A Phase I Study of Moxetumomab Pasudotox-tdfk (Lumoxiti (TM)) and Either Rituximab (Rituxan (R)) or Ruxience for Relapsed Hairy Cell Leukemia
Phase: PHASE1
Conditions: Hairy Cell Leukemia
Sponsor: National Cancer Institute (NCI)

Abbreviated Title: Moxe-R in HCL
Version Date: 04/16/2025
1
Abbreviated Title: Moxe-R in HCL
NIH Protocol #: 19C0042 
Version Date: 04/16/2025
NCT Number: NCT03805932
Title: A Phase I Study of Moxetumomab Pasudotox-tdfk (Lumoxiti™) and either Rituximab 
(Rituxan®) or Ruxience for Relapsed Hairy Cell Leukemia
NCI Principal Investigator:
Robert Kreitman, MD 
Chief, Clinical Immunotherapy Section
Laboratory of Molecular Biology (LMB)
Center for Cancer Research (CCR)
National Cancer Institute (NCI)
National Institutes of Health (NIH)
9000 Rockville Pike 
Building 37, Room 5124b
Bethesda, MD 20892 
Phone: 301-648-7375 
Email: kreitmar@mail.nih.gov
Commercial Agents: None
Drug Name:
Moxetumomab 
pasudotox-tdfk; CAT-
8015; HA22
Rituximab (Rituxan®)
Ruxience
IND Number:
140552
140552
140552
Sponsor:
Center for Cancer 
Research
Center for Cancer 
Research
Center for Cancer 
Research
Manufacturer:
AstraZeneca
Genentech
Pfizer
Supplier
AstraZeneca
CC Pharmacy
CC Pharmacy

Abbreviated Title: Moxe-R in HCL
Version Date: 04/16/2025
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PRÉCIS 
Background:
•
Hairy cell leukemia (HCL) is an indolent CD22+ B-cell leukemia comprising 2% of all 
leukemias, or approximately 1200 of the 62,130 new cases of leukemia/year in the US. HCL 
variant (HCLv), also CD22+, is 10-20% as common as HCL, but more common in the 
relapsed/refractory population due to its poor prognosis and response to standard purine analog 
chemotherapy. HCLv cells are CD25-negative and wild type for BRAF, so HCLv patients are 
not candidates for BRAF inhibitors. CD25+ classic-appearing HCL-cells that express 
unmutated IGHV4-34 are wild-type for BRAF, remain brightly CD22 positive, and confer a 
poor prognosis when treated with chemotherapy.
•
Moxetumomab pasudotox-tdfk is a recombinant immunotoxin containing a variable domain 
(Fv) fragment of an anti-CD22 monoclonal antibody and truncated Pseudomonas exotoxin, 
which kills CD22+ cells by binding to CD22 via the Fv fragment, and induction of apoptotic 
cell death catalytic inhibition of protein synthesis in the cytosol.
•
Moxetumomab pasudotox-tdfk in phase 1 testing demonstrated a high complete response (CR) 
rate in patients with chemoresistant HCL, without dose-limiting toxicity (DLT), but with 
reversible grade 2 hemolytic uremic syndrome (HUS) not requiring plasmapheresis.
•
Moxetumomab pasudotox-tdfk completed multicenter phase 3 testing in 80 patients, meeting 
its CR endpoint, with 8.8% incidence each of capillary leak syndrome (CLS, grade 3-4 2.5%), 
and HUS (grade 3-4 6.3%), both reversible.
•
Moxetumomab pasudotox-tdfk is the only known non-chemotherapy-containing regimen for 
HCL which can consistently eradicate minimal residual disease (MRD), and this is associated 
with prolonged CR durations. Recently, US Food and Drug Administration (FDA) has 
accepted the Biologics License Application (BLA) for moxetumomab pasudotox-tdfk as 
the treatment of adult patients with HCL. 
•
Patients who did not achieve CR, or CR with MRD, often made neutralizing antibodies to the 
bacterial-based toxin, and/or had collections of HCL cells not completely eradicated by 
moxetumomab pasudotox-tdfk. Both issues may be addressed by the addition of anti-CD20 
monoclonal antibody (Mab) rituximab or Ruxience to Moxetumomab pasudotox-tdfk.
Objective:
•
To determine the safety and toxicity of Moxetumomab pasudotox-tdfk and rituximab/Ruxience 
used at the planned dose level, in participants with HCL and HCLv.
Eligibility:
•
HCL or HCLv with at least 1 prior purine analog, and, for HCL participants with ≥2-years 1 
month response, at least 1 other therapy. 
•
Need for treatment, either 1) ANC <1/nL, 2) Hgb <10g/dL, 3) Plt <100/nL, 4) symptomatic 
splenomegaly, or enlarging HCL mass > 2cm in short axis
•
Serum creatinine < 1.5 mg/dL, or creatinine clearance ≥ 60 mL/min by Cockcroft-Gault 
equation, where creatinine clearance = (140-age)(kg weight)/(72 x Creatinine).
•
No uncontrolled infection or cardiopulmonary dysfunction

Abbreviated Title: Moxe-R in HCL
Version Date: 04/16/2025
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Design:
•
Phase I trial, two arm, non-randomized, dose escalation
•
Administration:
o
Participants 1-13: Moxetumomab pasudotox-tdfk 30-40 mcg/kg intravenous (iv) over 30 
min, rituximab 375 mg/m2 iv, 50-400 mg/hr.
o
Participants 14-26: Moxetumomab pasudotox-tdfk 40 mcg/kg intravenous (iv) over 30 
min, Ruxience 375 mg/m2 iv, 50-400 mg/hr
o
Rituximab or Ruxience day 1 (begin day -2 on cycle 1), Moxetumomab pasudotox-tdfk 
days 1, 3, and 5.
o
Participants will receive up to 4 cycles past documentation of CR without MRD, maximum 
8.
o
To prevent renal toxicity and hypovolemia, participants will be encouraged to drink water 
gradually, approximately 1 cup/hour or 6L/day, not going >3 hours without drinking from 
days 1 to 8 and to keep a hydration diary to record daily fluid consumption.
o
To prevent rituximab/Ruxience toxicity, participants will receive prophylactic 
dexamethasone orally 0.5-2 hours before the 1st dose of rituximab/Ruxience, and before 
subsequent doses until rituximab/Ruxience infusion reactions are not seen. Participants 
will also receive diphenhydramine, famotidine and acetaminophen.
o
Dexamethasone 4 mg orally (maximum 2 doses/day) will be given as needed to treat nausea 
or fever associated with Moxetumomab pasudotox-tdfk, which might prevent adequate 
water intake 
•
Statistical design:
o
Up to 26 participants are intended to be treated in the trial. While a total of 26 evaluable 
participants will be enrolled, the accrual ceiling will be set at 30 to include screen failures 
and inevaluable participants.

Abbreviated Title: Moxe-R in HCL
Version Date: 04/16/2025
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TABLE OF CONTENTS 
PRÉCIS............................................................................................................................................2
TABLE OF CONTENTS ................................................................................................................4
STATEMENT OF COMPLIANCE ................................................................................................6
1
INTRODUCTION ...................................................................................................................6
1.1
STUDY OBJECTIVES............................................................................................................6
1.2
BACKGROUND AND RATIONALE.........................................................................................6
2
ELIGIBILITY ASSESSMENT AND ENROLLMENT .......................................................11
2.1
ELIGIBILITY CRITERIA......................................................................................................11
2.2
SCREENING EVALUATION.................................................................................................13
2.3
PARTICIPANT REGISTRATION AND STATUS UPDATE PROCEDURES...................................14
2.4
BASELINE EVALUATION...................................................................................................15
3
STUDY IMPLEMENTATION .............................................................................................15
3.1
STUDY DESIGN.................................................................................................................15
3.2
DRUG ADMINISTRATION ..................................................................................................19
3.3
DOSE MODIFICATIONS .....................................................................................................22
3.4
STUDY CALENDAR...........................................................................................................23
3.5
COST AND COMPENSATION ..............................................................................................26
3.6
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA ...........26
4
CONCOMITANT MEDICATIONS/MEASURES...............................................................27
5
CORRELATIVE STUDIES FOR RESEARCH ...................................................................28
5.1
BIOSPECIMEN COLLECTION..............................................................................................28
5.2
PLANNED ANALYSES .......................................................................................................29
5.3
STORAGE, USE, AND SHARING OF SPECIMENS AND DATA (INCLUDING FOR SECONDARY 
RESEARCH).................................................................................................................................30
5.4
SAMPLES FOR GENETIC/GENOMIC ANALYSIS...................................................................31
6
DATA COLLECTION AND EVALUATION .....................................................................33
6.1
DATA COLLECTION..........................................................................................................33
6.2
DATA ELEMENTS..............................................................................................................33
6.3
DATA SHARING PLANS.....................................................................................................34
6.4
RESPONSE CRITERIA ........................................................................................................34
6.5
TOXICITY CRITERIA .........................................................................................................35
7
NIH REPORTING REQUIREMENTS / DATA AND SAFETY MONITORING PLAN...36
7.1
DEFINITIONS ....................................................................................................................36
7.2
OHSRP OFFICE OF COMPLIANCE AND TRAINING / IRB REPORTING................................36
7.3
NCI CLINICAL DIRECTOR REPORTING .............................................................................36
7.4
NIH REQUIRED DATA AND SAFETY MONITORING PLAN..................................................36
8
Sponsor safety reporting........................................................................................................37

Abbreviated Title: Moxe-R in HCL
Version Date: 04/16/2025
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8.1
DEFINITIONS ....................................................................................................................37
8.2
ASSESSMENT OF SAFETY EVENTS ....................................................................................38
8.3
REPORTING OF SERIOUS ADVERSE EVENTS......................................................................39
8.4
SAFETY REPORTING CRITERIA TO ASTRAZENECA(AZ) ...................................................39
8.5
REPORTING PREGNANCY..................................................................................................42
8.6
REGULATORY REPORTING FOR STUDIES CONDUCTED UNDER CCR-SPONSORED IND ....43
9
Clinical Monitoring ...............................................................................................................43
10
STATISTICAL CONSIDERATIONS ...............................................................................44
10.1
STATISTICAL HYPOTHESIS ...............................................................................................44
10.2
SAMPLE SIZE DETERMINATION ........................................................................................44
10.3
POPULATIONS FOR ANALYSES..........................................................................................46
10.4
STATISTICAL ANALYSES ..................................................................................................46
11
COLLABORATIVE AGREEMENTS...............................................................................47
11.1
CRADA...........................................................................................................................47
12
HUMAN SUBJECTS PROTECTIONS.............................................................................47
12.1
RATIONALE FOR SUBJECT SELECTION .............................................................................47
12.2
PARTICIPATION OF CHILDREN..........................................................................................47
12.3
PARTICIPATION OF SUBJECTS UNABLE TO GIVE CONSENT...............................................47
12.4
EVALUATION OF BENEFITS AND RISKS/DISCOMFORTS.....................................................47
12.5
CONSENT PROCESS AND DOCUMENTATION......................................................................50
13
REGULATORY AND OPERATIONAL CONSIDERATIONS.......................................51
13.1
STUDY DISCONTINUATION AND CLOSURE........................................................................51
13.2
QUALITY ASSURANCE AND QUALITY CONTROL ..............................................................52
13.3
CONFLICT OF INTEREST POLICY.......................................................................................52
13.4
CONFIDENTIALITY AND PRIVACY.....................................................................................52
14
PHARMACEUTICAL INFORMATION ..........................................................................53
14.1
MOXETUMOMAB PASUDOTOX-TDFK (LUMOXITI™) IND # 140552 .............................53
14.2
RITUXIMAB (RITUXAN®).................................................................................................54
14.3
RUXIENCE ........................................................................................................................56
15
REFERENCES ...................................................................................................................57
16
Appendices .........................................................................................................................60
16.1
APPENDIX A: PERFORMANCE STATUS CRITERIA..............................................................60
16.2
APPENDIX B: RITUXIMAB (RITUXAN®) AND RUXIENCE PREPARATION AND 
ADMINISTRATION .......................................................................................................................61
16.3
APPENDIX C: MOXETUMOMAB PASUDOTOX-TDFK (LUMOXITI™) PREPARATION AND 
ADMINISTRATION........................................................................................................................64
16.4
APPENDIX D: PARTICIPANT HYDRATION DIARY ..............................................................67

Abbreviated Title: Moxe-R in HCL
Version Date: 04/16/2025
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STATEMENT OF COMPLIANCE
The trial will be carried out in accordance with International Council for Harmonisation Good 
Clinical Practice (ICH GCP) and the following: 
•
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 
CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812) 
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are 
responsible for the conduct, management, or oversight of NIH-funded clinical trials have 
completed Human Subjects Protection and ICH GCP Training.
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the Institutional Review Board (IRB) for review and approval.  Approval of both 
the protocol and the consent form must be obtained before any participant is enrolled.  Any 
amendment to the protocol will require review and approval by the IRB before the changes are 
implemented to the study.  In addition, all changes to the consent form will be IRB-approved; an 
IRB determination will be made regarding whether a new consent needs to be obtained from 
participants who provided consent, using a previously approved consent form.
1
INTRODUCTION
1.1
STUDY OBJECTIVES
1.1.1
Primary Objective 
To determine the safety and toxicity of moxetumomab pasudotox-tdfk and rituximab/Ruxience 
treated at the planned dose level, in participants with HCL and HCLv.
1.1.2
Secondary Objectives
•
To determine the minimal residual disease (MRD)-free CR rate of the study drug 
combination is higher than that achieved with 40-50 mcg/kg dose levels of Moxetumomab 
pasudotox-tdfk alone.  
•
To determine response rates and duration of response.
1.1.3
Exploratory Objectives
•
To determine the incidence of anti-moxetumomab antibodies after combined treatment. 
•
To determine the plasma levels of moxetumomab pasudotox-tdfk with combined 
treatment.
•
To determine the effects of combined therapy on normal B and T-cells.
1.2
BACKGROUND AND RATIONALE
1.2.1
Background
Hairy cell leukemia (HCL) is an indolent CD22+ B-cell leukemia comprising 2% of all leukemias 
[1, 2], or approximately 1200 of the 62,130 new cases of leukemia/year in the US [3]. HCL variant 
(HCLv), also CD22+, is 10-20% as common as HCL, but more common in the relapsed/refractory 

Abbreviated Title: Moxe-R in HCL
Version Date: 04/16/2025
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population due to its poor prognosis and response to standard purine analog chemotherapy [4, 5]. 
HCLv cells are CD25-negative and wild type for BRAF, so HCLv patients are not candidates for 
BRAF inhibitors [6]. CD25+ classic-appearing HCL-cells that express unmutated IGHV4-34 are 
wild-type for BRAF, remain brightly CD22 positive, and confer a poor prognosis when treated 
with chemotherapy [7].
Moxetumomab pasudotox-tdfk is an anti-CD22 recombinant immunotoxin reported in the dose-
escalation part of a phase I trial to achieve 46% complete remission (CR) and 86% overall response 
(ORR) rates, without dose-limiting toxicity (DLT) [8]. Two patients had completely reversible 
grade 2 hemolytic uremic syndrome (HUS), but no chemotherapy-type myelosuppressive or 
cumulative toxicities were observed. 
Long-term follow-up of these 28 patients, including 12 who received the upper dose 50 mcg/kg 
every other day for 3 doses (QODx3), and an extension cohort of 21 patients receiving this dose, 
documented a CR rate of 64% in the 33 patients receiving 50 mcg/kg QODx3. Moreover, of 32 
patients evaluated for minimal residual disease (MRD) with bone marrow biopsy (BMBx) 
immunohistochemistry (IHC) and flow cytometry of blood and bone marrow aspirate (BMA), 11 
(34%) were MRD-negative. Median CR duration was not reached (up to 72 months) in those 
MRD-negative vs 13.5 months in those MRD+ (p<0.0001). Of the 3 tests for MRD, the most 
sensitive by far was BMA flow cytometry, and patients MRD+ by this study were sometimes 
positive by blood flow cytometry, IHC, or both [9]. Multicolor high sensitivity flow cytometry 
was used for both blood and BMA, and results read as suspicious are considered negative. MRD+ 
by IHC of BMBx requires at least as many B as T-cells, and for most of the B-cells to be consistent 
with HCL [10]. As exploratory endpoints, MRD is also determined by PCR, using consensus 
primers to a variable framework domain (FR1, FR2 or FR3), and a junctional or constant domain 
(JH or CH) of the immunoglobulin heavy chain rearrangement (IgH) [11, 12]. This assay, performed 
in the Molecular Pathology Section of the Laboratory of Pathology, NCI, is considered positive if 
the band corresponding to the HCL IgH can be recognized over a background of IgH bands from 
normal B-cells. Lack of normal B-cells, either due to HCL, chemotherapy or rituximab, may allow 
the HCL IgH band to more easily be seen. A research PCR assay is also done in the Kreitman Lab 
using patient- specific primers with a probe [11]. This patient- or clone-specific assay can detect 
1 HCL in 106 normal cells but requires a different PCR assay for each patient.
Of 32 patients at 50 mcg/kg QOD x3 evaluated for neutralizing (antidrug) antibodies, 24 (75%) 
had >50% neutralization of 200 ng/ml, and 17 (53%) had >75% neutralization of 1000 ng/ml of 
moxetumomab pasudotox-tdfk. Since CR duration was higher with compared to without 
consolidation cycles of moxetumomab pasudotox-tdfk (p=0.0004), and since early 
immunogenicity prevented consolidation cycles, prevention of immunogenicity is an important 
goal in immunotoxin treatment of HCL [9]. Further analysis of response vs immunogenicity, 
reported in the supplemental section of phase I report [9], showed trends for higher MRD-negative 
CR rate (8 of 15 vs. 3 of 17; P = .06) and longer CR duration (median undefined vs. 19.1 months, 
P = .05) in patients without vs. with antibodies neutralizing more than 75% of the activity of 1000 
ng/ml of moxetumomab pasudotox-tdfk. Pharmacokinetic analysis in this report showed that 
despite early neutralizing antibodies which made patients ineligible for future cycles (>50% 
neutralization of 200 ng/ml), we could observe increases in peak level and area under curve (AUC), 
and decreases in volume of distribution and clearance, from the 1st dose to the 3rd dose of the last 
cycle. This indicated that even secondary immunogenicity with moxetumomab pasudotox-tdfk in 

Abbreviated Title: Moxe-R in HCL
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HCL was too weak to prevent titration of antidrug antibodies by repeated dosing. This make it 
possible that an agent like rituximab, which could not prevent immunogenicity in solid tumors 
[13] receiving a large immunotoxin chemical conjugate, may prevent it in HCL patients with 
impaired immune system receiving a smaller recombinant immunotoxin. 
A phase 3 pivotal multicenter single-arm trial (NCT01829711) was designed for 
relapsed/refractory HCL patients with ≥2 prior systemic therapies including ≥1 prior purine 
analog. Patients received moxetumomab pasudotox-tdfk 40 mcg/kg intravenously on days 1, 3, 
and 5 of each 28-day cycle for 6 cycles, or until MRD-negative CR, disease progression, initiation 
of alternate therapy, or unacceptable toxicity. Disease response and immunohistochemistry MRD 
status were determined by blinded independent central review. The primary endpoint was durable 
CR, which required achieving CR and maintaining hematologic remission (HR) for >180 days). 
HR was defined as hemoglobin ≥11.0 g/dL, absolute neutrophil count ≥1.5/nL, and platelet count 
≥100/nL without transfusions or growth factors within the preceding 4 weeks of assessments. 
Eighty patients (63 males, 17 females; median age 60 years (range 34–84) were enrolled. The 
median number of previous systemic therapies was 3 (2–11); 48.8% of patients were purine analog 
refractory and 37.5% were unfit for purine analog retreatment. The median number of treatment 
cycles administered was 6 (1–7). As of May 24, 2017, the durable CR rate was 30.0%, 24/80 
patients; 95% confidence interval (CI): 20.3, 41.3). CR rate was 41.3% (33/80 patients; 95% CI: 
30.4, 52.8), and ORR was 75% (95% CI: 64.1, 84.0). Among 33 patients who achieved a CR, 27 
(81.8%) also achieved MRD negativity. Median time to OR was 5.7 months (95% CI: 5.7, 5.9). 
Sixty-four patients (80%) achieved hematologic remission. The median duration of hematologic 
remission from CR, median duration of response, and PFS were not reached.
Of 64 patients treated on the phase 1 (NCT01087333) and 3 (NCT01829711) trials at NIH with 
40-50 mcg/kg dose levels of moxetumomab pasudotox-tdfk and evaluated for MRD by bone 
marrow aspirate flow cytometry, the 30 (47%) of 64 achieved MRD-free CR.  
The most frequently reported adverse events (AEs) occurring in >40% of subjects overall were 
hypoalbuminemia (71.4%), increased ALT (67.3%); increased AST (63.3%), lymphopenia 
(59.2%), myalgia (57.1%); decreased white blood cell count (51.0%); pyrexia (49.0%); peripheral 
edema (44.9%); and hypertriglyceridemia (40.8%).
A total of 48 phase I subjects (98%) had AEs that were assessed by the investigator as related 
(possibly, probably, or definitely) to investigational product. The most frequent treatment-related 
AEs occurring in > 20% of subjects were hypoalbuminemia (69.4%), increased ALT (63.3%), 
increased AST (61.2%), peripheral edema (42.9%), pyrexia (42.9%), myalgia (40.8%), headache 
(36.7%), nausea (32.7%), fatigue (28.6%), edema (24.5%), hypotension (24.5%), and chills 
(22.4%). Treatment-related grade 3/4 AEs were reported in 30.0% of patients. Three deaths were 
reported (due to pneumonia, sepsis, and sepsis syndrome); none were considered treatment-related 
by the investigators. Treatment-related AEs that most frequently led to permanent discontinuation 
were hemolytic uremic syndrome (HUS), capillary leak syndrome (CLS), and blood creatinine 
increased, reported in 4 (5.0%), 2 (2.5%), and 2 (2.5%) patients, respectively. Seven patients 
(8.8%) had CLS (grade 2: n=5; grade 4: n=2), 7 patients (8.8%) had HUS (grade 2: n=2; grade 3: 
n=3; grade 4: n=2), and 4 patients (5.0%) had both CLS and HUS. In general, CLS and HUS events 
were manageable and reversible with appropriate supportive care, monitoring, and, in severe 
events, treatment discontinuation. Grade 3-4 AEs, regardless of attribution, occurring in at least 
2.5% of patients included lymphopenia (20%), hypophosphatemia or anemia (10%), leukopenia 

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(8.8%), hypertension, (7.5%), thrombocytopenia or neutropenia (6.3%), HUS, febrile neutropenia, 
or neutropenia (5%), and nausea, hypokalemia, hyponatremia, CLS, upper respiratory infection, 
hypoxia, lung infection, acute kidney injury, or erysipelas (2.5%). A number of eye changes have 
been reported in studies with moxetumomab pasudotox-tdfk; serious events including 
inflammation of the nerve for sight and retinal detachment have occurred in the acute 
lymphoblastic leukemia [14].
In this study, anti-drug antibodies were detected at baseline in 45/76 evaluable patients (59.2%). 
The frequency of neutralizing antibodies and anti-drug antibody titer increased with repeated 
cycles of treatment; reduced drug exposure was observed in patients with high-titer (>10,000) anti-
drug antibodies. Patients who achieved complete or partial response typically maintained antibody 
titers below 10,000 and therefore maintained drug exposure for more treatment cycles than patients 
with stable or progressive disease, suggesting that approaches to reduce the immunogenicity of 
moxetumomab pasudotox-tdfk might further improve response.
In the phase 3 trial, 70 (87.5%) patients received prior rituximab, and although we do not have 
extramural data regarding whether rituximab was used close to the time prior to enrollment, we do 
know that 2 of our patients received rituximab within 6 months prior to enrollment and therefore 
likely had positive rituximab levels during administration of moxetumomab pasudotox-tdfk. One 
patient had a transient HUS-like event, and one did not, both patients achieving MRD-negative 
CR. 
In summary, moxetumomab pasudotox-tdfk achieved a high rate of independently assessed, deep, 
and durable response, with ability to eradicate bone marrow MRD in heavily pretreated patients 
with HCL, and had a favorable safety profile, manageable and reversible CLS/HUS, and no 
associated myelo/immunosuppression. Both phase 1 and 3 data suggest its efficacy could be 
improved with addition of rituximab. Recently, US Food and Drug Administration (FDA) has 
accepted the Biologics License Application (BLA) for moxetumomab pasudotox-tdfk as the 
treatment of adult patients with HCL. 
Rituximab is a genetically engineered chimeric mouse/human IgG1 anti-CD20 monoclonal 
antibody (mAb) approved for the treatment of non-Hodgkin’s lymphoma, chronic lymphocytic 
leukemia, and moderate-to-severe rheumatoid arthritis [15]. Rituximab binds to CD20 on the 
surface of B cells and elicits a signaling cascade resulting in cell death. It also enhances antibody 
dependent and complement dependent cellular toxicity. Treatment with rituximab causes depletion 
of CD20+ B cells in peripheral blood and tissues, thereby reducing antigen presentation and 
activation of T cells, autoantibody production, and cytokine production [16, 17]. Rituximab has 
modest single-agent activity in relapsed HCL requiring treatment due to cytopenias, with CR rate 
13% and ORR 25% [18]. Rituximab has been used extensively at NCI for the treatment of HCL 
on two investigator sponsored trials (IST), either concurrently with the purine analogs cladribine, 
pentostatin or bendamustine, or in delayed fashion as a single agent for MRD clearance after 
cladribine. Rituximab reliably decreases circulating normal B-cells to undetectable levels for at 
least 6 months after the last dose. This decrease was not sufficient to block the immunogenicity of 
the highly immunogenic immunotoxin chemical conjugate LMB-1 in patients with solid tumors 
[13], but may be sufficient to block immunogenicity of the smaller recombinant immunotoxin 
moxetumomab pasudotox-tdfk in patients with HCL who have already compromised B-cell 
function and numbers. 
However, access to rituximab is limited by factors such as availability, reimbursement, and 

Abbreviated Title: Moxe-R in HCL
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10
insurance coverage. Moreover, patent portfolios for rituximab have expired or are nearing the end 
of term, which, in turn, has prompted the development of biosimilars [19]. Rituximab biosimilars 
are approved by the US Food and Drug Administration (FDA) (https://www.fda.gov/drugs/fda-
approves-truxima-biosimilar-rituxan-non-hodgkins-lymphoma). Ruxience was recently approved 
by the FDA for the treatment of non-Hodgkin’s lymphoma (NHL), chronic lymphocytic leukemia 
(CLL), 
and 
granulomatosis 
with 
polyangiitis 
and 
microscopic 
polyangiitis 
(https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/761103s000lbl.pdf). Ruxience has 
the same primary amino acid sequence as rituximab reference products [20]. Moreover, 
comparative studies have shown similar structural, functional, and animal toxicity profiles of 
Ruxience and rituximab [20]. Pharmacokinetic (PK) bioequivalence between Ruxience and 
rituximab-US has been demonstrated in subjects with rheumatoid arthritis [21].
Ruxience has been shown in several clinical trials to be equivalent to rituximab, including in a 
recent trial for follicular lymphoma in which similar CD19-positive B-cell depletion, safety, and 
immunogenicity between all treatment groups was demonstrated [22].
1.2.2
Rationale
Moxetumomab pasudotox-tdfk is the only known non-chemotherapy agent capable of eliminating 
HCL MRD in a high percentage of patients with relapse HCL, and in this patient population, 
elimination of MRD significantly prolongs CR duration. Of 11 participants on the phase I trial 
without MRD after 50 mcg/kg QODx3 of moxetumomab pasudotox-tdfk, 9 remained without 
MRD at 24-69 (median 42) months, suggesting that cure of this disease may be possible without 
chemotherapy.
Optimization of the effectiveness of moxetumomab pasudotox-tdfk, through combination with 
rituximab/Ruxience, may lead to more rapid and complete removal of tumor bulk and more 
effective tumor cell targeting of the immunotoxin, and at the same time, a decrease in 
immunogenicity through the action of both agents on normal B-cells. 
Avoidance of chemotherapy in the treatment of HCL may prevent long term and permanent 
damage to stem cells and CD4+ T-cell numbers, which might, to some extent, prevent 
opportunistic infections and secondary malignancies. In addition, purine analog chemotherapy is 
associated with cumulative neurotoxicity and myelodysplastic syndrome. Except in extremely rare 
cases, toxicity due to rituximab/Ruxience is limited to infusion reactions which can be mostly 
prevented by steroids and generally resolve after the 1st or 2nd of 8 weekly doses. Our experience 
with the cladribine-rituximab trial is that patients with significant HCL tumor burden cannot be 
safely initiated with rituximab without prophylactic steroid. 
If successful, this trial could potentially be used in newly diagnosed participants, since the standard 
of care is single-agent cladribine, which is associated with high CR rate but MRD in 76% of 
participants, and frequent late relapses. A chemo-free regimen capable of eliminating MRD would 
be a valuable goal for these participants.

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2
ELIGIBILITY ASSESSMENT AND ENROLLMENT 
2.1
ELIGIBILITY CRITERIA 
2.1.1
Inclusion Criteria
2.1.1.1
Diagnosis of HCL or HCLv. 
2.1.1.2
Treatment required for either 1) Absolute neutrophil count (ANC) <1/nL, 2) Hemoglobin 
<10g/dL, 3) Platelets<100/nL, 4) symptomatic splenomegaly, or 5) enlarging HCL mass 
> 2cm in short axis. Participants who have eligible blood counts within 4 weeks from the 
initiation of study will not be considered ineligible if subsequent blood counts prior to 
enrollment fluctuate and become ineligible up until the time of enrollment.
2.1.1.3
Participants must be Pseudomonas-immunotoxin naïve.
2.1.1.4
HCL or HCLv with at least 1 prior purine analog, and, for HCL participants with ≥2-
years 1 month response, at least 1 other therapy. 
2.1.1.5
Age >18 years as the disease under study, HCL/HCLv, has not been reported in children 
< age 18.
2.1.1.6
ECOG performance status <2 (Karnofsky >60%, see Appendix A: Performance Status 
Criteria).
2.1.1.7
Participants must have adequate organ and marrow function as defined below: 
• Total bilirubin ≤ 1.5 mg/dL, unless consistent with Gilbert’s (ratio between total and 
direct bilirubin > 5)
• AST and ALT ≤ 3x upper limit of normal (ULN)
• Alkaline phosphatase < 2.5 ULN
• Serum creatinine ≤ 1.5 mg/dL or creatinine clearance ≥ 60 mL/min by Cockcroft-Gault 
equation, where creatinine clearance = (140-age)(kg weight)/(72 x Creatinine)
• Serum albumin > 2 g/dL
• Partial thromboplastin time (PTT) or Prothrombin time (PT)/International Normalized 
Ratio < 2.5x ULN (If on warfarin, PT/INR < 3.5x ULN; If on any other anticoagulation, 
Prothrombin time (PT) < 2.5x baseline)
• Fibrinogen ≥ 0.5 lower limit of normal
2.1.1.8
The effects of moxetumomab pasudotox-tdfk and rituximab/Ruxience on the developing 
human fetus are unknown therefore participants must use effective methods of 
contraception as directed below. 
2.1.1.8.1 Females of childbearing potential (< 50 years) who are sexually active with a non-
sterilized 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 12 months after completion of rituximab/Ruxience 
administration. 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. Females of childbearing potential are 
defined as those who are not surgically sterile (i.e., bilateral tubal ligation, bilateral 
oophorectomy, or complete hysterectomy) or those who are premenarchal or 

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postmenopausal (defined as 12 months with no menses without an alternative 
medical cause). A highly effective method of contraception is defined as one that 
results in a low failure rate (i.e., less than 1% per year) when used consistently and 
correctly. Not all methods of contraception are highly effective. 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. 
2.1.1.8.2 Non-sterilized males who are sexually active with a female partner of childbearing 
potential must use an effective method of contraception from Day 1 until 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.
2.1.1.9
Ability of subject to understand and the willingness to sign a written informed consent 
document.
2.1.1.10 Participants must be willing to co-enroll in the investigator’s companion protocol 10-C-
0066 titled “Collection of Human Samples to Study Hairy Cell and other Leukemias, and 
to Develop Recombinant Immunotoxins for Cancer Treatment.”
2.1.2
Exclusion Criteria
2.1.2.1
Participants who have had chemotherapy, immunotherapy or radiotherapy within 4 weeks 
or treatment with rituximab/Ruxience within last 3 months prior to initiation of treatment.
2.1.2.2
Participants who are receiving any other investigational agents.
2.1.2.3
Breastfeeding within the projected duration of the study, starting with the screening visit 
through 6 months after the last dose of rituximab/Ruxience. Pregnant women are 
excluded from this study because moxetumomab pasudotox-tdfk and rituximab/Ruxience 
are agents with the potential for teratogenic or abortifacient effects. Because there is an 
unknown but potential risk for adverse events in nursing infants secondary to treatment 
of the mother with moxetumomab pasudotox-tdfk and rituximab/Ruxience, breastfeeding 
should be discontinued if the mother is treated with moxetumomab pasudotox-tdfk and 
rituximab/Ruxience. 
2.1.2.4
Participants 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.
2.1.2.5
Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, 
uncontrolled hypertension, uncontrolled pulmonary infection, pulmonary edema or 
psychiatric illness/social situations that would limit compliance with study requirements.
2.1.2.6
Participants with retinal or choroidal detachment.
2.1.2.7
Positive for Hepatitis B core antibody or surface antigen unless the participant is on 
Tenofovir or Entecavir and Hepatitis B Viral deoxyribonucleic acid (DNA) load is <2000 
IU/mL
2.1.2.8
Active second malignancy requiring treatment other than minor resection of indolent 

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cancers like basal cell and squamous skin cancers.
2.1.2.9
Human immunodeficiency virus (HIV)-positive participants unless taking appropriate 
anti-HIV medications with a CD4 count of > 200. Otherwise, there may be an increased 
risk of lethal infections when temporarily suppressing normal B-cells.
2.1.2.10 History of an allogeneic bone marrow transplant.
2.1.2.11 Participants with a history of both thromboembolism and known congenital 
hypercoagulable conditions.
2.1.2.12 Radioimmunotherapy within 2 years prior to enrollment in the study.
2.1.2.13 Participants 
with 
history 
of 
thrombotic 
microangiopathy 
or 
thrombotic 
microangiopathy/HUS.
2.1.2.14 Participants with corrected QT interval (Frederica) elevation > 500 msec (manually over-
read by medically qualified person) based on at least two separate 12-lead ECGs.
2.1.2.15 Participants on high dose estrogen (defined as > 0.625 mg/day of an estrogen compound).
2.1.2.16 Oxygen saturation at rest < 88% measured by pulse oximetry or PaO2 ≤ 55 mm Hg.
2.1.2.17 Participants with life expectancy of less than 6 months.
2.1.2.18 Participants with clinical evidence of disseminated intravascular coagulation (Grade 3-
4).
2.1.2.19 Participants with < 50% of predicted forced expiratory volume (FEV1) or < 50% of 
predicted diffusing capacity for carbon monoxide, corrected for hemoglobin 
concentration and alveolar volume (DLCO). Note: Participants with no prior history of 
pulmonary illness are not required to have pulmonary function testing (PFT). Forced 
expiratory volume will be assessed after bronchodilator therapy.
2.1.3
Recruitment Strategies
Recruitment of participants from outside NIH is facilitated by multiple ongoing trials at NIH. 
Many participants find about NIH trials from NIH websites, such as https://clinicaltrials.gov/ or 
NIH social media, or from other participants through social media, and neither the PI nor the 
research staff interacts with these sites. The Hairy Cell Leukemia Foundation, which refers HCL 
and HCLv participants to trials, has an active website and is a significant source of recruitment. 
Finally, participants who are relapsing from NIH protocols for early HCL/HCLv may be eligible 
for NIH trials for relapsed HCL/HCLv.
2.2
SCREENING EVALUATION
Screening evaluation testing/procedures are conducted under the separate screening protocol, 01-
C-0129 (Eligibility Screening and Tissue Procurement for the NIH Intramural Research Program 
Clinical Protocols). See also Study Calendar in Section 3.4.
2.2.1.1
Laboratory evaluation (needed for eligibility)
2.2.1.1.1 Within 6 months before starting drug, provided >4 weeks after chemotherapy, 
immunotherapy or radiotherapy prior to entering the study:
•
Bone marrow biopsy (BMBx) with IHC for CD20 and CD3.

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•
BMBx is not needed if participants can provide test slides to be read at the Clinical Center 
along with reports. In case slides and reports are not available, fresh biopsy will be done. 
2.2.1.1.2 Within 6 months before starting drug
•
Hepatitis B (HBcAB and HBsAg), and HIV test 
•
CD4/CD8 (only in HIV participants)
2.2.1.1.3 Within 4 weeks before starting drug
•
CBC with differential
•
Chemistries including acute care panel (sodium, potassium, chloride, CO2, glucose, 
creatinine, and BUN), mineral panel (calcium, magnesium, phosphorus and albumin), 
hepatic panel (AST, ALT, total and direct bilirubin, alkaline phosphatase), total protein, 
creatine kinase (CK), uric acid, LDH, urinalysis, D-Dimer, Ferritin, Fibrinogen, PT/INR, 
PTT, amylase, lipase, GGT, IgA, IgG, IGM, CRP, TBNK, haptoglobin, Lipid panel 
(cholesterol, triglycerides, HDL, LDL), TSH, FT4, FT3, T4, T3,IFE. 
•
Flow cytometry of blood
•
EKG
•
History & Physical with documented performance status
•
Vital signs including ambulatory oxygen saturation by pulse oximetry. Pulmonary function 
test (PFTs) if measuring PaO2
2.2.1.1.4 Within 3 days before starting drug
Pregnancy test (urine or serum). Women of childbearing potential must have a negative 
pregnancy test
2.3
PARTICIPANT REGISTRATION AND STATUS UPDATE PROCEDURES
Registration and status updates (e.g., when a participant is taken off protocol therapy and when a 
participant is taken off-study) will take place per CCR SOP ADCR-2, CCR Participant 
Registration & Status Updates found at: https://nih.sharepoint.com/sites/NCI-CCR-OCD-
Communications/SitePages/OEC-Administrative---Clinical-Research-(ADCR).aspx?Mode=Edit. 
2.3.1
Treatment Assignment Procedures 
Cohort
Number
Name
Description
1
HCL/HCLv
Participants with HCL and HCLv

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Arm
Number
Name
Description
1
Arm 1 – Dose escalation
Treatment with moxetumomab pasudotox-tdfk and 
rituximab (participants 1-13)
2
Arm 2 – Dose expansion
Treatment with moxetumomab pasudotox-tdfk and 
Ruxience (participants 14-26)
Arm Assignment
Participants in cohort 1 will be directly assigned to arm 1 or 2 in sequential fashion. 
2.4
BASELINE EVALUATION 
See also Section 3.4, Study Calendar and Section 2.2, Screening Evaluation
2.4.1
Within 6 months before drug
•
MRI Cervical and Thoracic (C- and T-) Spine to correlate the status of the BMBx with the 
vertebral bone marrow aspiration (BMA) signal by MRI. May be cancelled at the discretion 
of the PI, including if participant unable to get MRI at NIH and not covered by insurance 
outside NIH.
•
CT Neck-pelvis or MRI
•
Abdominal Ultrasound (U/S) will be done to exclude lymph nodes potentially impacting 
the biliary tree
•
Echo, PFTs, stress test
•
BMA for FACS and PCR (if evaluable). Blood PCR should be done at the same time as 
BMA PCR in the CLIA certified laboratory at the Laboratory of Pathology, CCR/NCI. 
HLA test (May be done any time before initiation of study therapy)
2.4.2
Within 4 weeks before drug
•
PaxGene RNA & DNA
•
24 hour urine for protein and creatinine clearance 
•
Serum tube for tumor markers and antibodies
•
Peripheral blood mononuclear cells (PBMCs) in Sodium heparin tubes
3
STUDY IMPLEMENTATION
3.1
STUDY DESIGN
This is a Phase 1 trial, two-arm, non-randomized trial involving the administration of 
moxetumomab pasudotox-tdfk 30-40 mcg/kg iv and rituximab/Ruxience 375 mg/m2 iv, 50-400 
mg/hr. The purpose of the rituximab/Ruxience is to decrease the HCL tumor burden, allowing the 

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16
63 kDa immunotoxin to reach all the malignant cells, thereby facilitating tumor eradication, and 
prevention of neutralization of the immunotoxin by the immune system, through the action of 
rituximab/Ruxience on normal B-cells. To allow sufficient time for the rituximab/Ruxience to act 
prior to moxetumomab pasudotox-tdfk, in the first cycle, rituximab/Ruxience will be given on day 
-2 followed by moxetumomab pasudotox-tdfk on days 1, 3 and 5. Thus on cycle 1 only, 
moxetumomab pasudotox-tdfk will begin on the 3rd day after rituximab/Ruxience. On subsequent 
cycles, spaced ~ 4 weeks (as few as 25 days) apart, rituximab/Ruxience will begin on day 1 and 
moxetumomab pasudotox-tdfk on days 1, 3 and 5. Participants will receive up to 4 cycles past 
documentation of CR without MRD, up to a maximum of 8 cycles which means, no participant in 
this trial will receive more than 8 cycles. 
3.1.1
Schema
Cycle 1:
DAY -2
Day 
-1
Day 
0
DAY 1
Day 
2
DAY 3
Day 
4
DAY 5
Day 
>26
Rituximab
/Ruxience
Moxetumomab 
pasudotox-tdfk
Moxetumomab 
pasudotox-tdfk
Moxetumomab 
pasudotox-tdfk
(next 
cycle)
Cycles 2-8:
Day 
-2
Day 
-1
Day 
0
DAY 1
Day 
2
DAY 3
Day 
4
DAY 5
Day 
>26
Rituximab/Ruxience
(next 
cycle)
Moxetumomab pasudotox-
tdfk
Moxetumomab 
pasudotox-
tdfk
Moxetumomab 
pasudotox-
tdfk
3.1.2
Dose Limiting Toxicity
Dose limiting toxicity (DLT) is defined as all treatment related Grade 3 and greater AEs occurring 
from the initiation of moxetumomab pasudotox-tdfk therapy to within 30 days after the last dose 
of moxetumomab pasudotox-tdfk treatment. For example, grade >3 cytokine release syndrome, 
and failure to complete cycle 1 due to toxicity is considered DLT. 
Exceptions to DLT include:
•
Hematologic toxicity grade 3, or grade 4 resolving within 4 weeks.
•
Hematologic toxicity managed with transfusion and/or other support would not constitute 
DLT.
•
Grade 3-4 lymphopenia, leukopenia, or CD4 reductions.
•
Grade 3 gastrointestinal toxicity resolving within 72 hours.

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•
Transaminase and alkaline phosphates elevations grade 3 resolving within 4 weeks.
•
Bilirubin elevations associated with Gilbert’s syndrome, i.e. total/direct bilirubin ratio >4.
•
Electrolyte or mineral abnormalities which are grade 3-4, resolving within 4 weeks.
•
Grade 3 proteinuria, and fever
•
Lipid elevations grade 3 or grade 4 resolving within 4 weeks
•
Grade 3 HUS, including HUS-related grade 1-2 creatinine, will not be considered DLT if 
it resolves within 2 weeks to grade 0-1 creatinine, and is not associated with significant 
complications including bleeding or need for dialysis or plasmapheresis.
•
Allergic reactions to rituximab/Ruxience prevented by desensitization.
•
Dosing of both agents must be delayed for any grade 3-4 infection at least possibly related 
to either drug, and if not resolved despite a 4-week delay will be considered DLT requiring 
removal from treatment.
•
Other isolated grade 3 laboratory abnormalities (not related to CLS or HUS) without 
clinical signs or symptoms and not associated with clinical sequalae requiring therapeutic 
intervention.
3.1.3
Dose Escalation
The original plan was to treat up to 10 participants at the 40 mcg/kg dose level, up to 16 total 
participants could have been required (including up to 10 participants at the 30 mcg/kg dose level) 
if there were 2 DLTs within the first 6 participants treated at the 40 mcg/kg dose. The accrual 
ceiling was set at 20 participants considering screen failures and/or inevaluable participants. Please 
refer to Section 10.2 for dose-escalation rules and below.
Initially, 3 participants were to be treated with moxetumomab pasudotox-tdfk 30 mcg/kg and 
rituximab 375 mg/m2. If 0/3 had a DLT, then the next 3 participants would be treated with 
moxetumomab pasudotox-tdfk 40 mg/kg and rituximab 375 mg/m2. 
If 1/3 initial participants treated with 30 mcg/kg had a DLT, then 3 more would have been treated 
at 30 mcg/kg. If no more than 1 of the first 6 had a DLT, then 4 more participants were to have 
been enrolled at 30 mcg/kg provided that no more than a total of 2 of the 10 at the 30 mcg/kg level 
would have a DLT.
If participants were accrued to the 40mcg/kg level, if 0/3 or 1/3 had a DLT, then 3 more were to 
be treated using those dose levels. If no more than 1 of the first 6 had a DLT, then 4 more 
participants were to be enrolled provided that no more than 2 total of the 10 at the 40 mcg/kg level 
had a DLT with the exception of the types noted. If a 3rd participant had a DLT, accrual would end 
as soon as this is noted. 
If 2 of the first 3 participants, or 2 of the first 6 participants, treated with moxetumomab pasudotox-
tdfk 40 mcg/kg and rituximab 375 mg/m2 had a DLT, then 3 additional participants were to be 
treated with moxetumomab pasudotox-tdfk 30 mcg/kg and rituximab 375 mg/m2. If 0/3 or 1/3 of 
these next 3 had a DLT with these dose levels, then 4 more participants were to be enrolled at the 
30 mcg/kg level provided that no more than 2 total of the 10 at the 30 mcg/kg level had a DLT. If 
2 participants in the first 6 had a DLT at this level, then the trial would have ended accrual. 

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Furthermore, at any time in the 10 participants, if a 3rd participant had a DLT, accrual will also 
end as soon as that was noted.
3.1.3.1
Dose Escalation Schema
Though DLT will be evaluated for the duration of study therapy, the 4th and 7th evaluable 
participants could be enrolled after a minimum of 30 days after the previous participant received 
the last dose of cycle 2 or last dose of cycle 1 if the participant was not to receive a 2nd cycle. 
Dose Escalation Schedule
Dose Level
Dose of IND Agent * 
Level 1
Moxetumomab pasudotox-tdfk 30 mcg/kg
Level 2
Moxetumomab pasudotox-tdfk 40 mcg/kg
3.1.4
Dose Expansion 
As of 9/24/21, 12 participants were enrolled, 3 that received moxetumomab pasudotox-tdfk at 30 
mcg/Kg and 9 at 40 mcg/Kg. All participants were without DLT, therefore per protocol only 1 
additional eligible participant treated with moxetumomab pasudotox-tdfk at 40 mcg/Kg could be 
enrolled, making a total of 13 eligible participants.  After these participants, to better determine 
safety and efficacy, an additional 13 eligible participants will be enrolled and treated with 
moxetumomab pasudotox-tdfk at 40 mcg/Kg in combination with Ruxience instead of rituximab.  

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3.2
DRUG ADMINISTRATION
3.2.1
Moxetumomab pasudotox-tdfk
Moxetumomab pasudotox-tdfk is administered at 30-40 mcg/kg intravenous (IV) over 30 min 
using early call back/reverse flow method (intended dose level 1). Moxetumomab pasudotox-tdfk 
is given on days 1, 3, and 5 of each cycle. When given on the same day as a rituximab/Ruxience 
infusion, the rituximab/Ruxience will be given first followed by Moxetumomab pasudotox-tdfk. 
Participants will receive up to 4 cycles past documentation of CR without MRD, maximum 8. To 
prevent renal toxicity and hypovolemia, participants will be encouraged to drink water gradually, 
approximately 1 cup/hour or 6L/day, and to avoid going >3 hours without drinking from days 1 to 
8. To prevent rituximab/Ruxience toxicity, participants will receive prophylactic dexamethasone 
as indicated in Section 3.2.3, before the 1st dose of rituximab/Ruxience, and before subsequent 
doses until rituximab/Ruxience infusion reactions are not seen. Diphenhydramine, famotidine, and 
acetaminophen may be used as needed. Dexamethasone 4 mg orally (maximum 2 doses/24 hours) 
will be given to treat nausea or fever associated with moxetumomab pasudotox-tdfk, which 
otherwise might prevent adequate water intake.
Please refer to Appendix C for information related to moxetumomab pasudotox-tdfk 
administration and preparation. Handle moxetumomab pasudotox-tdfk with caution to avoid skin 
and mucus membrane contact, aerosol formation, or ingestion. Monitor participants for infusion 
reactions, CLS, TLS, and thrombotic microangiopathy/HUS. To monitor for HUS, before every 
infusion, hemoglobin levels, platelet count, and serum creatinine will be checked. If HUS is 
suspected, blood LDH, indirect bilirubin, blood smear schistocytes for evidence of hemolysis will 
be promptly checked.  Appropriate supportive measures will be taken, including fluid repletion 
and hemodynamic monitoring. Hospitalization should be considered if clinically indicated. If 
participants develop HUS, moxetumomab pasudotox-tdfk will be discontinued. To monitor for 
CLS, it is recommended that before every infusion, participants’ weight and blood pressure are 
checked. CLS will be considered if participant’s weight has increased by 5.5 pounds (2.5 kg) or 
≥5% from day 1 of each cycle and the participant is hypotensive. Peripheral edema, 
hypoalbuminemia, and respiratory symptoms, including shortness of breath and cough, will be 
checked. If CLS is suspected, decrease in oxygen saturation, evidence of pulmonary edema, and/or 
serosal effusions will be checked. Appropriate supportive measures, including administration of 
concomitant corticosteroids PO or IV, will be used. Hospitalization will be considered if clinically 
indicated. 
Vital signs will be obtained every 15 (± 10) minutes during the moxetumomab pasudotox-tdfk 
infusion, then every hour (±30 minutes) for an additional 4 hours during Cycle 1. During 
subsequent cycles, vital signs will be obtained as indicated in the Study Calendar. Weight, CBC 
+ Diff, chemistries and urinalysis will be assessed prior to each infusion of moxetumomab 
pasudotox-tdfk.
To mitigate risk for allergic reaction and fever, participants will be premedicated with 
acetaminophen and famotidine, as indicated in Section 3.2.3. Substitutions of cimetidine for 
famotidine is permitted. In participants experiencing infusion-related reactions, including, but not 
limited to pyrexia, nausea, or dyspnea, premedication with dexamethasone and/or 
diphenhydramine intravenous (IV) or oral may be administered at the investigator’s discretion as 
secondary prophylaxis.

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In an attempt to prevent renal insufficiency, participants will receive fluid and aspirin prophylaxis. 
Participants will receive low-dose aspirin orally (81 mg daily or local standard dose) 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. Participants will be hydrated (recommended over 2-4 hours) prior to 
the beginning of each moxetumomab pasudotox-tdfk infusion, as indicated in Section 3.2.3. 
Diuresis should be considered for a > 10% increase in weight above baseline and may be most 
safely given during the pre-hydration liter of fluid. Participants will be encouraged to measure and 
record their weight daily, as well as their fluid intake during days 1-8. Participants will be provided 
with a hydration diary (see Appendix D: Participant Hydration Diary), instructed in its use, and 
asked to bring the diary with them at each appointment.  Participants with hyperuricemia of > 10 
mg/dL (> 0.59 mmol/L) prior to administration of moxetumomab pasudotox-tdfk will receive 
allopurinol 300 mg once daily for tumor lysis syndrome (TLS) prophylaxis. Treatment of TLS will 
be based on institutional guidelines. Adequate Pneumocystis carinii pneumonia (PCP) prophylaxis 
will be considered for participants receiving > 1 week of corticosteroids ≥ 10 mg of prednisone 
daily or equivalent and CD4 lymphocyte count < 0.2 x 109/L, or at the discretion of the investigator. 
Viral prophylaxis will be also considered for participants receiving chronic corticosteroids or with 
lymphopenia. Participants 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-tdfk. 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 slitlamp 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.
Please refer to the proper prescribing information for full details regarding toxicity as this agent 
has recently been FDA approved. 
3.2.2
Rituximab and Ruxience 
See APPENDIX B for Guidelines for Rituximab and Ruxience Preparation and Administration 
for infusion times. Briefly, rituximab/Ruxience will be given on day -2 (2 days before day 1) of 
Cycle 1 and on day 1 of all subsequent cycles. Rituximab/Ruxience are given at 50-400 mg/hr for 
the 1st dose and may be escalated to 100-400 mg/hr for subsequent doses. Premedication consisting 
of acetaminophen, famotidine, and diphenhydramine should be considered before each infusion of 
rituximab/Ruxience (see Section 3.2.3). Since transient hypotension may occur during 
rituximab/Ruxience infusion, consideration should be given to withholding antihypertensive 
medications 
12 
hours 
before 
rituximab/Ruxience 
infusion. 
If 
a 
hypersensitivity 
(non-IgE-mediated) or an infusion reaction develops, the infusion rate should be reduced to half 
that rate, i.e. from 100 mg/h to 50 mg/h. Participants who experience a moderate to severe infusion 
related reaction (fever, chills, or hypotension) should have their infusion interrupted immediately 
and should receive aggressive symptomatic treatment. The infusion should not be restarted before 
all the symptoms have disappeared and then the infusion can continue at one-half the previous 
rate. Dexamethasone 12 mg PO should be given prior to rituximab/Ruxience infusions until 
moderate-severe infusion reactions are no longer observed. 

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3.2.3
Drug administration scheme
Cycle 1 only
Time point
d-2
d1
d2
d3
d4
d5
d6
d7
d8
Treatments
Rituximab/Ruxience 375 mg/m2
X
Moxetumomab pasudotox-tdfk 30-40 
mcg/kg
X
X
X
Hydration
H2O (6 L)
X
X
X
X
X
X
X
X
Pre-hydration-5% Dextrose 0.45% NaCl 
(1 L)2
X
X
X
Post-hydration-5% Dextrose 0.45% 
NaCl (1 L)2
X
X
X
Premedications
Dexamethasone (12 mg)
X
Acetaminophen (650 mg)
X1
X1
X1
X1
Diphenhydramine (25-50 mg)7
X
Famotidine (20-40 mg)
X
X6
X6
X6
Daily medication
Aspirin (81 mg)3 
X
X
X
X
X
X
X
X
Cycles 2-8
Time point
d1
d2
d3
d4
d5
d6
d7
d8
Rituximab/Ruxience
X
Moxetumomab pasudotox-tdfk
X
X
X
Hydration
H2O (6 L)
X
X
X
X
X
X
X
X
Pre-hydration-5% Dextrose 
0.45% NaCl (1 L)2 
X
X
X
Post-hydration-5% Dextrose 
0.45% NaCl (1 L)2 
X
X
X
Premedications
Dexamethasone (12 mg)
X4,5
Acetaminophen (650 mg)
X1,5
X1
X1
Diphenhydramine (25-50 mg)7
X5
Famotidine (20 – 40 mg)
X6,5
X6
X6
Daily medication
Aspirin (81 mg)3
X
X
X
X
X
X
X
X

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1
To be given 30-90 minutes prior to every moxetumomab pasudotox-tdfk infusion and recommended every 6 
hours x 4 after the end of infusion.
2
0.9% Sodium Chloride Injection may be substituted for 5% Dextrose 0.45%NaCl.
3
Only if platelet counts ≥ 100 x 109/L
4
Administer 0.5-2 hours before rituximab/Ruxience. If participant has previous reaction to 
rituximab/Ruxience, give 12mg.  If participant tolerates rituximab/Ruxience without problems, may hold at 
discretion of provider.
5
Premedications are given prior to rituximab/Ruxience on day 1.
6
Famotidine 20 – 40 mg to be given 30-90 minutes prior to every moxetumomab pasudotox-tdfk infusion and 
is recommended every 12 hours x 2 after the end of infusion
7
May be given prior to moxetumomab pasudotox-tdfk at discretion of PI
3.3
DOSE MODIFICATIONS
Dosing may be delayed up to 4 months for toxicity or logistical reasons, including the inability of 
the participant to get to the clinic. Treatment cycles need not be delayed for cytopenias but must 
be delayed for participants in CR presenting grade 3 cytopenia, for grade 3-4 infections and for 
grade 3-4 neutropenia combined with fever. Any grade >3 infection not resolving within the 4 
week delay will be considered DLT.
If participants develop grade 2 CLS, dosing will be delayed until recovery of symptoms; if CLS 
grade ≥3 develops, moxetumomab pasudotox-tdfk will be discontinued.
Any occurrence of DLT as defined in Section 3.1.2 will result in removal from study therapy. 

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3.4
STUDY CALENDAR
All cycles22
 (1 cycle=28 days)
Procedure
Screen/
Baseline
Pre-
Cycle23,32
Cycle 1 
Day -234
Cycle 1 
Day -135
Days
1-5
Day 
8
Day 
15±3
EOT1
EOT 
+
6m10
F/U5
Restage6
History & PE 
X3
X20
X
X
X
Vital signs including pulse oximetry19
X3
X20
X19,24
X
X
Performance Score
X3
X20
CBC + Diff
X3
X21
X
X
X
X
X
X
X
X4
X
Weight
X
X
X
Chemistries11, urinalysis 
X3
X21
X36
X36
X
X
X
X
X
X12
X
D-Dimer, Fibrinogen, Ferritin, 
PT/INR, PTT, amylase, lipase, GGT, 
IgA, IgG, IgM, CRP, haptoglobin
X3
X20
X37
X37
X13
X
X
X
Reticulocyte count, VWF antigen, 
VWF activity, PAI-1, FDP, p-selectin, 
thrombomodulin
X
X
Cytokine panel 13 33
X
X
Immunofixation electrophoresis (IFE) 
and TBNK
X
X31
X
X
X
X
Flow cytometry
X3
X20
X
X
X
X
EKG
X3
X20
X
X
X
Lipid panel, TSH, FT4, FT3, T4, T3, 
SPEP
X3
X
X
X
HBcAB, HBsAg, HIV test
X7
Pregnancy test (females < 50 years)
X15
24hr urine protein and creatinine
X16
X25
NIH Advance Directives Form2
X
CT Neck-pelvis or MRI9
X7
X
X
X
X
MRI C & T-spine14
X7
X
X
X
X

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Echo, PFTs, stress test, abdominal 
U/S, HLA
X7
Adverse Events17
X
X
X
Concomitant Medications17
X3
X
X
X
Correlative Studies18                                                                                                 (Please refer to Section Error! Reference source not found.) 
BMBx & BMA w/flow and PCR
X7
X27
X
X
X
Blood PCR
X
X
X38
X38
X38
PaxGene RNA & DNA
X3
X
X
X
X
X
Biomarker 
X3
X
X
X
X
X
X
ADAs30
X
X28
X
X29
PBMCs 
X3
Urine (renal proximal tubule cell 
damage)
X
X26
X
PK and PK bioassay30
X8
1.
End of treatment visit will occur 28-42 days after 1st dose of last cycle.
2.
All participants will be offered the opportunity to complete an NIH advance directives form (Section 12.3). This should be done preferably at baseline but 
can be done at any time during the study. The completion of the form is strongly recommended but not required.
3.
Within 4 weeks prior to enrollment, could be combined with pre cycle 1. Only anti-moxetumomab pasudotox-tdfk antibodies will be assessed.
4.
CBC + Diff should be done every 3 months until 2.5y after EOT, then every 6 months.
5.
Follow-up time points not requiring restaging are 1, 2 and 3.5 years after EOT, then every 2 years
6.
Restaging requiring imaging, labs (and bone marrow if CR suspected) is 1.5 and 2.5 years after EOT, then every 2 years.
7.
Within 6 months of initiation of study therapy provided within 4 weeks after last therapy. Baseline HLA may be done anytime.
8.
PK and PK bioassay Time points: On days 1 and 5 of cycles 1,2,3,5,7. For cycles 1 and 2: pre, and immediately post, +/- 8 min,  then 30+/-10, 60+/-15, 
180+/-20,, and 360+/-50 minutes after moxetumomab pasudotox-tdfk end of infusion; On cycles 3, 5, and 7: pre and post infusion, 1-8 min; on cycles 4, 6, 
and 8 no PK will be drawn. Each ~6cc in K2EDTA tubes.
9.
CT Neck-Pelvis is done at baseline to identify sites of disease, including spleen, and at EOT and restaging points MRI of these sites may be substituted. In 
asplenic participants without baseline sites of disease, MRI of the abdomen may be done at restaging time points. The entire neck to pelvis CT need not be 
repeated if the disease (splenomegaly) was contained within just the abdominal or abdominal-pelvis levels of the CT. Pre-cycle scans will only be performed 
if participant is being restaged.
10.
Deviations on post-EOT time points may be +/- 2 months until 2.5 years and +/- 4 months thereafter.
11.
Chemistries includes 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, creatine kinase (CK or CPK), 
and uric acid. Except on day 15.  Day 15 only acute care panel along with CBC with c diff and urine analysis will be required.
12.
Optional when not performed at NIH
13.
+/- 1 day, 

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14.
To be done at bone marrow time points, to correlate the status of the BMBx with the vertebral BMA signal by MRI. May be cancelled at the discretion of 
the PI, including if participant unable to get MRI at NIH and not covered by insurance outside NIH.
15.
This test will be conducted within 3 days prior to enrollment 
16.
Performed within 4 weeks before initiation of study therapy.
17.
Adverse events and concomitant medications will be monitored continuously in every visit.
18.
Samples collected during the course of this study will be stored, tracked, and disposed of as specified in investigator’s companion protocol, 10C0066, on 
which all participants will be co-enrolled.
19.
During the moxetumomab pasudotox-tdfk infusion, vital signs will be obtained every 15 (±10) minutes, 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 moxetumomab pasudotox-tdfk 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.
20.
May be done up to 3 days prior to day 1 of cycle.
21.
Must be done on day 1 of cycle 1 prior to treatment.
22.
Cycle interval may be shortened to 25-27 days due to logistical reasons.
23.
Pre-cycle tests may be done 0 to 2 days before and maybe combined with either baseline for cycle 1 or day 1 or both.
24.
During rituximab/Ruxience infusion on cycle 1 day -2 vital signs will be obtained with every dose change and as needed.
25.
Must be completed on day 8 but may be cancelled at PI discretion.
26.
Pre-cycle and pretreatment on days 3, 5, and 8.
27.
Pre-cycle bone marrow and scans to be done at the discretion of the PI based on the participants HR status.
28.
Sampling pre-dose before cycles 1,2,3,5, and 7.
29.
Sampling at 3 and 6 months after the end of treatment evaluation. 
30.
Sampling in case HUS or CLS are observed.
31.
Cycle 1 IFE to be done pre cycle may be combined with baseline labs +/- 1-4 days and again pre moxetumomab pasudotox-tdfk on Cycle 1 day1. 
32.
Screening labs can be combined with pre cycle 1 labs if done within 5 days of day -2 with the exception of the labs listed as day -2 labs
33.
Pre-rituximab/Ruxience and 6-8 hours post-rituximab/Ruxience. It includes: Tumor Necrosis Factor-alpha, interleukin 2, interleukin 2 receptor soluble, 
interleukin 12, interferon gamma, interleukin 4, interleukin 5, interleukin 10, interleukin 13, interleukin 17, interleukin 1 beta, interleukin 6, and interleukin 
8. 
34.
Day -2 pre Rituxan and 6-8 hours after the start of Rituxan.
35.
AM of day -1 
36.
LDH only
37.
D-dimer and haptoglobin only
38.
Optional

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3.5
COST AND COMPENSATION
3.5.1
Costs
NIH does not bill health insurance companies or participants for any research or related clinical 
care that participants receive at the NIH Clinical Center. If some tests and procedures are 
performed outside the NIH Clinical Center, participants may have to pay for these costs.
3.5.2
Compensation
Participants will not be compensated on this study.
3.5.3
Reimbursement
The NCI will cover the costs of some expenses associated with protocol participation.  Some of 
these costs may be paid directly by the NIH and some may be reimbursed to the 
participant/guardian as appropriate.  The amount and form of these payments are determined by 
the NCI Travel and Lodging Reimbursement Policy.
3.6
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA
Prior to removal from the study, effort must be made to have all participants complete a safety 
visit approximately 28-42 days following the last dose of study therapy.
3.6.1
Criteria for removal from protocol therapy
•
Completion of study therapy
•
Progressive disease or DLT
•
HUS
•
Unacceptable toxicities as described on Sections 3.1.2 and 3.3.
•
Intercurrent illness or medical circumstances, including uncontrolled infection at the discretion 
of the primary investigator
•
Radiation therapy or other treatment for HCL other than splenectomy
•
Voluntary withdrawal from the treatment regimen
•
PI determines further treatment on this study is not in participant’s best interest
•
Participants who are off-treatment but still on-study will be followed as per the schedule in 
Section 3.4, until they begin alternative therapy or voluntarily withdrawal from follow-up 
testing. Thereafter, they may be followed on-study for survival and other secondary endpoints.
•
Positive pregnancy test
3.6.2
Off-Study Criteria
•
Voluntary participant withdrawal from the study
•
Death

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•
Non-compliance with study treatment and/or testing, or lost to follow-up, at discretion of 
PI. 
The reason for removing participants from study will be documented in the medical record.
4
CONCOMITANT MEDICATIONS/MEASURES
•
Prophylactic measures for renal toxicity, hypvolemia, rituximab/Ruxience toxicity and nausea 
and vomiting will be administered as described in Section 3.1.4. 
•
Febrile Neutropenia, which is common in participants before responding to treatment, may 
require empiric antibiotics, either as an inpatient or outpatient. Hematopoietic growth factors 
may be used if clinically indicated, for example, if grade 3-4 neutropenia is associated with 
suspected infection. Fever is also common with rituximab/Ruxience and may be treated 
symptomatically and with interrupting or with decreasing the infusion rate.
•
Symptomatic anemia should be treated with appropriate red blood cell support. Transfusion is 
generally recommended if the hemoglobin falls below 7g/dL. Platelets are generally given 
when the platelet count is < 8,000/mmP3
P or when there is bleeding.
•
Participants receiving rituximab/Ruxience, particularly those with high concentrations of 
circulating malignant cells, commonly have infusional toxicities including fever, chills, nausea 
and vomiting, dyspnea, hypotension, and palpitations. Infusional reactions with 
rituximab/Ruxience have been observed in HCL as well as other malignancies and are best 
managed by slowing or interrupting the rate of infusion. 
•
Additional toxicities that may arise will be managed per current evidence-based practice 
guidelines in consultation with a medically responsible investigator if available.
•
Concurrent chemotherapy, radiotherapy, immunotherapy, and biologic therapies for treatment 
of HCL during the study are not permitted.
•
Use of steroids is not routinely recommended to prevent CLS or fever from moxetumomab 
pasudotox-tdfk; however, secondary prophylaxis for infusion-related reactions with 
dexamethasone IV or oral may be administered at the investigator’s discretion.
•
Participants will be informed that NSAIDs (except aspirin) should not be taken from the first 
dose of the cycle through 7 days after the last dose of the cycle. 

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5
CORRELATIVE STUDIES FOR RESEARCH 
5.1
 BIOSPECIMEN COLLECTION
5.1.1
Sample Collection Table
Test/assay
Vol
Tubea &
Storage
Timing
Location of specimen 
analysisb
Blood Flow 
cytometry using 
TBNK assay
18 cc
3 Na-heparin
Room temp
Flow Lab B1B58
BMA flow 
cytometry
2-5 cc
2 Na-heparin
Room temp
Flow Lab B1B58 &
Kreitman Lab
Blood PaxGene
2-3 cc
RNA & DNA 
tubes, Room 
temp
Biospecimen Processing 
Core (BPC)
Serum for 
biomarkers 
2-3 cc
1 SST (red top)
-20oC or colder
Kreitman Lab
Anti-drug 
antibodies 
(ADAs)
2 cc
Na-heparin
(green top)
-20oC or colder
Urine to test for 
renal proximal 
tubule cell 
damage 
2 cc
1 Urine yellow 
conical 8ml
4ºC
PK
2 cc 
1 K2-EDTA 
(lavender top)
-20oC or colder
PK bioassay
4 cc
Na-heparin
(green top)
-20oC or colder
Per Study Calendar
Blood PBMC
25 cc
5 Na-heparin 
Room temp
Baseline
BPC
a.
Tubes and media may be substituted based on availability with the permission of the PI or laboratory 
investigator
b.
The location of specimen analysis may be adjusted at the time the analyses are performed with the 
permission of the PI or laboratory investigator
Note: Samples collected during the course of this study will be stored, tracked, and disposed of as 
specified in investigator’s companion protocol, 10-C-0066, on which all participants will be co-
enrolled.
5.1.2
Biospecimen Sharing on Protocol
We may review the participant’s NIH medical records to obtain results of procedures conducted 
under another protocol in order to minimize repeating procedures/tests.
We may obtain existing identifiable research data and/or biospecimens collected under protocol # 
10-C-0066 titled “Collection of Human Samples to Study Hairy Cell and other Leukemias, and to 

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Develop Recombinant Immunotoxins for Cancer Treatment” to minimize repeating 
procedures/tests.
We may share identifiable research data and/or biospecimens with protocol # 10-C-0066 titled 
“Collection of Human Samples to Study Hairy Cell and other Leukemias, and to Develop 
Recombinant Immunotoxins for Cancer Treatment” to which participants are co-enrolled, in order 
to minimize repeating procedures/tests.
5.2
PLANNED ANALYSES
Note: Platforms and procedures may be adjusted based upon current technology and/or 
collaborations in place at the time of actual analyses.
5.2.1
PK of Moxetumomab Pasudotox-tdfk
Concentrations of moxetumomab pasudotox-tdfk will be measured using a validated assay. The 
PK assay is a sandwich ELISA, where moxetumomab pasudotox-tdfk present in K2EDTA plasma 
is captured on ELISA plates coated with anti-idiotypic mAb against the CD22-binding domain of 
moxetumomab pasudotox-tdfk (clone G09.4) and detected with biotinylated monoclonal antibody 
that binds to the PE38 portion of moxetumomab pasudotox-tdfk (IP-49), followed by addition of 
streptavidin HRP conjugate and TMB substrate. The color intensity (absorbance measured at 450 
nm with wavelength correction set to 650 nm) is proportional to the quantity of moxetumomab 
pasudotox-tdfk) is measured using the Spectramax plate reader (Molecular Devices, Sunnyvale, 
CA, US). Concentrations of moxetumomab pasudotox-tdfk in controls and clinical samples are 
interpolated from the standard curve constructed from moxetumomab pasudotox-tdfk spiked into 
K2EDTA plasma. If a participant develops any grade of HUS or CLS, or has an ocular event with 
new abnormality by ophthalmologic examination during study treatment, samples for 
immunogenicity evaluation will be collected within 24 hours of diagnosis, during the event as 
clinically indicated (e.g., in order to capture peak intensity of the event, as well as at least one 
timepoint during the period of improvement), and after resolution of the event.
Draw maximum volume of blood into 2.0 mL of potassium (K2) EDTA (lavender-top-tube) from 
a separate in-dwelling line that is not used for drug administration.
Tubes will be gently inverted 8-10 times to assure adequate mixing with the anticoagulant within 
2 hours after collection. Centrifuge within 2 hours of collection for 10 min at 1100-1300 x g to 
generate plasma. Transfer plasma into the cryovials and immediately freeze the cryovials upright 
at -20°C or colder. The procedures for the handling of PK samples will be further detailed in a 
separate Lab Manual.
5.2.2
Evaluation of Immunogenicity
Presence of antidrug antibodies (ADA) against moxetumomab pasudotox-tdfk will be assessed in 
samples taken from all participants prior to the start of Cycles 1, 2, 3, 5and 7 and at the end of 
treatment and 3 and 6 months after the last dose. A validated moxetumomab pasudotox-tdfk 
specific bridging immunoassay using the Meso Scale Discovery platform will be employed to 
detect anti-drug antibodies. Positive-negative cut points will be used for detecting the presence of 
ADA. The cut points will be established by statistical evaluation of drug naive validation samples.  
Due to pre-existing antibodies, cross-reactive with PE38 domain of moxetumomab pasudotox-
tdfk, in drug naïve human samples, cut point establishment will be done using pseudo-negative 

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samples where pre-existing signals will be inhibited by drug. Samples determined positive in the 
ADA bridging assay will subsequently be evaluated in a cell-based neutralization assay. This assay 
identifies neutralizing ADA (NAb), which has the ability to block moxetumomab pasudotox-tdfk-
induced cytotoxicity of the B-cell lymphoma line Raji (ATCC, Manassas, VA) as assessed by 
adenosine triphosphate production in the cells. Titer levels and the domain specificity of ADAs 
(anti-CD22-binding domain or anti-PE38 domain) will be determined for participants with positive 
neutralizing anti-drug antibodies (NAb) and may be determined in participants with negative NAb.
If a participant develops any grade of HUS or CLS, or has an ocular event with new abnormality 
by ophthalmologic examination during study treatment, samples for immunogenicity evaluation 
will be collected within 24 hours of diagnosis, during the event as clinically indicated (eg, in order 
to capture peak intensity of the event, as well as at least one timepoint during the period of 
improvement), and after resolution of the event.
At each sample collection time, draw maximum volume of blood (4.0 mL) in sodium heparin tube. 
Immediately after collection, the tube will be gently inverted 8 to 10 times to mix the anticoagulant 
with the blood sample collected. Centrifuge blood within 2 hours of collection. Centrifuge for 10 
min at 1100-1300 x g. Transfer plasma into cryovials and immediately freeze the cryovials upright 
at -20°C or colder. The procedures for the handling of immunogenicity samples will be further 
detailed in a separate Lab Manual.
5.3
STORAGE, USE, AND SHARING OF SPECIMENS AND DATA (INCLUDING FOR SECONDARY 
RESEARCH)
5.3.1
Sample Tracking and Processing
Samples will be ordered in CRIS and tracked through a Clinical Trial Data Management system. 
Should a CRIS screen not be available, the CRIS downtime procedures will be followed. Samples 
will not be sent outside NIH without appropriate approvals and/or agreements, if required.
5.3.1.1
Biospecimen Processing Core (BPC)
Please email NCIBloodcore@mail.nih.gov at least 24 hours before transporting samples (the 
Friday before is preferred).
For sample pickup, page 102-11964.
For immediate help, call 240-760-6180 (main BPC number) or, if no answer, 240-760-6190 (main 
clinical pharmacology lab number).
For questions regarding sample processing, contact NCIBloodcore@mail.nih.gov.
5.3.2
Sample Storage and Disposition
Barcoded samples are stored in barcoded boxes according to stability requirements. Access to 
stored clinical samples is restricted. Unless other permission obtained, samples are only to be used 
for research purposes associated with this trial (as per the IRB-approved protocol) by investigators 
named on the protocol. It is the responsibility of the Principal Investigator to ensure that samples 
are being used in a manner consistent with IRB approval. 
Sample barcodes are linked to participant demographics and limited clinical information. This 
information will only be provided to investigators listed on this protocol, via registered use of a 

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sample tracking database (e.g., Labmatrix). It is critical that the sample remains linked to 
participant information such as race, age, dates of diagnosis and death, and histological 
information about the tumor, to correlate results with sample characteristics.
5.3.3
Protocol Completion/Secondary Use/Sample Destruction
Any specimens remaining at the completion of the protocol will be stored indefinitely in the 
conditions described above. The study will remain open so long as sample or data analysis 
continues. All samples and data from consenting participants will be stored in identifiable format 
until they are no longer of scientific value or if a participant withdraws consent for their continued 
use, at which time they will be destroyed. 
If, at any time, a participant withdraws from the study and does not wish for their existing samples 
to be utilized, the individual must provide a written request. Following receipt of this request, the 
samples will be destroyed or returned to the participant, if so requested. The participant’s samples 
and data will be excluded from future distributions, but those which already been distributed for 
approved research use will not be able to be retrieved. 
The PI will record any loss or unanticipated destruction of samples as a deviation. Reporting will 
be per the requirements of Section 7.2. 
With the permission of the participant, specimens and data collected on this study, identifiable 
through a code available to the study team, will be stored indefinitely and used for secondary 
research, including genetic research.  Furthermore, the data and/or specimens, may be shared with 
other investigators in identifiable or coded (code key not available to recipient) format for 
secondary research. Any investigator conducting secondary research in human subjects will seek 
either additional regulatory approval or exemption for research as appropriate. 
Data will also be shared in public database per the study’s data sharing plan in compliance with 
NIH policies. 
In addition, specimens/data may be anonymized and further research, including genetic research, 
conducted at the site or other institutions without participant consent. Participants will be informed 
that the possibility for this type of research exists.
5.4
SAMPLES FOR GENETIC/GENOMIC ANALYSIS
5.4.1
Description of the scope of genetic/genomic analysis
Identification and prioritization of specific metastatic sites for further analysis will be made by the 
investigator after taking into account various factors including the prior rate of growth of disease, 
response to treatment and tumor fraction in the available sample. DNA and RNA will be extracted 
from tumor samples and germ line DNA and RNA will be extracted from PBMCs from whole 
blood for molecular genetic testing using Pax-gene as specified in investigator’s companion 
protocol, 10-C-0066.

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5.4.2
Description of how privacy and confidentiality of medical information/biological 
specimens will be maximized
•
As part of study efforts to provide confidentiality of participant information, this study will 
obtain a Certificate of Confidentiality which helps to protect personally identifiable 
research information. The Certificate of Confidentiality allows investigators on this trial to 
refuse to disclose identifying information related to the research participants, should such 
disclosure have adverse consequences for participants or damage their financial standing, 
employability, insurability or reputation. The informed consent includes the appropriate 
coverage and restrictions of the Certificate of Confidentiality.
•
Tissue and blood samples collected will be coded. DNA, RNA and protein isolated from 
these tissues and cell lines and xenografts generated will all be similarly coded. Only 
personnel involved in this study will have access to both the code and the name of the 
participant as specified in investigator’s companion protocol, 10C0066.
•
To help protect the privacy, investigators will obtain a Certificate of Confidentiality from 
the National Institute of Health. With this certificate, investigators cannot be forced to 
disclose information that may identify the participant or immediate family members, even 
by a court subpoena, in any federal, state, or local civil, criminal administrative, legislative 
or other proceedings. The researchers will use this Certificate of Confidentiality to resist 
any demands for information that would identify the participant or immediate family 
members. However, the Certificate cannot be used to resist a demand for information from 
personnel of the United States Government that is used for auditing or evaluation of 
federally funded projects or for information that must be disclosed in order to meet the 
requirements of the Food and Drug Administration (FDA).
•
To facilitate genetic research, and for the purpose of publication of research work, data 
from genomic and proteomic studies may be deposited in appropriate public databases. 
Coded data will be deposited in a manner that the participant’s identity cannot be traced.
5.4.3
Management of Results
Subjects will be contacted if a clinically actionable gene variant is discovered. Clinically 
actionable findings for the purpose of this study are defined as disorders appearing in the American 
College of Medical Genetics and Genomics recommendations for the return of incidental findings 
that is current at the time of primary analysis. 
Subjects will be contacted at this time with a request to provide a blood sample to be sent to a 
CLIA certified laboratory. If the research findings are verified in the CLIA certified lab, the subject 
will be offered the opportunity to come to NIH (at our expense) to have genetic education and 
counseling to explain this result. If the subject does not want to come to NIH, a referral to a local 
genetic healthcare provider will be provided (at their expense).
This is the only time during the course of the study that incidental findings will be returned. No 
interrogations regarding clinically actionable findings will be made after the primary analysis.

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5.4.4
Genetic Counseling
The costs of CLIA testing will be paid for by the Center for Cancer Research, the Branch, or the 
Principal Investigator. If the health history, family history, or tumor diagnosis from the Laboratory 
of Pathology at the NIH Clinical Center suggests that the participant might benefit from genetic 
testing, we will discuss this with him/her.
6
DATA COLLECTION AND EVALUATION 
6.1
DATA COLLECTION
The PI will be responsible for overseeing entry of data a 21 CFR Part 11-compliant data capture 
system provided by the NCI CCR and ensuring data accuracy, consistency and timeliness. The 
principal investigator, associate investigators/research nurses and/or a contracted data manager 
will assist with the data management efforts. Primary and final analyzed data will have identifiers 
so that research data can be attributed to an individual human subject participant.
All adverse events, including clinically significant abnormal findings on laboratory evaluations, 
regardless of severity, will be followed until return to baseline or stabilization of event. 
Document AEs from the first study intervention, Study Day 1, through the end of treatment. After 
30 days, only adverse events which are serious and related to the study intervention need to be 
recorded.
An abnormal laboratory value will be recorded in the database as an AE only if the laboratory 
abnormality is characterized by any of the following:
•
Results in discontinuation from the study
•
Is associated with clinical signs or symptoms 
•
Requires treatment or any other therapeutic intervention
•
Is associated with death or another serious adverse event, including hospitalization. 
•
Is judged by the Investigator to be of significant clinical impact
•
If any abnormal laboratory result is considered clinically significant, the investigator will 
provide details about the action taken with respect to the test drug and about the 
participant’s outcome.
End of study procedures: Data will be stored according to HHS, FDA regulations, and NIH 
Intramural Records Retention Schedule as applicable.
6.2
DATA ELEMENTS
6.2.1
Human Data Sharing Plan
•
Documentation of dosage and timing of drug administration
•
Outside laboratory, radiologic, and pathology results will be sent to the PI and entered into 
NCI C3D at NIH
•
NIH labs and tests will be downloaded into C3D

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•
A pre-existing (baseline) laboratory abnormality will be considered the last one obtained prior 
to the first dose of drug, unless the PI considers an abnormality of higher grade occurring 
within 100 days prior to the first dose to be a truer baseline.
6.3
DATA SHARING PLANS
6.3.1
Human Data Sharing Plan
What data will be shared?
Human data generated in this research will be shared for future research as follows:
•
Coded, linked data in an NIH-funded or approved public repository.
•
Coded, linked data in BTRIS (automatic for activities in the Clinical Center)
•
Identified or coded, linked with approved outside collaborators under appropriate agreements.
How and where will the data be shared?
Data will be shared through:
•
An NIH-funded or approved public repository: clinicaltrials.gov, and dbGaP
•
BTRIS (automatic for activities in the Clinical Center)
•
Approved outside collaborators under appropriate individual agreements.
•
Publication and/or public presentations.
When will the data be shared?
•
Before publication.
•
At the time of publication or shortly thereafter.
6.3.2
Genomic Data Sharing Plan
Unlinked genomic data will be deposited in public genomic databases such as dbGaP in 
compliance with the NIH Genomic Data Sharing Policy.
6.4
RESPONSE CRITERIA
6.4.1
Rules for response assessment
•
No G-CSF or GM-CSF at least 4 weeks before major response (i.e. partial response or complete 
response).
•
No transfusions at least 4 weeks before major response.
•
Hgb requirement for major response may be dropped if iron stores (ferritin or iron saturation) 
are low
6.4.2
Complete remission (CR) 
All of the following: 
•
Absolute neutrophil count (ANC) ≥ 1500/mmP3
•
Platelets ≥ 100,000/mmP3

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•
Hgb ≥ 11 g/dL
•
Regression of splenomegaly on physical exam or by imaging studies.
•
Lymph nodes ≤ 2 cm by short axis, unless larger lymph nodes not due to HCL
•
Absence of hairy cells on BM aspirate smears and H/E stain of the BM biopsy negative for 
HCL. If the negative BM is before 4 weeks off of growth factors or transfusions, the CR will 
begin after the 4 week time point once the normal blood counts are consistent with CR.
•
CR with MRD in the BMBx by IHC is defined as CR and a ratio of CD20+ cells to T cells of 
at least 1, and most of the CD20+ cells consistent with HCL. 
•
CR with MRD in the peripheral blood is defined as CR and a positive peripheral blood FACS 
or PCR. Suspicious flow is considered positive per protocol.
•
Participants meeting all criteria for CR except minimum levels of ANC, platelets and Hgb will 
be considered CR if MRD is absent by BMBx IHC and by flow cytometry of blood and bone 
marrow.
6.4.3
Partial Response (PR) 
All of the following for at least 4 weeks
•
Normal blood counts consistent with CR
•
 50% reduction in sum of products of perpendicular diameters or decrease to ≤ 2 cm in 
evaluable (> 2cm) lymphadenopathy 
•
 50% reduction in extent of spleen below costal margin by imaging or physical exam, if 
abnormal at baseline 
•
>50% reduction in BM infiltration on biopsy
6.4.4
Progressive disease (PD) 
Any of the following
•
An increase in symptoms or >25% decline in hematologic parameters related to disease, based 
on the judgement of the PI
•
50% increase in sum of products of perpendicular diameters of evaluable (> 2cm) 
lymphadenopathy or appearance of new evaluable lymph nodes > 2 cm short axis 
•
50% increase in extent of spleen below costal margin by imaging  or physical exam 
6.4.5
Stable disease (SD) 
None of the above
6.5
TOXICITY CRITERIA
The following adverse event management guidelines are intended to ensure the safety of each 
participant while on the study. The descriptions and grading scales found in the revised NCI 
Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for AE 

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reporting. All appropriate treatment areas should have access to a copy of the CTCAE version 5.0. 
A copy of the CTCAE version 5.0 can be downloaded from the CTEP web site 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm). 
7
NIH REPORTING REQUIREMENTS / DATA AND SAFETY MONITORING PLAN
7.1
DEFINITIONS
Please refer to definitions provided in Policy 801: Reporting Research Events found at: 
https://irbo.nih.gov/confluence/pages/viewpage.action?pageId=36241835#Policies&Guidance-
800Series-ComplianceandResearchEventReportingRequirements.
7.2
OHSRP OFFICE OF COMPLIANCE AND TRAINING / IRB REPORTING
7.2.1
Expedited Reporting 
Please refer to the reporting requirements in Policy 801: Reporting Research Events found at: 
https://irbo.nih.gov/confluence/pages/viewpage.action?pageId=36241835#Policies&Guidance-
800Series-ComplianceandResearchEventReportingRequirements. Note: Only IND Safety Reports 
that meet the definition of an unanticipated problem or present new information that might affect 
the willingness of participants to enroll or remain on the study will need to be reported per these 
policies.
7.2.2
IRB Requirements for PI Reporting at Continuing Review
Please refer to the reporting requirements in Policy 801: Reporting Research Events found at: 
https://irbo.nih.gov/confluence/pages/viewpage.action?pageId=36241835#Policies&Guidance-
800Series-ComplianceandResearchEventReportingRequirements.
7.3
NCI CLINICAL DIRECTOR REPORTING
Problems expeditiously reviewed by the OHSRP in the NIH eIRB system will also be reported to 
the NCI Clinical Director/designee; therefore, a separate submission for these reports is not 
necessary.  
In addition to those reports, all deaths that occur within 30 days after receiving a research 
intervention should be reported via email unless they are due to progressive disease.  
To report these deaths, please send an email describing the circumstances of the death to 
NCICCRQA@mail.nih.gov within one business day of learning of the death.
7.4
NIH REQUIRED DATA AND SAFETY MONITORING PLAN
7.4.1
Principal Investigator/Research Team 
The clinical research team will meet on a weekly basis when participants are being actively treated 
on the trial to discuss each participant. Decisions about dose level enrollment and dose de-
escalation if applicable will be made based on the toxicity data from prior participants. 
All data will be collected in a timely manner and reviewed by the principal investigator or a lead 
associate investigator. Events meeting requirements for expedited reporting as described in Section 
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The principal investigator will review adverse event and response data on each participant to 
ensure safety and data accuracy. The principal investigator will personally conduct or supervise 
the investigation and provide appropriate delegation of responsibilities to other members of the 
research staff. 
7.4.2
Safety Monitoring Committee (SMC) - CCR
This protocol will require oversight from the Safety Monitoring Committee (SMC). Initial review 
will occur as soon as possible after the annual NIH Intramural IRB continuing review date. 
Subsequently, each protocol will be reviewed as close to annually as the quarterly meeting 
schedule permits or more frequently as may be required by the SMC. For initial and subsequent 
reviews, protocols will not be reviewed if there is no accrual within the review period. 
The SMC will operate under the rules of an approved charter that will be written and reviewed at 
the organization meeting of the SMC. Each review will focus on unexpected protocol-specific 
safety issues that are identified during the conduct of the clinical trial.
Written outcome letters will be generated in response to the monitoring activities and submitted to 
the Principal Investigator and Clinical Director or Deputy Clinical Director, CCR, NCI.
8
SPONSOR SAFETY REPORTING
8.1
DEFINITIONS
8.1.1
Adverse Event 
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 adverse event (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 (investigational) product, whether or not related to the medicinal (investigational) 
product (ICH E6 (R2)).
8.1.2
Serious Adverse Event (SAE)
An adverse event or suspected adverse reaction is considered serious if in the view of the 
investigator or the sponsor, it results in any of the following:
•
Death,
•
A life-threatening adverse event (see Section 8.1.3)
•
Inpatient hospitalization or prolongation of existing hospitalization
o
A hospitalization/admission that is pre-planned (i.e., elective or scheduled surgery 
arranged prior to the start of the study), a planned hospitalization for pre-existing 
condition, or a procedure required by the protocol, without a serious deterioration in 
health, is not considered a serious adverse event.
o
A hospitalization/admission that is solely driven by non-medical reasons (e.g., 
hospitalization for patient or subject convenience) is not considered a serious adverse 
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o
Emergency room visits or stays in observation units that do not result in admission to 
the hospital would not be considered a serious adverse event. The reason for seeking 
medical care should be evaluated for meeting one of the other serious criteria.
•
Persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions
•
A congenital anomaly/birth defect.
•
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition.
8.1.3
Life-threatening 
An adverse event or suspected adverse reaction is considered "life-threatening" if, in the view of 
either the investigator or sponsor, its occurrence places the patient or subject at immediate risk of 
death. It does not include an adverse event or suspected adverse reaction that, had it occurred in a 
more severe form, might have caused death (21CFR312.32).
8.1.4
Severity
The severity of each Adverse Event will be assessed utilizing the CTCAE version 5.
8.1.5
Relationship to Study Product
All AEs will have their relationship to study product assessed using the terms: related or not 
related.  
•
Related – There is a reasonable possibility that the study product caused the adverse event. 
Reasonable possibility means that there is evidence to suggest a causal relationship 
between the study product and the adverse event.
•
Not Related – There is not a reasonable possibility that the administration of the study 
product caused the event.
8.2
ASSESSMENT OF SAFETY EVENTS
AE information collected (see Section 8.4.4) will include event description, date of onset, 
assessment of severity and relationship to study product and alternate etiology (if not related to 
study product), date of resolution (return to baseline or stabilization) of the event, seriousness and 
outcome. The assessment of severity and relationship to the study product will be done only by 
those with the training and authority to make a diagnosis and listed on the Form FDA 1572 as the 
site principal investigator or sub-investigator. AEs occurring during the collection and reporting 
period will be documented appropriately regardless of relationship. AEs will be followed through 
resolution.
SAEs will be:
•
Assessed for severity and relationship to study product and alternate etiology (if not related 
to study product) by a licensed study physician listed on the Form FDA 1572 as the site 

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principal investigator or sub-investigator.
•
Recorded on the appropriate SAE report form, the medical record and captured in the 
clinical database.
•
Followed through resolution by a licensed study physician listed on the Form FDA 1572 
as the site principal investigator or sub-investigator.
For timeframe of recording adverse events, please refer to Section 6.1. All serious adverse events 
recorded from the time of first investigational product administration must be reported to the 
sponsor.
8.3
REPORTING OF SERIOUS ADVERSE EVENTS
Any AE that meets a protocol-defined serious criteria that require expedited reporting must be 
submitted immediately (within 24 hours of awareness) to OSRO Safety using the CCR SAE report 
form. 
All SAE reporting must include the elements described in Section 8.4.4.
SAE reports will be submitted to the Center for Cancer Research (CCR) at: 
OSROSafety@mail.nih.gov and to the CCR PI and study coordinator.  CCR SAE report form and 
instructions 
can 
be 
found 
at: 
https://nih.sharepoint.com/:u:/r/sites/NCI-CCR-OCD-
Communications/SitePages/Forms-and-Instructions.aspx?csf=1&web=1&e=uWBXtI.
Following the assessment of the SAE by OSRO, other supporting documentation of the event may 
be requested by the OSRO Safety and should be provided as soon as possible.
8.4
SAFETY REPORTING CRITERIA TO ASTRAZENECA(AZ) 
8.4.1
Reporting to AZ by CCR Safety
8.4.1.1
Serious Adverse Events
All SAEs have to be reported to AZ, whether or not considered causally related to the 
investigational product. All SAEs will be documented. The investigator is responsible for 
informing the IRB and/or the Regulatory Authority of the SAE as per local requirements.
A copy of the MedWatch/AdEERs report must be faxed or emailed to AZ within 1 business day 
of PI awareness of the event. It is the responsibility of the investigator to compile all necessary 
information and ensure that the FDA receives a report according to the FDA reporting requirement 
timelines and to ensure that these reports are also submitted to AZ at the same time.
8.4.1.2
Deaths
Deaths that occur during the study, or within the protocol defined 30day poststudy followup period 
after the administration of the last dose of study treatment, must be reported to AZ as follows:
•
Where death is not due (or not clearly due) to progression of the disease under study, the 
AE causing the death must be reported to the study monitor as a SAE within 24 hours of 
PI awareness of the event. The report should contain a comment regarding the 
co-involvement of progression of disease, if appropriate, and should assign main and 
contributory causes of death. This information can be captured in the ‘‘SAE report”.

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•
Deaths with an unknown cause should always be reported as a SAE. A post mortem maybe 
helpful in the assessment of the cause of death, and if performed a copy of the post-mortem 
results should be forwarded to AZ within one business day of learning of the death.
8.4.1.3
Details for expedited reporting to AZ
* A cover page should accompany the MedWatch/AdEERs form indicating the following:
•
External Scientific Research (ESR)
•
The investigator IND number assigned by the FDA
•
The investigator’s name and address
•
The trial name/title and protocol reference number
* Investigative site must also indicate, either in the SAE report or the cover page, the causality of 
events in relation to all study medications and if the SAE is related to disease progression, as 
determined by the principal investigator.
* Send SAE report and accompanying cover page by way of Email to:
AEMailboxClinicalTrialTCS@astrazeneca.com   
8.4.2
Reporting to AZ by the Study Team
8.4.2.1
Overdose
Study drug overdose is the accidental or intentional use of the drug in an amount higher than the 
dose being studied. An overdose or incorrect administration of study drug is not an AE unless it 
results in untoward medical effects.
Any study drug overdose or incorrect administration of study drug should be noted on the 
appropriate CRF.
All AEs associated with an overdose or incorrect administration of study drug should be recorded 
on the CRF. If the associated AE fulfills serious criteria, the event should be reported to AZ per 
contractual guidelines. The Sponsor should report any SAEs to the IRB and Regulatory Authorities 
per institutional and/or regulatory guidelines, and to AZ per the CRADA.
For other overdoses, reporting should be done within 30 days. 
In the event of administration of more than the recommended dosage, observation for any 
symptomatic side effects should be instituted, and vital signs, biochemical and hematologic 
parameters should be followed closely (consistent with the protocol or more frequently, as needed).  
Appropriate supportive management to mitigate adverse effects should be initiated. 
8.4.3
Aggregated Reporting
All aggregated reporting will be done by study team/investigator on a monthly basis and under 
no circumstance less frequently than quarterly.
8.4.3.1
Reporting of Adverse Events (AEs) after the 30-day follow up period
At any time after a patient has completed the study therapy, if an Investigator learns of any SAE 
including sudden death of unknown cause, and he/she considers there is a reasonable possibility 
that the event is causally related to the investigational product, the investigator should notify AZ.

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If patients who are gaining clinical benefit are allowed to continue study treatment post data cut 
off and/or post study completion, then all SAEs must continue to be collected and reported to 
Patient Safety within the usual timeframe.
Otherwise, after study treatment completion (i.e., after any scheduled post treatment follow-up 
period has ended) there is no obligation to actively report information on new AEs or SAEs 
occurring in former study patients. This includes new AEs/SAEs in patients still being followed 
up for survival but who have completed the post treatment follow up period (30 days).
8.4.3.2
Reporting of Adverse events (AEs)
AEs for new primary malignant tumors reported during a study should generally be assessed as 
serious AEs. If no other seriousness criteria apply, the ‘important medical event’ criterion should 
be used. In certain situations, however, medical judgement on an individual event basis should be 
applied to clarify that the primary malignant tumor event should be assessed and reported as a non-
serious AE. For example, if the tumor is included as medical history and progression occurs during 
the study, but the progression does not change treatment and/or prognosis of the malignant tumor, 
the AE may not fulfil the attributes for being assessed as serious, although reporting of the 
progression of the malignant tumor as an AE is valid and should occur. Also, some types of 
malignant tumors, which do not spread remotely after a routine treatment that does not require 
hospitalization, may be assessed as non-serious; examples include Stage I basal cell carcinoma 
and Stage IA1 cervical cancer removed via cone biopsy.
Non-serious adverse events and SAEs will be collected from the time consent is given, throughout 
the treatment period and up to and including the 30-day follow-up period. After withdrawal from 
treatment, subjects must be followed up for all existing and new AEs for 30 calendar days after 
the last dose of trial drug and/or until event resolution. All new AEs occurring during that period 
must be recorded (if SAEs, then they must be reported as indicated in Sections 8.3 and 8.4.1). All 
study-related toxicities/ SAEs must be followed until resolution, unless in the Investigator’s 
opinion, the condition is unlikely to resolve due to the patient’s underlying disease.
8.4.4
Requirements of adverse events (AEs) reporting
The following variables will be collected for each AE:
AE (verbatim)
•
The date and time when the AE started and stopped
•
Select the appropriate if needed: maximum intensity or intensity or changes in intensity
•
Changes in NCI CTCAE grade and the maximum CTC grade attained
•
Whether the AE is serious or not
•
Investigator causality rating against the Investigational Product (yes or no) 
comparator/combination drug (yes/no)
•
Action taken with regard to investigational product/comparator/combination agent
•
Outcome
In addition, the following variables will be collected for SAEs:
•
Date AE met criteria for serious AE
•
Date Investigator became aware of serious AE

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•
AE is serious due to
•
Date of hospitalization
•
Date of discharge
•
Probable cause of death
•
Date of death
•
Autopsy performed
•
Description of AE
•
Causality assessment in relation to Study procedure(s)
•
Causality assessment in relation to other medication
•
Causality assessment in relation to Additional Study Drug
Send reports and accompanying cover page by way of Email to:
AEMailboxClinicalTrialTCS@astrazeneca.com 
8.5
REPORTING PREGNANCY
All 
required 
pregnancy 
reports/follow-up 
to 
OSRO 
will 
be 
submitted 
to: 
OSROSafety@mail.nih.gov and to the CCR PI and study coordinator.  Forms and instructions can 
be 
found 
here: 
https://nih.sharepoint.com/:u:/r/sites/NCI-CCR-OCD-
Communications/SitePages/Forms-and-Instructions.aspx?csf=1&web=1&e=uWBXtI.
8.5.1
Maternal Exposure
If a participant becomes pregnant during the course of the study or until 12 months after the last 
dose of Moxetumomab pasudotox-tdfk and rituximab/Ruxience, the study treatment should be 
discontinued immediately, and the pregnancy reported to the Sponsor no later than 24 hours of 
when the Investigator becomes aware of it. The Investigator should notify the Sponsor no later 
than 24 hours of when the outcome of the pregnancy becomes known,
Pregnancy itself is not regarded as an SAE. However, congenital abnormalities or birth defects 
and spontaneous miscarriages that meet serious criteria (see Section 8.1.2) should be reported as 
SAEs. 
The outcome of all pregnancies from the date of the first dose of study therapy until 12 months 
after the last dose of study therapy should be followed up and documented.
8.5.2
Paternal Exposure
Male participants should refrain from fathering a child or donating sperm during the study and for 
90 days after the last dose of Moxetumomab pasudotox-tdfk and rituximab/Ruxience.
Pregnancy of the participant’s partner is not considered to be an AE. The outcome of all 
pregnancies occurring from the date of the first dose until 90 days after the last dose should, if 
possible, be followed up and documented. Pregnant partners may be offered the opportunity to 
participate in an institutional pregnancy registry protocol (e.g., the NIH IRP pregnancy registry 
study) to provide data about the outcome of the pregnancy for safety reporting purposes.

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8.6
REGULATORY REPORTING FOR STUDIES CONDUCTED UNDER CCR-SPONSORED IND
Following notification from the investigator, CCR, the IND sponsor, will report any suspected 
adverse reaction that is both serious and unexpected.  CCR will report an AE as a suspected adverse 
reaction only if there is evidence to suggest a causal relationship between the study product and 
the adverse event.  CCR will notify FDA and all participating investigators (i.e., all investigators 
to whom the sponsor is providing drug under its INDs or under any investigator’s IND) in an IND 
safety report of potential serious risks from clinical trials or any other source, as soon as possible, 
in accordance to 21 CFR Part 312.32. 
All serious events will be reported to the FDA at least annually in a summary format.
8.7
Sponsor Protocol Deviation Reporting
A Protocol Deviation is defined as any non-compliance with the clinical trial Protocol, Manual of 
Operational Procedures (MOP) and other Sponsor approved study related documents, GCP, or 
protocol-specific procedural requirements on the part of the participant, the Investigator, or the 
study site staff inclusive of site personnel performing procedures or providing services in support 
of the clinical trial.
It is the responsibility of the study Staff to document any protocol deviation identified by the Staff 
or the site Monitor in the CCR Protocol Deviation Tracking System (PDTS) online application. 
The entries into the PDTS online application should be timely, complete, and maintained per CCR 
PDTS user requirements.
In addition, any deviation to the protocol should be documented in the participant’s source records 
and reported to the reviewing IRB per their guidelines. OSRO required protocol deviation 
reporting is consistent with E6(R2) GCP: Integrated Addendum to ICH E6(R1): 4.5 Compliance 
with Protocol; 5.18.3 (a), and 5.20 Noncompliance; and ICH E3 16.2.2 Protocol deviations.
9
CLINICAL MONITORING 
Clinical site monitoring is conducted to ensure:
•
that the rights of the participants are protected; 
•
that the study is implemented per the approved protocol, Good Clinical Practice and 
standard operating procedures; and, 
•
the quality and integrity of study data and data collection methods are maintained.  
Monitoring for this study will be performed by NCI CCR Office of Sponsor and Regulatory 
Oversight (OSRO) Sponsor and Regulatory Oversight Support (SROS) Services contractor. 
Clinical site monitoring activities will be based on OSRO standards, FDA Guidance E6(R2) Good 
Clinical Practice: Integrated Addendum to ICH E6(R1) March 2018, and applicable regulatory 
requirements.
Details of clinical site monitoring will be documented in a Clinical Monitoring Plan (CMP) 
developed by OSRO. CMPs will be protocol-specific, risk-based and tailored to address human 
subject protections and integrity of the study data. OSRO will determine the intensity and 
frequency of monitoring based on several factors, including study type, phase, risk, complexity, 
expected enrollment rate, and any unique attributes of the study and the site. The Sponsor will 
conduct a periodic review of the CMP to confirm the plan's continued appropriateness. A change 

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to the protocol, significant or pervasive non-compliance with GCP, or the protocol may trigger 
CMP updates.
OSRO SROS Monitoring visits and related activities will be conducted throughout the life cycle 
of each protocol. The first activity is before the study starts to conduct a Site Assessment Visit 
(SAV) (as warranted), followed by a Site Initiation Visit (SIV), Interim Monitoring Visit(s) 
(IMVs), and a study Close-Out Visit (COV).
Some monitoring activities may be performed remotely, while others will occur at the study site(s). 
Monitoring visit reports will describe visit activities, observations, and associated action items or 
follow-up required for resolution of any issues, discrepancies, or deviations. Monitoring reports 
will be distributed to the study PI, NCI CCR QA, CCR Protocol Support Office, coordinating 
center (if applicable), and the Sponsor regulatory file.
The site Monitor will inform the study team of any deviations observed during monitoring visits. 
If unresolved, the Monitor will request that the site Staff enter the deviations in the CCR Protocol 
Deviation Tracking System (PDTS) for deviation reporting to the Sponsor and as applicable per 
institutional and IRB guidance.
10 STATISTICAL CONSIDERATIONS 
10.1 STATISTICAL HYPOTHESIS
Moxetumomab pasudotox-tdfk may be combined with rituximab/Ruxience safely in participants 
with relapsed/refractory HCL.
•
Primary Endpoint(s): To determine the safety and toxicity of moxetumomab pasudotox-
tdfk and rituximab/Ruxience treated at the planned dose level, in participants with HCL 
and HCLv.
•
Secondary Endpoints: 
o
To determine the minimal residual disease (MRD)-free CR rate of the study drug 
combination is higher than that achieved with 40-50 mcg/kg dose levels of 
Moxetumomab pasudotox-tdfk alone.  
o
To determine response rate and duration of response. 
10.2 SAMPLE SIZE DETERMINATION
•
The initial sample size determination: Up to 10 participants are intended to be treated in the 
trial using the following plan; if a different dose of moxetumomab pasudotox-tdfk is required, 
up to 16 participants will be needed to be enrolled. 
Initially, 3 participants will be treated with moxetumomab pasudotox-tdfk 30 mcg/kg and 
rituximab 375 mg/m2. If 0/3 have a DLT, then the next 3 participants will be treated with 
moxetumomab pasudotox-tdfk 40 mg/kg and rituximab 375 mg/m2. 
If 1/3 initial participants treated with 30 mcg/kg have a DLT, then 3 more will be treated at 30 
mcg/kg. If no more than 1 of the first 6 have a DLT, then 4 more participants will be enrolled 
at 30 mcg/kg provided that no more than a total of 2 of the 10 have a DLT with the exception 

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of the types noted. The upper one-sided 90% confidence bound on 2/10 is 45.0%. if a 3rd 
participant has a DLT, accrual will end as soon as this is noted. 
If participants are accrued to the 40mcg/kg level, if 0/3 or 1/3 have a DLT (with the exception 
of the types noted), then 3 more will be treated using those dose levels. If no more than 1 of 
the first 6 have a DLT, then 4 more participants will be enrolled provided that no more than 2 
total of the 10 have a DLT. The upper one-sided 90% confidence bound on 2/10 is 45.0%. if a 
3rd participant has a DLT, accrual will end as soon as this is noted. 
If 2 of the first 3 participants, or 2 of the first 6 participants, treated with moxetumomab 
pasudotox-tdfk 40 mcg/kg and rituximab 375 mg/m2 have a DLT, then 3 additional participants 
will be treated with moxetumomab pasudotox-tdfk 30 mcg/kg and rituximab 375 mg/m2. If 0/3 
or 1/3 of these next 3 have a DLT with these dose levels, then 4 more participants will be 
enrolled at the 30 mcg/kg level provided that no more than 2 total of the 10 have a DLT with 
the exception of the types noted. If 2 participants in the first 6 have a DLT at this level, then 
the trial will end accrual. Furthermore, at any time in the 10 participants, if a 3rd participant 
has a DLT, accrual will also end as soon as this is noted. The upper one-sided 90% confidence 
bound on 2/10 is 45.0%.
•
Sample size determination for amendment dated 9/21/2021: As of July 2021, a total of 12 
participants were enrolled without DLT up to that point, making it likely that 3 participants 
will be enrolled with moxetumomab pasudotox-tdfk 30 mcg/kg and rituximab 375 mg/m2, and 
10 with moxetumomab pasudotox-tdfk 40 mcg/kg and rituximab 375 mg/m2.  Of the first 9 
participants so far evaluated for response, 7 (78%) achieved CR, all MRD-free.
Given the encouraging safety and efficacy data from the phase 1 trial, it is desirable to increase 
the number of participants to gain more experience with moxetumomab pasudotox-tdfkand 
rituximab and be able to determine whether the efficacy of the combination at 30-40 mcg/kg 
of moxetumomab pasudotox-tdfk is better than our historical experience of 40-50 mcg/kg of 
moxetumomab pasudotox-tdfk alone tested for MRD at NIH.  Historically, 30 of 64 evaluable 
phase 1-3 participants treated with moxetumomab pasudotox-tdfk alone achieved MRD-free 
CR assessed by bone marrow aspirate flow.  
To enable additional participants to be enrolled affordably, starting with participant 14, 
participants will receive the biosimilar Ruxience instead of rituximab.  Moxe-R thus represents 
the combination of moxetumomab pasudotox-tdfk with either rituximab or Ruxience.
If we are being conservative, the 7 of 9 participants who achieved MRD-free CR to date on 
Moxe-R would need to be considered an interim evaluation and its successful result would be 
the basis for deciding to add more participants. As such, it would be statistically appropriate to 
aim for a 0.025 one-sided test between 30/64 and the participants on the current trial. With a 
total of 26 evaluable participants on Moxe-R and 64 prior participants, a Fisher’s exact test 
with a one sided 2.5% significance level will have 79.8% power to detect a difference between 
80% MRD-free CR rate on the present trial and 47% from the 30/64 participants in the prior 
trials.
While a total of 26 evaluable participants will be enrolled, the accrual ceiling will be set at 30 
to include screen failures and inevaluable participants.

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10.3 POPULATIONS FOR ANALYSES
10.3.1 Evaluable for toxicity 
All participants will be evaluable for toxicity from the time of their first treatment 
10.3.2 Evaluable for objective response: 
Only those participants who have measurable disease present at baseline, have received at least 
one cycle of therapy, and have had their disease re-evaluated will be considered evaluable for 
response. These participants will have their response classified according to the definitions stated 
below. (Note: Participants who exhibit objective disease progression prior to the end of cycle 1 
will also be considered evaluable.)
10.3.3 Evaluable Non-Target Disease Response: 
Participants who have lesions present at baseline that are evaluable but do not meet the definitions 
of measurable disease, have received at least one cycle of therapy, and have had their disease re-
evaluated will be considered evaluable for non-target disease. The response assessment is based 
on the presence, absence, or unequivocal progression of the lesions.
10.4 STATISTICAL ANALYSES
10.4.1 General Approach 
10.4.2 Safety data will be evaluated, as well as the MRD-free CR rate, in comparison to 
results from prior trials. Analysis of the Primary Endpoints
Meeting the primary safety endpoint will require treatment of 10 participants with no more than 2 
DLT.
10.4.3 Analysis of the Secondary Endpoint(s)
•
Response rates, MRD-free rates, and response durations will be reported descriptively, and the 
latter will be determined using Kaplan Meier Analyses. 
•
The MRD-free CR rates will be compared between evaluable participants on this trial and the 
30 of 64 evaluable phase 1-3 participants who achieved MRD-free CR from moxetumomab 
pasudotox-tdfk using a Fisher’s exact test, taking the interim results from this trial into 
consideration. 
•
The change from rituximab to Ruxience is not expected to result in a change to the CD20 Mab, 
and the comparison between participants 1-13 treated with moxetumomab pasudotox-tdfk - 
rituximab and participants 14-26 treated with moxetumomab pasudotox-tdfk - Ruxience will 
have limited power to detect a difference between rituximab and Ruxience in HCL.  After 
enrollment of 26 participants, if the difference in MRD-free CR rate from moxetumomab 
pasudotox-tdfk - rituximab vs moxetumomab pasudotox-tdfk - Ruxience results is p>0.30 or 
higher, the results from the 2 groups will be considered close enough to be pooled and the full 
26 participants could be compared against the 64 from the moxetumomab pasudotox-tdfk 
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10.4.4 Safety Analyses
Safety analysis will focus on presence and absence of DLT, and incidence of lesser toxicities to 
each agent or both.
10.4.5 Sub-Group Analyses
Not Applicable.
10.4.6 Exploratory Analyses
Results of exploratory analyses will be descriptive.
11 COLLABORATIVE AGREEMENTS 
11.1 CRADA
Conduct of this study and supply of moxetumomab pasudotox-tdfk and rituximab/Ruxience will 
be addressed by amendment (#13) to existing NCI CRADA (#1975) with AZ. 
12 HUMAN SUBJECTS PROTECTIONS 
12.1 RATIONALE FOR SUBJECT SELECTION
Participants eligible will be relapsed. Defining the safety of moxetumomab pasudotox-tdfk in 
participants with relapsed HCL will be needed before considering extending this regimen to 
participants after only 1 or no prior therapy. 
12.2 PARTICIPATION OF CHILDREN
HCL has not been reported in individuals < 18 therefore children will not participate in this 
study.
12.3 PARTICIPATION OF SUBJECTS UNABLE TO GIVE CONSENT 
Adults unable to give consent are excluded from enrolling in the protocol. However, it is possible 
that subjects enrolled in the protocol may permanently lose the capacity to consent for themselves 
during the course of this study. In the event this occurs, the subjects will remain in the study 
because there is a prospect of direct benefit from research participation (Section 12.5.1). ,All 
subjects ≥ age 18 will be offered the opportunity to fill in their wishes for research and care, and 
assign a substitute decision maker on the “NIH Advance Directive for Health Care and Medical 
Research Participation” form so that another person can make decisions about their medical care 
in the event that they become incapacitated or cognitively impaired during the course of the study. 
Note: The PI or AI will contact the NIH Ability to Consent Assessment Team (ACAT) for 
evaluation to assess ongoing capacity of the subjects and to identify an LAR, as needed. 
Please see Section 12.5.1 for consent procedure.
12.4 EVALUATION OF BENEFITS AND RISKS/DISCOMFORTS
Participants will receive evaluation of their disease at the National Cancer Institute’s Clinical 
Center. This protocol may or may not benefit an individual, but the results may help the 

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investigators learn more about the disease and develop new treatments for participants with this 
disease.
Potential adverse reactions attributable to the administration of the drugs utilized in this trial are 
discussed in Sections 14.1.2 and 14.2.2. All care will be taken to minimize side effects, but they 
can be unpredictable in nature and severity. Participants will be examined and evaluated prior to 
enrollment. All evaluations to monitor the treatment of participants will be recorded in the 
participant chart. If participants suffer any physical injury as a result of the participation in this 
study, immediate medical treatment is available at the Clinical Center, National Cancer Institute, 
Bethesda, Maryland.
Although no compensation is available, any injury will be evaluated and treated in keeping with 
the benefits or care to which participants are entitled under applicable regulations. In all 
publications and presentations resulting from this trial, participants’ anonymity will be protected 
to the maximum extent possible. Authorized personnel from the National Cancer Institute (NCI) 
and Food and Drug Administration (FDA) or other regulatory authorities may have access to 
research files in order to verify that participants’ rights have been safeguarded. In addition, 
participant names will be given to the Central Registration to register and verify participants’ 
eligibility.
12.4.1 Potential Risks Associated with Administration of Moxetumomab pasudotox-tdfk 
The primary risks of participation in this study include the possible occurrence of any of a range 
of side effects from moxetumomab pasudotox-tdfk are described in Sections 1.2.1, 14.1.2 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. 
Moxetumomab pasudotox-tdfk is administered intravenously. Possible risks associated with IV 
administration of moxetumomab pasudotox-tdfk are infection, redness, swelling, pain, and 
induration at the administration site.
12.4.2 Potential Risks Associated with Administration of Rituxan
Refer to Section 14.2.2 for details.
12.4.3 Potential Risks Associated with Administration of Ruxience
Refer to Section 14.3 for details.
12.4.4 Identified Risks to Study Procedures
12.4.4.1 Blood Sampling
Side effects of blood draws include pain and bruising, lightheadedness, and rarely, fainting. Up to 
123 mL of research blood may be collected at any visit but no more than 315 ml in an 8 week 
period. Refer to study calendar (Section 3.4) for frequency of blood draws.
12.4.4.2 Urine Collection
There is no physical risk involved with urine collection.

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12.4.4.3 Bone marrow aspirate and/or biopsy 
Bone marrow biopsy is minimally invasive and is typically a very safe procedure. Usually, hipbone 
is numbed with anesthesia. Using a needle, the solid and liquid portion of bone marrow is taken 
out. This procedure causes some pain. Very rarely, infection or bleeding may occur at the needle 
site.
12.4.4.4 Electrocardiogram
Some skin irritation can occur where the ECG/EKG electrodes are placed. The test is completely 
painless and generally takes less than a minute to perform.
12.4.4.5 Stress test
A stress test is generally safe, and complications are rare. Risks include hypotension, arrhythmias, 
or myocardial infarction.
12.4.4.6 Pulmonary function tests (PFTs)
PFTs are usually safe for most people. Risks include dizziness, asthma attack, or collapsed lung. 
12.4.4.7 Abdominal ultrasounds and echocardiogram
There is no physical risk involved with abdominal ultrasounds or echo.
12.4.4.8 Imaging
In addition to the radiation risks discussed below, CT scans may include the risks of an allergic 
reaction to the contrast. Participants might experience hives, itching, headache, difficulty 
breathing, increased heartrate and swelling. 
The risks of MR imaging are relatively small.
The US Food and Drug Administration has issued warnings that administration of gadolinium 
(updated September 9, 2010), the MRI contrast imaging agent used in this protocol, has been 
associated with development of a disease called nephrogenic systemic fibrosis (NSF). The 
syndrome is rare (approximately 600 cases reported worldwide as of September 2010, out of 
several million administrations of gadolinium), but disabling and in some cases, fatal. All cases to 
date have occurred in participants with severe renal disease, including participants on dialysis. 
NSF has been nearly eradicated secondary to careful screening of renal function and avoiding use 
of gadolinium in participants with eGFR <30 ml/min/1.73 BSA. Even in participants with end 
stage renal disease, there have been only rare occurrences of NSF because of precautions taken to 
use more stable contrast agents at lower doses. This protocol excludes participants with severe 
renal insufficiency (eGFR <30 ml/min/1.73 BSA). The FDA has issued warnings in 2017 and 2018 
that some gadolinium may be retained in the brain, bone and skin although health risks of 
accumulation have not been reported to date. In accordance with the FDA Drug Safety 
Communication of 05/16/2018, the Medication Guide for gadobutrol (or other macrocyclic 
gadolinium contrast agent if applicable) will be made available to all participants with scans that 
will involve gadolinium-based contrast agent administration.

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12.4.5 Risks from Radiation Exposure
On this study, participants will receive up to 3 CT scans/year (excluding screening as these are 
performed on another study). The total radiation dose for research purposes will be approximately 
3.9 rem. An increased risk of cancer is associated with this exposure. 
12.4.6 Non-Physical Risks of Genetic Research
12.4.6.1 Risk of receiving unwanted information
Anxiety and stress may arise as a result of the anticipation that unwanted information regarding 
disease related genetic analysis. Patients will be clearly informed that the data related to genetic 
analysis is coded, investigational and will not be shared with patients, family members or health 
care providers.
12.4.6.2 Risk related to possibility that information may be released
This includes the risk that data related to genotype or risk for disease tendency or trait can be 
released to members of the public, insurers, employers, or law enforcement agencies. Although 
there are no plans to release results to the patients, family members or health care providers, this 
risk will be included in the informed consent document.
12.4.6.3 Risk to family or relatives
Family members or relatives may or may not want to be aware of familial tendencies or genetic 
risks of disease which may cause anxiety about possible future health problems. As previously 
noted, patients will be notified of any medically significant and actionable incidental findings. 
Study results will not be shared with patients.
12.5 CONSENT PROCESS AND DOCUMENTATION
The informed consent document will be provided as a physical or electronic document to the 
participant or consent designee(s) as applicable for review prior to consenting.  A designated study 
investigator will carefully explain the procedures and tests involved in this study, and the 
associated risks, discomforts and benefits. In order to minimize potential coercion, as much time 
as is needed to review the document will be given, including an opportunity to discuss it with 
friends, family members and/or other advisors, and to ask questions of any designated study 
investigator. A signed informed consent document will be obtained prior to entry onto the study.
The initial consent process as well as re-consent, when required, may take place in person or 
remotely (e.g., via telephone or other NIH approved remote platforms used in compliance with 
local policy, including HRPP Policy 303) per discretion of the designated study investigator and 
with the agreement of the participant/consent designee(s).  Whether in person or remote, the 
privacy of the participant will be maintained. Consenting investigators (and participant/consent 
designee, when in person) will be located in a private area (e.g., clinic consult room). When 
consent is conducted remotely, the participant/consent designee will be informed of the private 
nature of the discussion and will be encouraged to relocate to a more private setting if needed.
Consent will be documented with required signatures on the physical document (which includes 
the printout of an electronic document sent to participant) or as described below, with a manual 
(non-electronic) signature on the electronic document. When required, witness signature will be 
obtained similarly as described for the investigator and participant.

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Manual (non-electronic) signature on electronic document:
When a manual signature on an electronic document is used for the documentation of consent at 
the NIH Clinical Center, this study will use the following to obtain the required signatures:
•
Adobe platform (which is not 21 CFR Part 11 compliant); or,  
•
iMedConsent platform (which is 21 CFR Part 11 compliant)
During the consent process, participants and investigators will view individual copies of the 
approved consent document on screens at their respective locations (if remote consent); the same 
screen may be used when in the same location but is not required.  
Both the investigator and the participant will sign the document using a finger, stylus or mouse. 
Note: Refer to the CCR SOP PM-2, Obtaining and Documenting the Informed Consent Process 
for additional information (e.g., verification of participant identity when obtaining consent 
remotely) 
found 
https://nih.sharepoint.com/sites/NCI-CCR-OCD-
Communications/SitePages/OEC-Administrative---Clinical-Research-(ADCR).aspx?Mode=Edit.
12.5.1 Consent Process for Adults Who Lack Capacity to Consent to Research Participation
For participants addressed in Section 12.3, an LAR will be identified consistent with Policy 403 
and informed consent obtained from the LAR, as described in Section 12.5.
13 REGULATORY AND OPERATIONAL CONSIDERATIONS
13.1 STUDY DISCONTINUATION AND CLOSURE
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause.  Written notification, documenting the reason for study suspension or 
termination, will be provided by the suspending or terminating party to study participants, 
investigator, funding agency, the Investigational New Drug (IND) sponsor and regulatory 
authorities.  If the study is prematurely terminated or suspended, the Principal Investigator (PI) 
will promptly inform study participants, the Institutional Review Board (IRB), and sponsor and 
will provide the reason(s) for the termination or suspension.  Study participants will be contacted, 
as applicable, and be informed of changes to study visit schedule.
Circumstances that may warrant termination or suspension include, but are not limited to:
•
Determination of unexpected, significant, or unacceptable risk to participants
•
Demonstration of efficacy that would warrant stopping   
•
Insufficient compliance to protocol requirements
•
Data that are not sufficiently complete and/or evaluable
•
Determination that the primary endpoint has been met
•
Determination of futility
Study may resume once concerns about safety, protocol compliance, and data quality are 
addressed, and satisfy the sponsor, IRB and as applicable, Food and Drug Administration (FDA).

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13.2 QUALITY ASSURANCE AND QUALITY CONTROL
The clinical site will perform internal quality management of study conduct, data and biological 
specimen collection, documentation and completion.  An individualized quality management plan 
will be developed to describe a site’s quality management.
Quality control (QC) procedures will be implemented beginning with the data entry system and 
data QC checks that will be run on the database will be generated. Any missing data or data 
anomalies will be communicated to the site(s) for clarification/resolution.
Following written Standard Operating Procedures (SOPs), the monitors will verify that the clinical 
trial is conducted and data are generated and biological specimens are collected, documented 
(recorded), and reported in compliance with the protocol, International Council for Harmonisation 
Good Clinical Practice (ICH GCP), and applicable regulatory requirements (e.g., Good Laboratory 
Practices (GLP), Good Manufacturing Practices [GMP]). 
The investigational site will provide direct access to all trial related sites, source data/documents, 
and reports for the purpose of monitoring and auditing by the sponsor, and inspection by local and 
regulatory authorities.
13.3 CONFLICT OF INTEREST POLICY
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical.  Therefore, any actual conflict of interest of persons who have 
a role in the design, conduct, analysis, publication, or any aspect of this trial will be disclosed and 
managed. Furthermore, persons who have a perceived conflict of interest will be required to have 
such conflicts managed in a way that is appropriate to their participation in the design and conduct 
of this trial.  The study leadership in conjunction with the National Cancer Institute has established 
policies and procedures for all study group members to disclose all conflicts of interest and will 
establish a mechanism for the management of all reported dualities of interest.
13.4 CONFIDENTIALITY AND PRIVACY
Participant confidentiality and privacy is strictly held in trust by the participating investigators, 
their staff, and the sponsor(s). This confidentiality is extended to cover testing of biological 
samples and genetic tests in addition to the clinical information relating to participants. Therefore, 
the study protocol, documentation, data, and all other information generated will be held in strict 
confidence. No information concerning the study or the data will be released to any unauthorized 
third party without prior written approval of the sponsor. 
All research activities will be conducted in as private a setting as possible.
The study monitor, other authorized representatives of the sponsor, representatives of the 
Institutional Review Board (IRB), and/or regulatory agencies may inspect all documents and 
records required to be maintained by the investigator, including but not limited to, medical records 
(office, clinic, or hospital) and pharmacy records for the participants in this study. The clinical 
study site will permit access to such records.
The study participant’s contact information will be securely stored at the clinical site for internal 
use during the study. At the end of the study, all records will continue to be kept in a secure location 

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for as long a period as dictated by the reviewing IRB, Institutional policies, or sponsor 
requirements.
Study participant research data, which is for purposes of statistical analysis and scientific reporting, 
will be stored at the NCI CCR. This will not include the participant’s contact or identifying 
information. Rather, individual participants and their research data will be identified by a unique 
study identification number. The study data entry and study management systems used by the 
clinical site and by NCI CCR research staff will be secured and password protected. At the end of 
the study, all study databases will be archived at the NIH.
To further protect the privacy of study participants, a Certificate of Confidentiality has been issued 
by the National Institutes of Health (NIH). This certificate protects identifiable research 
information from forced disclosure. It allows the investigator and others who have access to 
research records to refuse to disclose identifying information on research participation in any civil, 
criminal, administrative, legislative, or other proceeding, whether at the federal, state, or local 
level. By protecting researchers and institutions from being compelled to disclose information that 
would identify research participants, Certificates of Confidentiality help achieve the research 
objectives and promote participation in studies by helping assure confidentiality and privacy to 
participants.
14 PHARMACEUTICAL INFORMATION 
14.1 MOXETUMOMAB PASUDOTOX-TDFK (LUMOXITI™) IND # 140552
Note:  The oversight and future plans for Moxetumomab pasudotox-tdfk is conducted by AZ. The 
manufacturer and supplier for the Moxetumomab pasudotox-tdfk used in this study is AZ.
14.1.1 Source
Moxetumomab pasudotox-tdfk (other names: CAT-8015, HA22, LUMOXITI™) is an 
investigational agent supplied to investigator by AZ. It is a recombinant anti-CD22 MAb 
conjugated immunotoxin (MW=63.5kda) composed of a disulfide-stabilized anti-CD22 Ig Fv 
genetically fused to a truncated form of Pseudomonas exotoxin, PE38. Moxetumomab pasudotox-
tdfk 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.
14.1.2 Toxicity
Please refer to background Section 1.2.1 and FDA-approved prescribing information for complete 
list of side effects.
14.1.3 Formulation and preparation
Please refer to Appendix C (FDA-approved prescribing information) for details.
14.1.4  Stability and Storage
Please refer to Appendix C (FDA-approved prescribing information) for details.

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14.1.5 Administration procedures
Please refer to Appendix C (FDA-approved prescribing information) for details.
14.1.6 Incompatibilities 
None known 
14.2 RITUXIMAB (RITUXAN®)
14.2.1 Source
The finished injectable dosage form is jointly marketed by Biogen Idec, Inc. and Genentech, Inc. 
under the trade name Rituxan®. Rituximab is a highly purified, 1328-amino acid antibody with an 
approximate molecular mass of 145 kD. The chimeric mouse/human anti-CD20 antibody is a 
glycosylated IgG1  immunoglobulin containing murine light and heavy chain variable regions 
and human 1 heavy chain and  light chain constant regions. Rituximab induces apoptosis and 
either complement or antibody dependent cytotoxicity (ADCC or CDC). 
NIH CC pharmacy will dispense commercial supplies of Rituxan.
14.2.2 Toxicity 
Toxicities (% grade 3, grade 4) in non-Hodgkin’s lymphoma:
•
Body as a Whole: fever (53, 1%), chills (33, 3%), infection (31, 4%), asthenia (26, 1%), 
headache (19, 1%), abdominal Pain (14, 1%), pain (12, 1%), back Pain (10, 1%), throat 
Irritation (9, 0%), flushing (5, 0%)
•
Cardiovascular System: Hypotension (10, 1%), hypertension (6, 1%)
•
Digestive System: Nausea (23, 1%), diarrhea (10, 1%), vomiting (10, 1%)
•
Hematologic and Lymphatic: Lymphopenia (48, 40%), leukopenia (14, 4%), neutropenia (14, 
6%), thrombocytopenia (12, 2%), anemia (8, 3%)
•
Metabolic and Nutritional: Angioedema (11, 1%), hyperglycemia (9, 1%), peripheral edema 
(8, 0%), LDH increase (7, 0%)
•
Musculoskeletal System: Myalgia (10, 1%), arthralgia (10, 1%)
•
Nervous System: Dizziness (10, 1%), anxiety (5, 1%)
•
Respiratory System: Increased cough (13, 1%), rhinitis (12, 1%), bronchospasm (8, 1%), 
dyspnea (7, 1%), sinusitis (6, 0%)
•
Skin and Appendages: Night sweats (15, 1%), rash (15, 1%), pruritis (14, 1%), urticaria (8, 
1%)
•
Infusion reaction: In rituximab rheumatoid arthritis placebo-controlled studies, 32% of 
rituximab-treated patients experienced an adverse event during or within 24 hours following 
their first infusion, compared to 23% of placebo-treated patients receiving their first infusion. 
The incidence of adverse events during the 24-hour period following the second infusion, 
rituximab or placebo, decreased to 11% and 13%, respectively. Acute infusion reactions 

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(manifested by fever, chills, rigors, pruritis, urticaria/rash, angioedema, sneezing, throat 
irritation, cough, and/or bronchospasm, with or without associated hypotension or 
hypertension) were experienced by 27% of rituximab-treated patients following their first 
infusion, compared to 19% of placebo-treated patients receiving their first placebo infusion. 
The incidence of these acute infusion reactions following the second infusion of rituximab or 
placebo decreased to 9% and 11%, respectively. Serious acute infusion reactions were 
experienced by <1% of patients in either treatment group. Acute infusion reactions required 
dose modification (stopping, slowing or interruption of the infusion) in 10% and 2% of patients 
receiving rituximab or placebo, respectively, after the first course. The proportion of patients 
experiencing acute infusion reactions decreased with subsequent courses of rituximab. The 
administration of IV glucocorticoids prior to rituximab infusions reduced the incidence and 
severity of such reactions, however, there was no clear benefit from the administration of oral 
glucocorticoids for the prevention of acute infusion reactions. Patients in clinical studies also 
received antihistamines and acetaminophen prior to rituximab infusions.
•
Hematologic Events: In clinical trials, Grade 3 and 4 cytopenias [23] were reported in 48% of 
patients treated with rituximab; these include: lymphopenia (40%), neutropenia (6%), 
leukopenia (4%), anemia (3%), and thrombocytopenia (2%). The median duration of 
lymphopenia was 14 days (range, 1 to 588 days) and of neutropenia was 13 days (range, 2 to 
116 days). A single occurrence of transient aplastic anemia (pure red cell aplasia) and two 
occurrences of hemolytic anemia following rituximab therapy were reported. In addition, there 
have been a limited number of post-marketing reports of prolonged pancytopenia, marrow 
hypoplasia, and late onset neutropenia (defined as occurring 40 days after the last dose of 
rituximab) in patients with hematologic malignancies. In reported cases of late onset 
neutropenia (NCI-CTC Grade 3 and 4), the median duration of neutropenia was 10 days (range 
3 to 148 days). Documented resolution of the neutropenia was described in approximately one-
half of the reported cases; of those with documented recovery, approximately half received 
growth factor support. In the remaining cases, information on resolution was not provided. 
More than half of the reported cases of delayed onset neutropenia occurred in patients who had 
undergone a prior autologous bone marrow transplantation. In an adequately designed, 
controlled, clinical trial, the reported incidence of NCI-CTC Grade 3 and 4 neutropenia was 
higher in patients receiving rituximab in combination with fludarabine as compared to those 
receiving fludarabine alone, 39/51 (76%) vs. 21/51 (39%) [24]
14.2.3 Formulation and preparation 
Please refer to APPENDIX B for details.
14.2.4 Stability and Storage
Please refer to APPENDIX B for details.
14.2.5 Administration Procedures 
Please refer to APPENDIX B for details.
14.2.6 Incompatibilities 
None known.

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14.3 RUXIENCE
Please see FDA-approved packet insert for Ruxience for complete agent information. 
Manufacturer: Pfizer.
14.3.1 Source
Ruxience will be obtained from commercial sources and dispensed by the NIH CC pharmacy.
14.3.2 Administration
Please refer to APPENDIX B for details.

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Bouroncle BA, Wiseman BK, Doan CA: Leukemic reticuloendotheliosis. Blood 1958, 
13:609-630.
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Kreitman RJ, Pastan I: Immunoconjugates in the management of HCL. Best Pract Res 
Clin Haematol 2015, 28(4):236-245.
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Siegel RL, Miller KD, Jemal A: Cancer Statistics, 2017. CA Cancer J Clin 2017, 
67(1):7-30.
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Kreitman RJ, Wilson W, Calvo KR, Arons E, Roth L, Sapolsky J, Zhou H, Raffeld M, 
Stetler-Stevenson M: Cladribine with immediate rituximab for the treatment of 
patients with variant hairy cell leukemia. Clin Cancer Res 2013, 19(24):6873-6881.
5.
Matutes E, Martinez-Trillos A, Campo E: Hairy cell leukaemia-variant: Disease 
features and treatment. Best Pract Res Clin Haematol 2015, 28(4):253-263.
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Xi L, Arons E, Navarro W, Calvo KR, Stetler-Stevenson M, Raffeld M, Kreitman RJ: 
Both variant and IGHV4-34-expressing hairy cell leukemia lack the BRAF V600E 
mutation. Blood 2012, 119(14):3330-3332.
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Arons E, Suntum T, Stetler-Stevenson M, Kreitman RJ: VH4-34+ hairy cell leukemia, a 
new variant with poor prognosis despite standard therapy. Blood 2009, 
114(21):4687-4695.
8.
Kreitman RJ, Tallman MS, Robak T, Coutre S, Wilson WH, Stetler-Stevenson M, 
FitzGerald DJ, Lechleider R, Pastan I: Phase I trial of anti-CD22 recombinant 
immunotoxin moxetumomab pasudotox (CAT-8015 or HA22) in patients with hairy 
cell leukemia. J Clin Oncol 2012, 30(15):1822-1828.
9.
Kreitman RJ, Tallman MS, Robak T, Coutre S, Wilson WH, Stetler-Stevenson M, 
FitzGerald DJ, Santiago L, Gao G, Lanasa MC et al: Minimal Residual Hairy Cell 
Leukemia Eradication with Moxetumomab Pasudotox: Phase I Results and Long-
term Follow-up. Blood 2017:submitted.
10.
Tallman MS, Hakimian D, Kopecky KJ, Wheaton S, Wollins E, Foucar K, Cassileth PA, 
Habermann T, Grever M, Rowe JM et al: Minimal residual disease in patients with 
hairy cell leukemia in complete remission treated with 2-chlorodeoxyadenosine or 2- 
deoxycoformycin and prediction of early relapse. Clin Cancer Res 1999, 5(7):1665-
1670.
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Arons E, Margulies I, Sorbara L, Raffeld M, Stetler-Stevenson M, Pastan I, Kreitman RJ: 
Minimal residual disease in hairy cell leukemia patients assessed by clone-specific 
polymerase chain reaction. Clin Cancer Res 2006, 12(9):2804-2811.
12.
Ravandi F, O'Brien S, Jorgensen J, Pierce S, Faderl S, Ferrajoli A, Koller C, 
Challagundla P, York S, Brandt M et al: Phase 2 study of cladribine followed by 
rituximab in patients with hairy cell leukemia. Blood 2011, 118(14):3818-3823.
13.
Hassan R, Williams-Gould J, Watson T, Pai-Scherf L, Pastan I: Pretreatment with 
rituximab does not inhibit the human immune response against the immunogenic 

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protein LMB-1. Clinical cancer research : an official journal of the American 
Association for Cancer Research 2004, 10(1 Pt 1):16-18.
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Wayne AS, Shah NN, Bhojwani D, Silverman LB, Whitlock JA, Stetler-Stevenson M, 
Sun W, Liang M, Yang J, Kreitman RJ et al: Phase 1 study of the anti-CD22 
immunotoxin moxetumomab pasudotox for childhood acute lymphoblastic 
leukemia. Blood 2017, 130(14):1620-1627.
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Reff ME, Carner K, Chambers KS, Chinn PC, Leonard JE, Raab R, Newman RA, Hanna 
N, Anderson DR: Depletion of B cells in vivo by a chimeric mouse human 
monoclonal antibody to CD20. Blood 1994, 83(2):435-445.
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Edwards JC, Cambridge G: Prospects for B-cell-targeted therapy in autoimmune 
disease. Rheumatology (Oxford) 2005, 44(2):151-156.
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Edwards JC, Szczepanski L, Szechinski J, Filipowicz-Sosnowska A, Emery P, Close DR, 
Stevens RM, Shaw T: Efficacy of B-cell-targeted therapy with rituximab in patients 
with rheumatoid arthritis. N Engl J Med 2004, 350(25):2572-2581.
18.
Nieva J, Bethel K, Saven A: Phase 2 study of rituximab in the treatment of 
cladribine-failed patients with hairy cell leukemia. Blood 2003, 102(3):810-813.
19.
Baer Ii WH, Maini A, Jacobs I: Barriers to the Access and Use of Rituximab in 
Patients with Non-Hodgkin's Lymphoma and Chronic Lymphocytic Leukemia: A 
Physician Survey. Pharmaceuticals (Basel) 2014, 7(5):530-544.
20.
Ryan AM, Sokolowski SA, Ng CK, Shirai N, Collinge M, Shen AC, Arrington J, Radi Z, 
Cummings TR, Ploch SA et al: Comparative nonclinical assessments of the proposed 
biosimilar PF-05280586 and rituximab (MabThera(R)). Toxicol Pathol 2014, 
42(7):1069-1081.
21.
Cohen S, Emery P, Greenwald M, Yin D, Becker JC, Melia LA, Li R, Gumbiner B, 
Thomas D, Spencer-Green G et al: A phase I pharmacokinetics trial comparing PF-
05280586 (a potential biosimilar) and rituximab in patients with active rheumatoid 
arthritis. Br J Clin Pharmacol 2016, 82(1):129-138.
22.
Sharman JP, Liberati AM, Ishizawa K, Khan T, Robbins J, Alcasid A, Rosenberg JA, 
Aurer I: A Randomized, Double-Blind, Efficacy and Safety Study of PF-05280586 (a 
Rituximab Biosimilar) Compared with Rituximab Reference Product 
(MabThera((R))) in Subjects with Previously Untreated CD20-Positive, Low-
Tumor-Burden Follicular Lymphoma (LTB-FL). BioDrugs 2020, 34(2):171-181.
23.
Natkunam Y, Stanton TS, Warnke RA, Horning SJ: Durable remission in recurrent T-
cell-rich B-cell lymphoma with the anti-CD20 antibody rituximab. Clin Lymphoma 
2001, 2(3):185-187.
24.
Shih WJ, Ghesani N, Hongming Z, Alavi A, Schusper S, Mozley D: F-18 FDG positron 
emission tomography demonstrates resolution of non-Hodgkin's lymphoma of the 
parotid gland in a patient with Sjogren's syndrome: before and after anti-CD20 
antibody rituximab therapy. Clin Nucl Med 2002, 27(2):142-143.

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16 APPENDICES
16.1 APPENDIX A: PERFORMANCE STATUS CRITERIA
ECOG Performance Status Scale
Karnofsky Performance Scale
Grade
Descriptions
Percent
Description
100
Normal, no complaints, no 
evidence of disease.
0
Normal activity. Fully active, able 
to carry on all pre-disease 
performance without restriction.
90
Able to carry on normal activity; 
minor signs or symptoms of 
disease.
80
Normal activity with effort; 
some 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).
70
Cares for self, unable to carry on 
normal activity or to do active 
work.
60
Requires occasional assistance 
but is able to care for most of 
his/her needs.
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.
50
Requires considerable assistance 
and frequent medical care.
40
Disabled, requires special care 
and assistance.
3
In bed >50% of the time. Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours.
30
Severely disabled, 
hospitalization indicated. Death 
not imminent.
20
Very sick, hospitalization 
indicated. Death not imminent.
4
100% bedridden. Completely 
disabled. Cannot carry on any 
self-care. Totally confined to bed 
or chair.
10
Moribund, fatal processes 
progressing rapidly.
5
Dead.
0
Dead.

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16.2 APPENDIX B: RITUXIMAB (RITUXAN®) 
AND RUXIENCE PREPARATION 
AND 
ADMINISTRATION
How Supplied
Rituximab (Rituxan®) and Ruxience will be supplied in 50-mL vials containing 500 mg of 
antibody (50 mL of solution) at a concentration of 10 mg/mL and 10-mL vials containing 100 mg 
of antibody (10 mL of solution) at a concentration of 10mg/ML. Rituximab vials are sterile, 
preservative-free, and intended for single use only. 
Stability and Storage
Rituximab and Ruxience are biologically and chemically stable at 2C to 8C (36F to 46F) and 
has a proposed shelf-life stability of 30 months. Once reconstituted into IV bags, rituximab and 
Ruxience are chemically stable for up to 24 hours at 2C to 8C (36F to 46F), followed by up to 
24 hours at room temperature (23C). However, since rituximab solutions do not contain 
preservative, diluted solutions should be stored refrigerated (2°C to 8°C). No incompatibilities 
between rituximab and Ruxience and polyvinylchloride or polyethylene bags have been observed. 
Rituximab vials should be protected from direct sunlight. Rituximab vials are intended for single 
use only. Do not use beyond the expiration date stamped on the carton. 
Dose Calculation 
1.
Before the first infusion only, calculate the participant’s body surface area (BSA). Actual 
body weight measured within 4 weeks prior to initial treatment with rituximab will be used 
for calculation of body surface area.
2.
Calculate the dose to be administered. The formula for the dose calculation is as follows:
U(Subject BSA in mUP2PU) (375mg/ 
mUP2P)
 10 mg/mL
= ___mL (volume of rituximab/Ruxience for 
reconstitution) 
3.
The same volume of rituximab for reconstitution will be used for each subsequent infusion.
Preparation of Rituximab or Ruxience for Intravenous Administration (First Infusion)
1.
Using aseptic technique, withdraw the necessary amount of rituximab and dilute to a final 
concentration of 1 to 4 mg/mL into an infusion bag containing either 0.9% Sodium 
Chloride, USP, or 5% Dextrose in Water, USP. It is recommended that a dilution of 2 
mg/mL be used for ease in calculating dose. Gently invert the bag to mix the solution. 
Discard any unused portion left in the vial. Parenteral drug products should be inspected 
visually for particulate matter and discoloration prior to administration. 
2.
DO NOT ADMINISTER AS AN INTRAVENOUS PUSH OR BOLUS.  Rituximab and 
Ruxience can be diluted with 5% dextrose or normal saline. In general they should not be 
infused with other fluids or medications, but nurses may consult with a pharmacist to check 
for y-site compatibility with other medications if needed.
3.
The first infusion of rituximab or Ruxience should be administered IV at an initial rate of 
50 mg/hr. If hypersensitivity or infusion-related reactions do not occur, the infusion rate 

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can be escalated in 50 mg/hr increments every 30 minutes, to a maximum of 400 mg/hr. 
Such an infusion schedule is listed below for a 1000 mg total dose:
Time
(Minutes)
Infusion Rate
(mg/h)
Dose in 30 minutes
(mg)
Cumulative Dose
(mg)
0-30
50
25
25
31-60
100
50
75
61-90
150
75
150
91-120
200
100
250
121-150
250
125
375
151-180
300
150
525
181-210
350
175
700
212-240
400
200
900
241-255*
400
200
1000
*Should complete at 255 minutes (4h 15min) to complete a 1000mg total dose.
4.
Infusion and hypersensitivity reactions may occur. Premedication consisting of 
acetaminophen and diphenhydramine should be considered before each infusion of 
rituximab. Premedication may attenuate infusion reactions. Since transient hypotension 
may occur during rituximab infusion, consideration should be given to withholding 
antihypertensive medications 12 hours before rituximab infusion. 
5.
If a hypersensitivity (non-IgE-mediated) or an infusion reaction develops, the infusion rate 
should be reduced to half that rate, i.e. from 100 mg/h to 50 mg/h. Participants who 
experience a moderate to severe infusion related reaction (fever, chills, or hypotension) 
should have their infusion interrupted immediately and should receive aggressive 
symptomatic treatment. The infusion should not be restarted before all the symptoms have 
disappeared and then the infusion can continue at one-half the previous rate. 
Dexamethasone PO should be given prior to rituximab or Ruxience infusions until 
moderate-severe infusion reactions are no longer observed.
6.
After the end of infusion, the intravenous line should remain in situ for at least 1 hour in 
order to be able to administer drugs intravenously if necessary. If there are no adverse 
events during this period of time, the intravenous line may be removed.
Preparation of Rituximab or Ruxience for Subsequent Intravenous Infusions
1.
Using aseptic technique, withdraw the necessary amount of rituximab or Ruxience and 
dilute to a final concentration of 1 to 4 mg/mL into an infusion bag containing either 0.9% 
Sodium Chloride, USP, or 5% Dextrose in Water, USP. It is recommended that a dilution 
of 2 mg/mL be used for ease in calculating dose. Gently invert the bag to mix the solution. 
Discard any unused portion left in the vial. Parenteral drug products should be inspected 
visually for particulate matter and discoloration prior to administration. 
2.
DO NOT ADMINISTER AS AN INTRAVENOUS PUSH OR BOLUS. Rituximab or 
Ruxience can be diluted with 5% dextrose or normal saline. In general they should not be 
infused with other fluids or medications, but nurses may consult with a pharmacist to check 
for y-site compatibility with other medications if needed.

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3.
If the participant tolerated the first infusion well, subsequent study drug infusions can be 
administered at an initial rate of 100 mg/hr and increased by 100 mg/hr increments at 
30-minute intervals to a maximum of 400 mg/hr as tolerated. Such an infusion schedule is 
listed below. If the participant did not tolerate the first infusion well, the above guidelines 
for the first infusion should be followed for subsequent infusions.
Time
(Minutes)
Infusion Rate
(mg/h)
Dose in 30 minutes
(mg)
Cumulative Dose
(mg)
0-30
100
50
50
31-60
200
100
150
61-90
300
150
300
91-120
400
200
500
121-150
400
200
700
151-180
400
200
900
181-195*
400
200
1000
Should complete at 195 minutes (3h 15 min) to complete a 1000mg total dose
4.
Infusion and hypersensitivity reactions may occur. Premedication consisting of 
acetaminophen and diphenhydramine will be required before each infusion of rituximab or 
Ruxience. Premedication may attenuate infusion reactions. Since transient hypotension 
may occur during rituximab or Ruxience infusion, consideration should be given to 
withholding antihypertensive medications 12 hours before rituximab or Ruxience infusion. 
5.
If a hypersensitivity (non-IgE-mediated) or an infusion reaction develops, the infusion rate 
should be reduced to half that rate, i.e. from 100 mg/h to 50 mg/h. Participants who 
experience a moderate to severe infusion related reaction (fever, chills, or hypotension) 
should have their infusion interrupted immediately and should receive aggressive 
symptomatic treatment. The infusion should not be restarted before all the symptoms have 
disappeared and then the infusion can continue at one-half the previous rate.
6.
After the end of infusion, the intravenous line should remain in situ for at least 1 hour in 
order to be able to administer drugs intravenously if necessary. If there are no adverse 
events during this period of time, the intravenous line may be removed.

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16.3 APPENDIX C: MOXETUMOMAB PASUDOTOX-TDFK (LUMOXITI™) PREPARATION AND 
ADMINISTRATION
How Supplied
•
LUMOXITI and IV Solution Stabilizer are packaged separately.
•
Prior to preparation, LUMOXITI and IV Solution Stabilizer should be stored at 2°C to 8°C 
(36°F to 46°F) in original cartons to protect from light.
LUMOXITI (moxetumomab pasudotox-tdfk)
•
Each single-dose vial supplies LUMOXITI 1 mg/vial (moxetumomab pasudotox-tdfk) for 
injection as a lyophilized cake or powder for reconstitution and dilution prior to intravenous 
infusion.
•
Multiple vials of LUMOXITI may be required to administer a single dose (See Step 1: 
Calculate Dose on next page).
•
Reconstitute LUMOXITI vials with Sterile Water for Injection, USP only (not supplied).
Solution Stabilizer
•
Each single-dose vial contains 1 mL IV Solution Stabilizer.
•
Only one vial of IV Solution Stabilizer is needed per administration of LUMOXITI, 
regardless of the number of vials of LUMOXITI used to prepare the infusion.
•
Do not use IV Solution Stabilizer to reconstitute LUMOXITI.
•
Do not flush IV lines with IV Solution Stabilizer.
Storage and Handling of Reconstituted and Diluted LUMOXITI
Table 1. Storage Times and Conditions for Reconstituted and Diluted LUMOXITI Solution
Diluted LUMOXITI Solution in Infusion Bag
Reconstituted Solution
After Dilution
Administration
LUMOXITI does not 
contain bacteriostatic 
preservatives.
Use reconstituted solution 
immediately. 
DO NOT STORE 
reconstituted LUMOXITI 
vials.
Use diluted solution 
immediately or after storage at 
room temperature (20°C to 
25°C; 68°F to 77°F) for up to 4 
hours or store refrigerated at 
2°C to 8°C (36°F to 46°F) for 
up to 24 hours.
PROTECT FROM LIGHT. 
DO NOT FREEZE.
DO NOT SHAKE.
If the diluted solution is refrigerated 
(2°C to 8°C; 36°F to 46°F), allow it 
to equilibrate at room temperature 
(20°C to 25°C; 68°F to 77°F) for no 
more than 4 hours prior to 
administration.
Administer diluted solution within 
24 hours of reconstitution as a 30- 
minute infusion.
PROTECT FROM LIGHT.
 1: se

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•
Calculate the dose (mg) and the number of LUMOXITI vials (1 mg/vial) to be 
reconstituted. The final concentration of the reconstituted LUMOXITI solution is 1 
mg/mL.
•
Individualize dosing based on the participant's actual body weight prior to the first dose 
of the first treatment cycle.
•
A change in dose should only be made between cycles when a change in weight of greater 
than 10% is observed from the weight used to calculate the first dose of the first treatment 
cycle. No change in dose should be made during a particular cycle.
•
Do not round down the dose for partial vials.
Step 2: Gather Supplies
•
LUMOXITI 1 mg/vial (number of vials to be reconstituted are based on Step 1)
•
1 vial of IV Solution Stabilizer (packaged separately)
•
Alcohol swabs
•
1 infusion bag containing 50 mL or 100 mL 0.9% Sodium Chloride Injection, USP
•
Sterile Water for Injection, USP
•
Syringes and needles
Step 3: Reconstitution
•
Reconstitute each LUMOXITI vial with 1.1 mL Sterile Water for Injection, USP using 
aseptic technique.
•
Direct the Sterile Water for Injection, USP slowly along the walls of the LUMOXITI vial 
and not directly at the lyophilized cake or powder.
•
Do not reconstitute LUMOXITI vials with the IV Solution Stabilizer.
•
Gently swirl the vial until completely dissolved. Invert the vial to ensure all cake or powder 
in the vial is dissolved. Do not shake.
•
Visually inspect that the reconstituted solution is clear to slightly opalescent, colorless to 
slightly yellow, and free from visible particles.
•
Do not use if solution is cloudy, discolored, or contains any particles.
•
The resulting 1 mg/mL solution allows a withdrawal volume of 1 mL.
Note: Use reconstituted solution immediately. Do not store reconstituted LUMOXITI 
vials. See Table 1 for storage times and conditions for the reconstituted solution.
Step 4: Preparation of Infusion Bag with IV solution Stabilizer
•
Obtain a 50 mL 0.9% Sodium Chloride Injection, USP infusion bag.
•
Only one vial of IV Solution Stabilizer is needed per administration of LUMOXITI, 
regardless of the number of vials of LUMOXITI used to prepare the infusion.
•
Add 1 mL IV Solution Stabilizer to the infusion bag containing 50 mL 0.9% Sodium 
Chloride Injection, USP.
•
Gently invert the bag to mix the solution. Do not shake.
Step 5: Dilution
•
Slowly withdraw the required volume of reconstituted LUMOXITI solution needed from 
each vial, per the calculated dose based on the participant’s actual body weight (kg).
•
Inject LUMOXITI into the infusion bag containing 50 mL 0.9% Sodium Chloride 
Injection, USP and 1 mL IV Solution Stabilizer.
•
Gently invert the bag to mix the solution. Do not shake.

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•
Discard any partially used or empty vials of LUMOXITI and IV Solution Stabilizer.
•
See Table 1 for storage times and conditions for the diluted solution.
Step 6: Intravenous Hydration and Pre-Infusion Medications:
•
Administer intravenous hydration and premedication to the participant.
•
Intravenously administer 1 L of isotonic solution (e.g. 5% Dextrose Injection, USP and 
0.45% or 0.9% Sodium Chloride Injection, USP) over 2 to 4 hours before each LUMOXITI 
infusion. Administer 0.5 L to participants under 50 kg. On day 1 of cycles 2-8, pre-
hydration may be started during the rituximab infusion provided it is completed no earlier 
than 2 hours prior to the LUMOXITI infusion.
•
Premedicate 30 to 90 minutes prior to each LUMOXITI infusion with an antihistamine (e.g. 
diphenhydramine), acetaminophen, and a histamine-2 receptor antagonist (e.g. famotidine, 
or cimetidine), with the exception of day 1 of cycles 2-8, when premedications are to be 
given prior to Rituxan.
Step 7: Administration 
•
Infuse the diluted LUMOXITI solution intravenously using early call back/reverse flow 
method over 30 +/- 5 minutes.
•
Do not mix LUMOXITI, or administer as an infusion with other medicinal products.
•
After the infusion, flush the intravenous administration line with of 0.9% Sodium Chloride 
Injection, USP at the same rate as the infusion. This ensures that the full LUMOXITI dose 
is delivered.
Step 8: Post-infusion Medications
•
Administer post-infusion medications.
•
Intravenously administer 1 L of isotonic solution (e.g. 5% Dextrose Injection, USP and 
0.45% or 0.9% Sodium Chloride Injection, USP) over 2 to 4 hours after each LUMOXITI 
infusion. Administer 0.5 L to participants under 50 kg.
•
Consider oral antihistamines and acetaminophen for up to 24 hours following LUMOXITI 
infusions.
•
Consider oral corticosteroid (e.g. 4 mg dexamethasone) to manage nausea and vomiting.
•
Maintain adequate oral fluid intake.
•
Advise all participants to adequately hydrate with up to 6 L (twelve 8-oz glasses) of oral 
fluids (e.g. water, milk, or juice) per 24 hours on Days 1 through 8 of each 28-day treatment 
cycle. In participants under 50 kg, up to 2 L (eight 8-oz glasses) per 24-hour period is 
recommended.
•
Consider low-dose aspirin on Days 1 through 8 of each 28-day treatment cycle.
Note: This Healthcare Provider Instructions for Use has been approved by the U.S. 
Food and Drug Administration.

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16.4 APPENDIX D: PARTICIPANT HYDRATION DIARY
19C0042 - Moxe-R in HCL 
Cycle #_______
Participant Name________________________________ Participant Study ID _____________________________
INSTRUCTIONS TO THE PARTICIPANT:
1.
Complete one form for each Cycle.
2.
You will drink at least 24 cups of fluid each day (1 cup/hour; 1 cup = 8 oz; total of 1.5 gal).  Do not go more than 3 hours without drinking.
3.
Record the date, number of cups of fluid that you drank, and the time you took them.  
4.
Please bring this form to your physician when you go for your next appointment.
DAY 1
Date:
CUPS (#)
Time
DAY 2
Date:
CUPS (#)
Time

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19C0042 - Moxe-R in HCL 
Cycle #_______
Participant Name________________________________ Participant Study ID _____________________________
DAY 3
Date:
CUPS (#)
Time
DAY 4
Date:
CUPS (#)
Time
DAY 5
Date:
CUPS (#)
Time

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19C0042 - Moxe-R in HCL 
Cycle #_______
Participant Name________________________________ Participant Study ID _____________________________
DAY 6
Date:
CUPS (#)
Time
DAY 7
Date:
CUPS (#)
Time
DAY 8
Date:
CUPS (#)
Time

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19C0042 - Moxe-R in HCL 
Cycle #_______
Participant Name________________________________ Participant Study ID _____________________________
Participant’s Signature: ___________________________________  Date: ____________________
Staff Signature: ___________________________________        Date: ____________________