 
administration to relapse, PD, or death from any cause.” 
 
12. Section 13.4.1.5 (Progression-Free Survival) – The text “PFS will be censored on the 
last hematologic assessment for subjects without relapse, PD, alternate therapy, or 
death” was changed to “PFS will be censored on the last hematologic assessment for 
subjects without relapse, PD, or death.” 
 








































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Appendix 1
Signatures


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Sponsor Signature(s)
A Pivotal Multicenter Trial of Moxetumomab Pasudotox in Relapsed/Refractory Hairy Cell 
Leukemia
I agree to the terms of this protocol.
Signature and date: 
 
One MedImmune Way, Gaithersburg MD, 20878, USA 


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Signature of Principal Investigator
A Pivotal Multicenter Trial of Moxetumomab Pasudotox in Relapsed/Refractory Hairy Cell 
Leukemia 
I, the undersigned, have reviewed this protocol and all amendments, and I agree to conduct 
this protocol in accordance with ethical principles that have their origin in the Declaration of 
Helsinki and are consistent with the International Conference on Harmonisation (ICH) 
guidelines on Good Clinical Practice (GCP), any applicable laws and requirements, and any 
conditions required by a regulatory authority and/or Institutional Review Board/Independent 
Ethics Committee (IRB/IEC). 
I understand that the protocol may not be modified without written approval of the sponsor. 
All changes to the protocol must be submitted to the applicable regulatory authority and 
IRB/IEC, and must be approved by the IRB/IEC prior to implementation except when 
necessary to eliminate immediate hazards to the subjects or when the change(s), as deemed 
by the sponsor, involves only logistical or administrative changes. Documentation of 
IRB/IEC approval must be sent to the sponsor immediately upon receipt.
Signature and date: 
Name and title: 
Address including postal code: 
Telephone number: 
Site/Center Number (if available)
This document contains confidential information, which should not be copied, referred to, released, or published 
without written approval from MedImmune or AstraZeneca. Investigators are cautioned that the information in 
this protocol may be subject to change and revision.


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Appendix 2
Performance Status Criteria
ECOG Performance Status Scale
Karnofsky Performance Scale
Grade
Descriptions
Percent
Description
0
Normal activity.  Fully active, able to 
carry on all pre-disease performance 
without restriction.
100
Normal, no complaints, no evidence of 
disease.
90
Able to carry on normal activity; minor 
signs or symptoms of disease.
1
Symptoms, but ambulatory.  Restricted 
in physically strenuous activity, but 
ambulatory and able to carry out work 
of a light or sedentary nature (e.g., light 
housework, office work).
80
Normal activity with effort; some signs or 
symptoms of disease.
70
Cares for self, unable to carry on normal
activity or to do active work.
2
In bed <50% of the time.  Ambulatory 
and capable of all self-care, but unable 
to carry out any work activities.  Up and 
about more than 50% of waking hours.
60
Requires occasional assistance, but is able 
to care for most of his/her needs.
50
Requires considerable assistance and 
frequent medical care.
3
In bed >50% of the time.  Capable of 
only limited self-care, confined to bed 
or chair more than 50% of waking 
hours.
40
Disabled, requires special care and 
assistance.
30
Severely disabled, hospitalization 
indicated.  Death not imminent.
4
100% bedridden.  Completely disabled.  
Cannot carry on any self-care.  Totally 
confined to bed or chair.
20
Very sick, hospitalization indicated. Death 
not imminent.
10
Moribund, fatal processes progressing 
rapidly.
5
Dead.
0
Dead.


MedImmune
Protocol CD-ON-CAT-8015-1053 Amendment 9
Moxetumomab pasudotox
29Mar2017; Final
CONFIDENTIAL AND PROPRIETARY
107 of 111
Appendix 3
Cockcroft-Gault Equation
A commonly used surrogate marker for actual creatinine clearance is the Cockroft-Gault 
formula, which employs creatinine measurements and a patient's weight to predict the 
clearance (Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum 
creatinine. Nephron., 16(1):31-41 (1976)). 
The formula, as originally published, is: 
This formula expects weight (actually mass) to be measured in kilograms and creatinine to be 
measured in mg/dL, as is standard in the USA. The resulting value is multiplied by a constant 
of 0.85 if the patient is female. This formula is useful because the calculations are relatively 
simple and can often be performed without the aid of a calculator. 


MedImmune
Protocol CD-ON-CAT-8015-1053 Amendment 9
Moxetumomab pasudotox
29Mar2017; Final
CONFIDENTIAL AND PROPRIETARY
108 of 111
Appendix 4
Additional Safety Guidance
Assessment of Severity
Assessment of severity is one of the responsibilities of the investigator in the evaluation of 
AEs and SAEs. Severity will be graded according to the National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI CTCAE) V4.0 as provided in below. The 
determination of severity for all other events not listed in the CTCAE should be made by the 
investigator based upon medical judgment and the severity categories of Grade 1 to 5 as 
defined below.
Grade 1 (mild)
An event that is usually transient and may require only minimal 
treatment or therapeutic intervention. The event does not 
generally interfere with usual activities of daily living.
Grade 2 (moderate)
An event that is usually alleviated with additional specific 
therapeutic intervention. The event interferes with usual 
activities of daily living, causing discomfort but poses no 
significant or permanent risk of harm to the subject.
Grade 3 (severe)
An event that requires intensive therapeutic intervention. The 
event interrupts usual activities of daily living, or significantly 
affects the clinical status of the subject.
Grade 4 (life threatening)
An event, and/or its immediate sequelae, that is associated with 
an imminent risk of 
Grade 5 (fatal)
Death (loss of life) as a result of an event.
It is important to distinguish between serious criteria and severity of an AE. Severity is a 
measure of intensity whereas seriousness is defined by the criteria in Section 7.2. A Grade 3 
AE need not necessarily be considered an SAE. For example, a Grade 3 headache that 
persists for several hours may not meet the regulatory definition of an SAE and would be 
considered a nonserious event, whereas a Grade 2 seizure resulting in a hospital admission 
would be considered an SAE.


MedImmune
Protocol CD-ON-CAT-8015-1053 Amendment 9
Moxetumomab pasudotox
29Mar2017; Final
CONFIDENTIAL AND PROPRIETARY
109 of 111
Assessment of Relationship
Relationship to Investigational Product
The investigator is required to provide an assessment of relationship of AEs and SAEs to the 
investigational product.
An event will be considered “not related” to use of the investigational product if any of the 
following tests are met:
•
An unreasonable temporal relationship between administration of the investigational 
product and the onset of the event (eg, the event occurred either before, or too long after, 
administration of the investigational product for it to be considered product-related)
•
A causal relationship between the investigational product and the event is biologically 
implausible (eg, death as a passenger in an automobile accident)
•
A clearly more likely alternative explanation for the event is present (eg, typical adverse 
reaction to a concomitant drug and/or typical disease-related event)
Individual AE/SAE reports will be considered “related” to use of the investigational product 
if the “not related” criteria are not met. 
“Related” implies that the event is considered to be “associated with the use of the drug” 
meaning that there is “a reasonable possibility” that the event may have been caused by the 
product under investigation (ie, there are facts, evidence, or arguments to suggest possible 
causation).
Relationship to Protocol Procedures
The investigator is also required to provide an assessment of relationship of SAEs to protocol 
procedures on the SAE Report Form. This includes nontreatment-emergent SAEs (ie, SAEs 
that occur prior to the administration of investigational product) as well as treatment-
emergent SAEs. A protocol-related SAE may occur as a result of a procedure or intervention 
required during the study (eg, blood collection, washout of an existing medication). The 
following guidelines should be used by investigators to assess the relationship of SAEs to the 
protocol:
Protocol related:
The event occurred due to a procedure/intervention that was described 
in the protocol for which there is no alternative etiology present in the 
subject’s medical record.


MedImmune
Protocol CD-ON-CAT-8015-1053 Amendment 9
Moxetumomab pasudotox
29Mar2017; Final
CONFIDENTIAL AND PROPRIETARY
110 of 111
Not protocol related: The event is related to an etiology other than the procedure/ 
intervention that was described in the protocol (the alternative etiology 
must be documented in the study subject’s medical record).


MedImmune
Protocol CD-ON-CAT-8015-1053 Amendment 9
Moxetumomab pasudotox
29Mar2017; Final
CONFIDENTIAL AND PROPRIETARY
111 of 111
Appendix 5
National Institute of Allergy and Infectious Diseases 
(NIAID) and Food and Allergy Anaphylaxis Network 
(FAAN) Guidance for Anaphylaxis Diagnosis
Sampson HA, Muñoz-Furlong A, Campbell RL, Adkinson FN Jr, Bock SA, Branum A, et al. 
Second symposium on the definition and management of anaphylaxis: Summary report --
Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis 
Network symposium. J Allergy Clin Immunol. 2006;117:391-7.
NAID and FAAN define anaphylaxis as a serious allergic reaction that is rapid in onset and 
may cause death. They recognize 3 categories of anaphylaxis, with criteria designated to 
capture from 80% of cases (category 1) to >95% of all cases of anaphylaxis (for all 3 
categories). 
1. Acute onset of an illness (minutes to several hours) with involvement of the skin, 
mucosal tissue, or both (eg, generalized hives, pruritus or flushing, swollen lips-tongue-
uvula)
AND AT LEAST ONE OF THE FOLLOWING
2. Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced PEF, 
hypoxemia)
3. Reduced BP or associated symptoms of end-organ dysfunction (eg, hypotonia [collapse], 
syncope, incontinence)
4. Two or more of the following that occur rapidly after exposure to a likely allergen for 
that patient (minutes to several hours):
5. Involvement of the skin-mucosal tissue (eg, generalized hives, itch-flush, swollen lips-
tongue-uvula)
6. Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced PEF, 
hypoxemia)
7. Reduced BP or associated symptoms (eg, hypotonia [collapse], syncope, incontinence)
8. Persistent gastrointestinal symptoms (eg, crampy abdominal pain, vomiting)
9. Reduced BP after exposure to known allergen for that patient (minutes to several hours):
a.
Infants and children: low systolic BP (age specific) or greater than 30% decrease in 
systolic BP
b. Adults: systolic BP of less than 90 mm Hg or greater than 30% decrease from that 
person’s baseline

SAP_000.pdf: 


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1 
INTRODUCTION 
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2 
STUDY OVERVIEW 
2.1.1 
Study Objectives 
2.1.2 
Primary Study Objective 
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2.1.3 
Secondary Study Objectives 
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2.1.4 
Exploratory Study Objectives 
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2.2 
Study Design 
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3.2 
Analysis Populations 
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Table 3.2-1 
Analysis Populations 
Population 
Description 
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3.3 
Study Subjects 
3.3.1 
Subject Disposition and Completion Status 
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3.3.2 
Demographics and Baseline Characteristics 
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3.3.3 
Study Drug Exposure 
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3.3.4 
Concomitant Medications 
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3.4 
Protocol Deviations 
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3.5 
Efficacy Endpoints and Analyses 
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3.5.1 
Efficacy Endpoints  
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3.5.1.1 
Durable CR 
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Table 3.5.1.1-1 
Summary of Censoring Guidelines for Duration of HR 
Situation 
Date of Event or Censoring 
Outcome 
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Table 3.5.1.1-2 
Sensitivity Analysis 1: Summary of Censoring Guidelines for 
Duration of HR 
Situation 
Date of Event or Censoring 
Outcome 
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Table 3.5.1.1-2 
Sensitivity Analysis 1: Summary of Censoring Guidelines for 
Duration of HR 
Situation 
Date of Event or Censoring 
Outcome 
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Table 3.5.1.1-3 
Sensitivity Analysis 2: Summary of Censoring Guidelines for 
Duration of HR 
Situation 
Date of Event or Censoring 
Outcome 
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3.5.1.2 
CR
 
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3.5.1.3 
Time to CR 
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3.5.1.4 
Duration of CR 
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Table 3.5.1.4-1 
Summary of Censoring Guidelines for Duration of CR per 
BICR 
Situation 
Date of PD/Relapse/Death or 
Censoring 
PFS Outcome 
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KHPDWRORJLFDVVHVVPHQW
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5HODSVHLPPHGLDWHO\DIWHUFRQVHFXWLYHPLVVHG
RUQRQHYDOXDEOHGLVHDVHDVVHVVPHQWV
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UHODSVH
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RUKHPDWRORJLFDVVHVVPHQWSULRUWR
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Table 3.5.1.4-2 
Summary of Censoring Guidelines for Duration of CR per 
Investigator 
Situation 
Date of PD/Relapse/Death or 
Censoring 
PFS Outcome 
5HODSVH
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RUFOLQLFDOUHVSRQVHDVVHVVPHQW
VKRZLQJDQRQ&5UHVSRQVHDIWHU&5
RQVHWGDWHRIORVVRI+5RUGDWHRI
GHDWKZKLFKHYHULVHDUOLHU
(YHQW
1RUHODSVHRUGHDWKDWWKHWLPHRIDQDO\VLV
'DWHRIWKHODVWGLVHDVHDVVHVVPHQW
FOLQLFDOUHVSRQVHDVVHVVPHQWRU
KHPDWRORJLFDVVHVVPHQWZKLFKHYHU
RFFXUUHGODVW
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5HODSVHLPPHGLDWHO\DIWHUFRQVHFXWLYHPLVVHG
RUQRQHYDOXDEOHGLVHDVHDVVHVVPHQWV
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FOLQLFDOUHVSRQVHDVVHVVPHQWRU
KHPDWRORJLFDVVHVVPHQWSULRUWR
PLVVHGRUQRQHYDOXDEOHDVVHVVPHQWV
ZKLFKHYHURFFXUUHGODVW
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UHODSVH
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FOLQLFDOUHVSRQVHDVVHVVPHQWRU
KHPDWRORJLFDVVHVVPHQWSULRUWR
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3.5.1.5 
Objective Response 
2EMHFWLYHUHVSRQVHLVGHILQHGDVWKH%25RI&5RU35
3.5.1.6 
Time to Objective Response 
7LPHWRREMHFWLYHUHVSRQVHLVGHILQHGDVWKHWLPHIURPWKHVWDUWRIPR[HWXPRPDESDVXGRWR[
DGPLQLVWUDWLRQWRWKHILUVWGRFXPHQWDWLRQRIUHVSRQVH&5RU35DQGZLOORQO\EHHYDOXDWHG
IRUVXEMHFWVZLWKDQ25
3.5.1.7 
Duration of Objective Response 
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FHQVRUHGRQWKHGDWHRIODVWGLVHDVHDVVHVVPHQWFOLQLFDOUHVSRQVHDVVHVVPHQWRUKHPDWRORJLF
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3.5.1.8 
Progression Free Survival 
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 5HODSVH
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Table 3.5.1.8-1 
Summary of Censoring Guidelines for PFS per BICR 
Situation 
Date of PD/Relapse/Death or 
Censoring 
PFS Outcome 
'HDWKGRFXPHQWHG3URJUHVVLYH'LVHDVH3'RU
UHODSVH
(DUOLHVWGDWHRIDGLVHDVHDVVHVVPHQW
VKRZLQJD3'UHODSVHHDUOLHVWGDWH
RIKHPDWRORJLFUHODSVHDRUGDWHRI
GHDWKZKLFKHYHULVHDUOLHU
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'HDWKSULRUWRVHFRQGVFKHGXOHGSRVWEDVHOLQH
GLVHDVHDVVHVVPHQWZLWKRXWDQ\SRVWEDVHOLQH
GLVHDVHDVVHVVPHQWRULPPHGLDWHO\DIWHU 
PLVVHGRUQRQHYDOXDEOHGLVHDVHDVVHVVPHQW
IROORZLQJDQDGHTXDWHSRVWEDVHOLQHGLVHDVH
DVVHVVPHQW
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KHPDWRORJLFDVVHVVPHQWZKLFKHYHU
RFFXUUHGODVW
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WUHDWPHQW
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Table 3.5.1.8-2 
Summary of Censoring Guidelines for PFS per Investigator 
Situation 
Date of PD/Relapse/Death or 
Censoring 
PFS Outcome 
'HDWKGRFXPHQWHG3URJUHVVLYH'LVHDVH3'RU
UHODSVH
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RUFOLQLFDOUHVSRQVHDVVHVVPHQW
VKRZLQJD3'UHODSVHHDUOLHVWGDWH
RIKHPDWRORJLFUHODSVHDRUGDWHRI
GHDWKZKLFKHYHULVHDUOLHU
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GLVHDVHDVVHVVPHQWRULPPHGLDWHO\DIWHU 
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IROORZLQJDQDGHTXDWHSRVWEDVHOLQHGLVHDVH
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KHPDWRORJLFDVVHVVPHQWZKLFKHYHU
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Table 3.5.1.8-2 
Summary of Censoring Guidelines for PFS per Investigator 
Situation 
Date of PD/Relapse/Death or 
Censoring 
PFS Outcome 
'HDWKRU3'UHODSVHLPPHGLDWHO\DIWHU
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DVVHVVPHQWV
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3.5.1.9 
Time to Treatment Failure 
7LPHWRWUHDWPHQWIDLOXUH77)LVGHILQHGDVWKHWLPHIURPWKHVWDUWRIPR[HWXPRPDE
SDVXGRWR[DGPLQLVWUDWLRQWRWKHGDWHRIWKHILUVWRIUHODSVH3'LQLWLDWLRQRIDOWHUQDWLYH
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3.5.2 
Efficacy Analyses 
3.5.2.1 
Analyses of Primary Efficacy Endpoint 
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Exploratory Efficacy Endpoints and Analyses 
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Patient Reported Outcomes 
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Safety Analyses 
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3.9.5 
Other Safety Evaluations 
3.9.5.1 
Vital Signs 
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