HM2014-26 DT2219 Immunotoxin for the Treatment of Relapsed or Refractory CD19 (+) and/or CD 22 (+) B-lineage Leukemia or Lymphoma
Phase: PHASE1
Conditions: Refractory B-Lineage Leukemia, Relapsed B-Lineage Leukemia, Refractory B-Lineage Lymphoma, Relapsed B-Lineage Lymphoma
Sponsor: Masonic Cancer Center, University of Minnesota

 
Masonic Cancer Center, University of Minnesota 
Cancer Experimental Therapeutics Initiative 
 
 
DT2219 Immunotoxin for the Treatment of Relapsed or Refractory CD19 (+) 
and/or CD 22 (+) B-Lineage Leukemia or Lymphoma  
HM2014-26 
CPRC #2014LS093 
IND 100780 
 
 
Principal Investigator/IND Sponsor: 
Veronika Bachanova, MD, PhD 
 
 
Co-Investigators: 
Peter Gordon, MD, PhD  
Aleksandr Lazaryan, MD, MPH, PhD 
 
 
Study Agent Design and Production: 
Daniel Vallera, PhD 
 
 
Biostatistician: 
Qing Cao, MS 
 
 
 
 
Version Date: 
July 10, 2017 
 
 
 
 
 
 
 
Confidential 
 
 

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CPRC #2014LS093 
 
Revision History 
Revision 
# 
Version 
Date 
Summary Of Changes 
Consent 
Changes 
 
12/18/2014 
original to CPRC 
 
 
01/20/2015 
In response to CPRC’s initial review, original to FDA and IRB: 
Section 11 – correct stopping rule calculations  
Page 19 – clarify requirements and procedures for an individual patient to continue on 
DT2219ARL after experiencing a DLT or stopping rule event, edit elsewhere in the 
protocol to match changes 
Other edits as detailed in the CPRC stip response letter 
Additional edits: 
• Replace DT2219ARL with DT2219 in title and throughout document, replace 
treatment course with treatment cycle 
• Section 7.2 Simplify the research related lab draws 
• Clarify follow-up ends at 1 year for all patients  
n/a 
n/a 
03/30/2015 
In response to FDA’s review (interim version not submitted to CPRC/IRB):  
• Revise the Phase II component to use Simon’s Optimum two-stage design with each 
disease assessed independently. Stage 1 will enroll 9 lymphoma patients and 9 
leukemia patients (including any treated at MTD during phase I and completed 1 
cycle) and if 1 more responses, stage 2 will be activated enrolling an additional 8 
patients per disease cohort – previous version stratified by diagnosis enrolling 19 
patients per type. 
• Section 2.4 – update table 1 
• Revise definition of dose limiting toxicity 
• Add that a grade 3 or higher hypersensitivity reaction to DT2219 will result in 
permanent discontinuation of the study drug  
• Clarify to be eligible for Re-Treatment a patient must meet the eligibility criteria in 
section 4 and test negative for antibodies to be eligible and that treatment will be per 
section 6 of the protocol and the schedule of tests and procedures will be guided by 
section 7 with follow-up for survival thorough 1 year after 1st re-treatment dose 
• Add toxicity assessment to the standard of care chart in section 7.1 to occur at every 
patient encounter  
• Add a final treatment visit at day 50 (approximately 30 days after the last dose of 
DT2219) 
• Define in section 9.2 that all adverse events grade 3 or greater, regardless of 
attribution or expectedness, will be documented in OnCore on the AE log form 
• Limit targeted toxicity collection to the 1st cycle of DT2219 
• Clarify the process for DLT and stopping rule events form processing in section 9.2 
based on MCC CTO SOPs 
• Recalculate the stopping rule to be more stringent 
• Add antibody testing to cycle 3, previously 1 and 2 only 
yes 
n/a 
04/28/2015 
In response to FDA review (interim version not submitted to CPRC/IRB) 
• Sections 6.2.1 and 11.1 – delete grade 4 transaminase elevations and the selected 
grade 3 events occurring after completion of the DT2219 infusion from the definition 
of DLT 
• Sections 6.1, 6.3, and 6.5 - update to read if a grade 2 or greater hypersensitivity 
reaction occurs despite pre-medication, the patient will be permanently discontinued. 
• Section 9.2 – revise to record all adverse events regardless of grade, attribution and 
expectedness in the Cancer Center’s clinical database (OnCore) from the 1st infusion 
until 30 days after the last infusion or the start of a new therapy, whichever comes 1st; 
expanded the procedure for potential serious adverse event recording and reporting 
• Section 11.5 – delete the exclusion that grade 4 transaminase elevations need to 
persist for more than 2 weeks to be considered excessive toxicity for the early study 
stopping rule 
• Appendix IV – replace anaphylaxis with hypersensitivity reaction in targeted toxicity  
 
1 
07/28/2015 
1st submission to the IRB/CPRC since January 2015 version – all FDA mandated 
changes summarized in the 3/30/2015 and 4/28/2015 are incorporated in this version, 
plus the following additional changes: 
yes 

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CPRC #2014LS093 
Revision 
# 
Version 
Date 
Summary Of Changes 
Consent 
Changes 
• Synopsis and Section 1.3 – update correlative objective regarding neutralizing 
antibody from “measure level of” to “test for presence of” neutralizing antibody 
• Section 4.5 inclusion criteria clarification of recovery from previous treatments by 
specifying “acute” toxicities and must have recovered to “grade 1 or better”. Also 
removed waiting period since last treatment in patients with rapidly progressing 
disease as defined in section 4.5. 
• Section 4.13 exclusion criteria – replace “uncontrolled” with “untreated” systemic 
infection 
• Section 6.5 – replace “despite pre-medication” in regards to grade 3 toxicity as all 
patients are pre medicated and clarify with a reoccurrence of toxicity despite pre-
medication “with methylprednisone  
• Section 7.1 – add BM Bx to the 30 day screening window, tweak day 1 tests and 
procedures to indicate specific days rather than “x” 
• Section 9.2 – add disease progression (in addition to start of new therapy) as a 
situation when AE monitoring and follow-up would end 
• Section 11.3 – Correlative endpoints: add “documentation of neutralizing antibody 
presence” in addition to measuring its level. 
• Minor edits section 4.7 replace PFTs with DLCOcorr; section 4.10 expand consent 
statement to include “with appropriate parent/guardian consent and minor 
information sheet for participants < 18 years of age” since minors may be enrolled; 
sections 5.4, 9.2, and 10.2 - replace Study Nurse with Study Coordinator; Section 6.1 
minor edits including deletion of duplicative language 
• Update to current protocol template – section 9.2 and 10.3 
• Update appendix I – Eligibility checklist 
 
12/15/2015 
Interim version – not submitted to IRB 
Remove Jeffrey Miller as a co-investigator 
no 
2 
 
05/10/2016 
• Modify treatment schedule to allow flexibility using guidelines of at least 48 hours, 
but not more than 72 hours between doses within a 4 dose set with further 
modification to accommodate rare instances (e.g. Monday  holiday) 
• Section 4.8 – remove requirement to stay for 48 hours after the 4 and 8th doses from 
eligibility 
• Section 4.12 – simplify active CNS leukemia exclusion 
• Section 6.1 – criteria for additional treatment cycles – clarify presence of neutralizing 
antibodies at any time (not just after the 1st cycle) will deem patient ineligible for 
future treatment courses 
• Section 7.1 add footnote to day 10 and 24 visits that only apply to phase I cycle 1 
• Section 7.2 – revise and update research related testing  
- Reduce the number of  days PK samples will be collected, but increase the number 
of samples 
- Delete days 10 and 29 as sample collection days, replace it with day 22-24 time 
point  
- Increase neutralizing ab sample from 2 ml to 5 ml, except at baseline collect 10 ml 
- Add 2 green top tubes for immune environment assessment 
- Add additional bone marrow sample for research at the time of each SOC BM 
biopsy 
- Add a tumor or lymph node biopsy pre-treatment and optional post-treatment 
- Revise and add footnotes to match table 
- All samples to go to TTL (previously Vallera’s lab) 
- Add new sections detailing neutralizing antibody testing (sect 7.2.2), pre-treatment 
tumor biopsy (sect 7.2.3), and post-treatment tumor biopsy (sect 7.2.4) 
Additional clarifications and edits including: 
• Synopsis and section 1.3 – re-word correlative objective to match endpoint in section 
11.3 
• Section 4.2, Appendix I – reword for clarity 
• Section 6.1 – clarify DT2219 will be piggy backed onto an existing line and dosing 
will be based on Day 1 (-3 days) weight 
• Section 7.1 – SOC  table of events – clarify PET/CT requirements for lymphoma pts, 
clarify footnote #1, clarify which baseline tests can be done within 30 days of start 
• Section 9.2 – edit adverse event collection for clarity 
yes 

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CPRC #2014LS093 
Revision 
# 
Version 
Date 
Summary Of Changes 
Consent 
Changes 
• Section 11.5 – edit for clarity 
• Update title page, page 2 and sections 6.6 and 10.3  : IND sponsor transferred to V. 
Bachanova (PI) – paperwork previously submitted to FDA, retain Dr. Vallera on 
cover page as study agent design and production 
3 
11/10/2016 
Begin enrollment at 80 mcg/kg per protocol design with the following adjustments: 
• Add a separate screening consent form to collect 10 cc of blood to test for the 
presence of diphtheria antibodies prior to full work-up 
• Schema and section 6.1 - shorten duration of infusion by half – 1st infusion over 2 
hours (previously 4 hours) and all subsequent infusions as 1 hour (previously 2 
hours), Section 6.1 only - reduce post infusion monitoring to 30 minutes; remove 
post-DT2219 normal saline infusion language, and cut back on hydrocortisone pre-
med dose (from 100 mg to 25-50mg) 
• Section 4 – remove from eligibility the requirement to stay in the Twin Cities 
metropolitan area during treatment – will be reiterated at time of consent  
• Section 7.2: Reduce PK times to mid infusion and end of infusion 
• Section 9.2 update targeted toxicity time points to match 30 minute post-infusion 
monitoring and clarify time points may be adjusted or eliminated to match SOC visits 
in section 7.1 
• Update co-investigators on cover page – replace M Verneris who left the institution 
with Peter Gordon, MD/PhD 
• Other minor edits and updates to protocol template 
Yes and 
add 
screening 
consents 
for 
antibody 
testing 
4 
03/06/2017 
Declare DT2219 MTD at 60 µg/kg/dose and proceed to Phase II expansion 
• Section 4 - In response to liver function related toxicity seen at 80 µg/kg/dose, revise 
patient eligibility to stricter liver function requirements and exclude patients with 
active Hepatitis B or Hepatitis C (virus detectable by PCR) 
• Section 6.1 – correct pediatric dose conversion for hydrocortisone 
• Section 6.3 - Add management of increased liver function tests 
• Section 7: Add hepatitis B and C screening at baseline  
• Other minor edits 
yes 
5 
07/10/2017 
• Section 6.1 - clarify use of allopurinol is at the treating physician’s discretion as part 
of good medical care and is not required as part of the study treatment plan.  
• Minor edits including correcting CPRC number in section 1 of the footer, update 
expediting reporting table in section 9.3, add new DSMP link in section 10.3 
yes, 
treatment 
consent 
 
 
 
 
 
 
 
Principal Investigator/IND Sponsor Contact Information: 
Veronika Bachanova MD, PhD 
Medicine Hematology Office 
MMC 480  
420 Delaware Street SE 
Minneapolis, MN 55455 
phone: 612-625-5469 
email: bach0173@umn.edu 
 
 
 

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Table of Contents 
 
Protocol Synopsis .......................................................................................................................................... 7 
Schema .......................................................................................................................................................... 8 
1 
Objectives ............................................................................................................................................. 9 
1.1 
Primary Objectives ........................................................................................................................ 9 
1.2 
Secondary Objectives .................................................................................................................... 9 
1.3 
Correlative Objectives................................................................................................................... 9 
2 
Background and Rationale .................................................................................................................... 9 
2.1 
The Disease ................................................................................................................................... 9 
2.2 
The Treatment - DT2219 ............................................................................................................ 10 
2.3 
Preclinical Studies ....................................................................................................................... 11 
2.4 
Clinical Experience ..................................................................................................................... 11 
2.5 
Pharmacology ............................................................................................................................. 13 
2.6 
Study Rationale ........................................................................................................................... 15 
3 
Study Design ....................................................................................................................................... 16 
4 
Patient Selection .................................................................................................................................. 17 
5 
Patient Registration/DT2219 Dose Level Assignment ....................................................................... 18 
5.1 
Registration with the Masonic Cancer Center Clinical Trials Office ......................................... 19 
5.2 
DT2219 Dose Level Assignment ................................................................................................ 19 
5.3 
Patient Re-Treatment (Compassionate) ...................................................................................... 19 
5.4 
Patients Who Are Registered and Do Not Receive Study Treatment ......................................... 19 
6 
Treatment Plan .................................................................................................................................... 19 
6.1 
DT2219 Administration .............................................................................................................. 19 
6.2 
DT2219 Dose Level Assignment ................................................................................................ 22 
6.3 
Guidelines for the Management of Selected Toxicities .............................................................. 23 
6.4 
Supportive Care and Prohibited Therapies ................................................................................. 24 
6.5 
Duration of Treatment ................................................................................................................. 25 
6.6 
Duration of Study Participation .................................................................................................. 25 
7 
Schedule of Patient Activities ............................................................................................................. 26 
7.1 
Standard of Care ......................................................................................................................... 27 
7.2 
Research Related Procedures and Activities ............................................................................... 28 
8 
DT2219 ............................................................................................................................................... 30 
8.1 
Procurement ................................................................................................................................ 30 

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CPRC #2014LS093 
8.2 
Formulation ................................................................................................................................. 30 
8.3 
Reconstitution ............................................................................................................................. 30 
8.4 
Storage and Stability ................................................................................................................... 30 
8.5 
Administration ............................................................................................................................ 30 
8.6 
Toxicity ....................................................................................................................................... 30 
9 
Adverse Event Reporting .................................................................................................................... 31 
9.1 
Definitions ................................................................................................................................... 32 
9.2 
Adverse Event Monitoring and Documentation ......................................................................... 33 
9.3 
Required Reporting: FDA, IRB, and MCC’s SAE Coordinator ................................................. 37 
10 
Study Data Collection and Monitoring ........................................................................................... 38 
10.1 
Data ManagementS ..................................................................................................................... 38 
10.2 
Case Report Forms ...................................................................................................................... 38 
10.3 
Data and Safety Monitoring Plan (DSMP) ................................................................................. 38 
10.4 
Study Monitoring and Audits ...................................................................................................... 39 
10.5 
Record Retention ........................................................................................................................ 39 
11 
Statistical Considerations ................................................................................................................ 39 
11.1 
Study Design ............................................................................................................................... 39 
11.2 
Rationale for Sample Size ........................................................................................................... 41 
11.3 
Study Endpoints .......................................................................................................................... 42 
11.4 
Statistical Analysis ...................................................................................................................... 42 
11.5 
Early Stopping Rules for Excessive Toxicity During Expansion Component ............................ 43 
12 
Conduct of the Study ...................................................................................................................... 43 
12.1 
Good Clinical Practice ................................................................................................................ 43 
12.2 
Ethical Considerations ................................................................................................................ 43 
12.3 
Informed Consent ........................................................................................................................ 44 
13 
References ....................................................................................................................................... 44 
Appendix I – Eligibility Checklist .............................................................................................................. 46 
Appendix II – Performance Status Criteria ................................................................................................. 48 
Appendix III – Disease Specific Response Criteria .................................................................................... 49 
Appendix IV –Targeted Toxicity Form (CTCAE 4.0) ................................................................................ 53 
 
 

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Protocol Synopsis 
DT2219 Immunotoxin for the Treatment of Relapsed or Refractory CD19 (+) and/or CD 22 
(+) B-Lineage Leukemia or Lymphoma 
Study 
Design: 
This is a phase I/II study of DT2219 for the treatment of relapsed or refractory CD19 (+) and/or CD 22 (+) 
B-lineage leukemia and lymphoma. The study consists of two phases - a phase I dose/schedule finding 
component using the maximum tolerated dose identified during the previous phase I study, but with a 
higher number of doses and a two-stage phase II extension component to confirm safety and make a 
preliminary determination of the activity level by disease using the dose identified in phase I. 
 
Patients will receive a minimum of one cycle of DT2219 as an intravenous infusion days 1, 3, 5, 8 and 
days 15, 17, 19 and 22 of a 28 day treatment cycle. A disease reassessment will be done at day 29. If a 
patient has clinical benefit and no unacceptable side effects, they may receive up to 2 additional cycles of 
DT2219 until disease progression, unacceptable toxicity and/or development of antibodies. 
 
The primary goal of the dose/schedule finding component is to determine if the maximum tolerated dose 
(MTD) of DT2219 identified in our previous dose escalation study can be repeated after a short break. 
Enrollment will begin at the DT2219 dose of 60 µg/kg/dose using an eight dose schedule with the ability 
to move up or down a dose level (40 or 80 µg/kg/dose) in subsequent patients based on the tolerance of 60 
µg/kg. Tolerance is evidenced by an inability to receive at least 6 out of 8 planned doses at the assigned 
dose level. If toxicity develops, an individual patient may move to a lower dose-level to allow 
administration of 8 doses. A minimum of 6 patients will be enrolled to confirm that the previous MTD is 
tolerable when used on an 8 dose schedule. The phase I component was completed in March 2017 with 60 
µg/kg/dose declared as the MTD. 
 
The MTD from phase I will be carried forward into a two-stage phase II component to confirm safety and 
make a preliminary determination of the activity level for non-Hodgkin lymphoma (NHL) patients (Arm 
1) and leukemia (Leukemia) patients (Arm 2).  
 
Primary 
Objective: 
Phase I Dose/Schedule Confirmation: To determine if the maximum tolerated dose (MTD) of DT2219 
dose of 60 µg/kg/dose identified during the previous phase I study is well tolerated on an 8 dose schedule 
of day 1, 3, 5, 8 and day 15, 17, 19 and 22 
Phase II Component: To establish a preliminary estimate of overall response at day 29 while gaining a 
more detailed toxicity profile of repeat dosing of DT2219 
 
Secondary 
Objectives: 
• To determine incidence of serious adverse events through day 29 
• To determine duration of response for up to 1 year 
• To evaluate 1 year disease-free survival  
• To evaluate 1 year overall survival  
• To determine time to relapse/progression for up to 1 year 
 
Correlative 
Objectives: 
• To determine the pharmacokinetic (PK) profile (Cmax, T1/2, AUC, Cl, Vd) of DT2219 
• To document presence and to measure levels of human anti-DT2219 antibodies and correlate with 
response  
• To determine if there is a correlation between PK parameters and toxicity or response 
• To determine if the expression of the CD19 and CD22 cell surface antigens is affected by treatment 
with DT2219 using flow cytometric analysis of lymphoblasts in peripheral blood and bone marrow and 
B-lymphocytes in peripheral blood  
• To correlate CD19 and CD22 surface antigen expression on patient blasts or lymphoma cells with 
response 
  
Population: 
Patients ≥ 12 years with  relapsed or refractory CD19+ and/or CD22+ B-lineage leukemia/ lymphoma 
 
Enrollment: 
Phase I: Standard 3+3 design  requiring 6 to 12 patients (completed March 2017) 
Phase II: Two stage design by disease – assigned to Arm 1(NHL) or Arm 2 (Leukemia)  
stage 1: enroll a total of 9 patients (including all treated at the MTD in phase I and evaluable after 1st cycle 
of treatment)   
If 1 or more responds within the Arm, activate stage 2 enrolling an additional 8 patients to that Arm  

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Schema 
                                                     1 treatment cycle 
 
 
 
 
 
 
 
 
 
 
 
Disease            Final                       Disease & 
                                                                                                          Reassessment    Rx Visit         F/U*   Survival Status 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day              1      3     5         8           15    17    19       22           29                   50                          1 yr 
 
          DT2219 at assigned dose IV on day 1, 3, 5, and 8 and day 15, 17, 19, and 22 
 
The day 1, 3, 5, 8 and day 15, 17, 19 and 22 dosing schedule is based on a Monday start day; however this is not always feasible. 
Therefore, general dosing rules will be followed within a 4 dose set: 1) each dose will be separated by a minimum 48 hours but 2) 
no more than 72 hours will lapse between doses except in cases where it is unavoidable (e.g. Monday holidays). Situations where 
the dosing falls outside of these guidelines will be discussed with and approved by the PI or her designee. No deviation will be 
filed in these cases. 
 
The 1st dose will be administered over 2 hours; if well tolerated, subsequent doses may be given over 1 hour. 
 
Adults may be treated in the outpatient setting (Early Phase Unit with Masonic Clinic or BMT Clinic, as appropriate for back-
up). Pediatric patients will be admitted through the Journey Clinic to Masonic Children’s Hospital for treatment.  
 
Additional Treatment Cycles: 
For patients experiencing clinical benefit (CR, PR, or SD per disease specific response criteria) at the time of re-assessment, up to 2 
additional cycles of DT2219 may be given on the same schedule at the same or lower dose beginning no sooner than 7 days after 
the last dose of the previous cycle provided they meet the criteria in section 6.1    
 
Final Treatment Visit – Day 50 or 30 days after the last dose of DT2219, whichever is shorter 
 
F/U* – if in remission at the time of treatment end, patients will be followed every 3 months for disease re-assessment until 
relapse or progression or the start of a new treatment for a maximum of 1 year from the 1st dose. 
Retreatment with DT2219 may be an option.  
 
Phase I Component: (Completed March 2017 – MTD = 60 µg/kg/dose) 
The phase I component will follow standard 3 or 6 patients per dose level. Enrollment will begin at dose level 1. Dose level -1 
will be used only if dose limiting toxicity is encountered with the 1st group. 
Dose Cohort 
DT2219 Dose 
-1 
40 µg/kg/dose 
1 
60 µg/kg/dose 
2 
80 µg/kg/dose 
Patients will receive a minimum of one cycle of DT2219. Dose escalation will proceed within each cohort according to the 
scheme found in section 11.1. Escalation to dose level 2 may not occur before the last patient in dose level 1 is at least 7 days 
from the last dose of the 1st treatment cycle to rule out dose limiting toxicity (DLT).  
 
Dose limiting toxicity (DLT) is defined as any of the following occurring from study day 1 through 7 days after the last dose of 
DT2219 of cycle 1 and clearly not attributed to the primary malignancy or intercurrent illness:  
• Any Grade 5 adverse event 
• Grade 4 neutropenia or thrombocytopenia lasting for more than 7 days 
• Grade 3 thrombocytopenia with bleeding 
• Any Grade 4 non-hematologic adverse event during the DT2219 infusion   
• Any Grade 3 non-hematologic adverse event occurring after completion of DT2219 infusion  
 
Maximum tolerated dose (MTD) is defined as the dose level where no more than 1 out 6 patients experience DLT when at least 
6 out of 8 planned DT2219 doses are given over 28 days 
 
Phase II Component (stratify by diagnosis: Arm 1 - NHL, Arm 2 - Leukemia):  
Two stage design – Stage 1: enroll 9 patients (including any from phase I treated at MTD and evaluable after 1st cycle of 
treatment), if 1 or more respond within a diagnosis, activate Stage 2 for that diagnosis: enroll 8 additional patients  

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1 
Objectives 
1.1 
Primary Objectives 
Phase I Dose/Schedule Confirmation: To determine if the MTD of DT2219 dose 
of 60 µg/kg/dose identified during the previous phase I study is well tolerated on 
an 8 dose schedule of day 1, 3, 5, 8 and day 15, 17, 19 and 22 of a 28 day treatment 
cycle. 
Phase II Component: To establish a preliminary estimate of overall response at 
day 29 while gaining a more detailed toxicity profile of repeat dosing of DT2219 
1.2 
Secondary Objectives 
• To determine incidence of serious adverse events through day 29 
• To determine duration of response for up to 1 year 
• To evaluate 1 year disease-free survival  
• To evaluate 1 year overall survival  
• To determine time to relapse/progression for up to 1 year 
1.3 
Correlative Objectives 
• To determine the pharmacokinetic (PK) profile (Cmax, T1/2, AUC, Cl, Vd) of 
DT2219 
• To document presence and to measure levels of human anti-DT2219 
antibodies and correlate with response   
• To determine if there is a correlation between PK parameters and toxicity or 
response 
• To determine if the expression of the CD19 and CD22 cell surface antigens is 
affected by treatment with DT2219 using flow-cytometric analysis of 
lymphoblasts in peripheral blood and bone marrow and blood B-lymphocytes.  
• To correlate CD19 and CD22 surface antigen expression on patient blasts or 
lymphoma cells with response 
 
2 Background and Rationale 
2.1 
The Disease 
The incidence of acute lymphoblastic leukemia (ALL) is 5,200 cases in 2007 
including 2,400 children and adolescents and 2,800 adults. While 95% of children 
and 70% of adults achieve remission with aggressive induction combination 
chemotherapy, only 85% of children and 35% of adults are cured of their disease. 
Salvage treatments include further chemotherapy, tyrosine kinase inhibitors, 
antibody therapy and stem cell transplantation, but most relapsed patients suffer 
severe morbidities and death from chemo-resistant disease. Non-Hodgkin 

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lymphoma is the 6th most common malignancy in adults. Although curable by 
chemotherapy for over 60-70% of patient, patients refractory to chemotherapy have 
a poor prognosis.  
An effective biologically based, molecularly targeted therapy for these patients is 
needed.  One therapeutic approach would be to use recombinant immunotoxins 
(ITs). We have recently developed DT2219, a new recombinant bispecific 
antibody-targeted toxin with reactivity with most ALL blasts. The anti-CD19 Mab 
hybridoma HD37 and the anti-CD22 hybridoma RFB4 were used to create the IT. 
DT2219 was constructed using a hybrid gene encoding the first 390 amino acids of 
the diphtheria toxin (DT) and the VH and VL regions of anti-CD22 (sFv) and anti-
CD19 (sFv).  This IT takes advantage of the high level of expression of both the 
CD19 and CD22 antigens present on the surface of B-lineage leukemia cells. CD19 
molecules expressing the HD37 epitope and CD22 molecules expressing the RFB4 
epitope are present on a mean of 80% and 50% of B-precursor ALL blasts, 
respectively. We have demonstrated that DT2219 binds to B-lineage ALL cells and 
has potent in vitro anticancer activity against B-lineage lymphoma cells. In 
addition, our in vivo model significantly prolonged the survival of mice with 
established B-cell leukemia. Based on these results, we propose to conduct a phase 
I trial utilizing DT2219 in adults and adolescents with relapsed or refractory B-
lineage leukemia or lymphoma. 
2.2 
The Treatment - DT2219 
Monoclonal antibodies (MoAbs) when linked to toxic moieties form highly specific 
and potent anti-cancer agents called immunotoxins (ITs). Plant toxins and bacterial 
toxins including diphtheria toxin are highly potent such that even one single 
molecule in the cytoplasm is sufficient to kill a tumor cell. A variety of these agents 
are currently undergoing development for the treatment of hematologic 
malignancies [2]. Importantly, investigators have determined that when two ITs 
targeting two different cell surface receptors on the same tumor cell are combined, 
the anti-tumor effect is often superior than when the agents are used individually [3 
- 5]. A mixture of two ITs targeting CD19 and CD22 using a deglycosylated ricin-
A chain moiety as the toxin (Combotox) was recently proven to be effective in 
killing Pre-B ALL cells in vitro [6] and in curing SCID mice of disseminated 
leukemia in vivo [7].  
Diphtheria toxin has recently been used in the development of several ITs currently 
undergoing testing for treating leukemia. A truncated form of diphtheria toxin 
conjugated to a single chain of IL2 known as DAB386IL2 tested in 22 patients with 
chronic lymphocytic leukemia (CLL) yielded a 27% response rate [8]. Another 
example is the recombinant diphtheria toxin fusion protein, DT388IL3, composed 

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CPRC #2014LS093 
of the translocation domain of diphtheria toxin fused to human interleukin-3. 
DT388IL3 has produced remissions in patients with acute myeloid leukemia at 
tolerable doses [9]. DT388 has also been fused to granulocyte-macrophage colony 
stimulating factor (GMCSF) and again produced remissions in acute myeloid 
leukemia but at doses producing hepatic injury [10]. 
2.3 
Preclinical Studies  
DT2219 has undergone in vitro testing on the Daudi Burkitt’s lymphoma cell line 
known to highly express both CD19 and CD22. It was cytotoxic to Daudi cells with 
an IC50 of 0.3 nmol/L. DT2219 was also found to be reactive with leukemia cells 
obtained from two children with newly diagnosed Pre-B ALL. The cytotoxic effect 
was specific and reproducible. The cytotoxicity and reactivity of DT2219 was 
greater than the anti-cancer activity of either monovalent or bivalent ITs made with 
the anti-CD19 and anti-CD22 sFv alone prompting us to propose the use of the 
bispecific IT for this study [11]. 
In vivo, when DT2219 was given to SCID mice with established flank tumors, as 
i.p. injections of 20 μg (2.8 mg/m2) for four doses, there was a significant reduction 
in tumor volume. To simulate leukemia, the investigators injected the same cells 
i.v. into mice resulting in the infiltration of all major organs. The mice were given 
nine daily injections of 20 μg of DT2219. The mice receiving treatment survived 
significantly longer than control mice receiving an irrelevant control.  
2.4 
Clinical Experience 
In a phase 1 study conducted at Baylor Scott and White Medical Center, MD 
Anderson Cancer Center and the Masonic Cancer Center, University of Minnesota, 
patients received DT2219 in a single course at doses ranging from 0.5 µg/kg/day 
(1/500th of the MTD in rabbits) to 80 µg/kg/day intravenously (IV) over 2 hours (4 
hours for 1st dose) every other day for 4 total doses (days 1, 3, 5 and 8). The dose 
was escalated in 9 cohorts until a dose limiting toxicity (DLT) was observed (Table 
1). The first 15 patients were treated by rapid escalation design (dose cohorts 1-3) 
or by standard 3+3 dose escalation design (cohorts 4-7) at Baylor. The study then 
transferred to the University of Minnesota where the Continual Reassessment 
Method [12] was applied to the last 10 patients (dose cohorts 7 (last dose level at 
Baylor), 8, 9) with the goal to identify the dose level which corresponds to a desired 
toxicity rate of 33% or less using grade 3 or greater DT2219 related toxicity except 
blood pressure changes and fever as the targeted toxicity (based on NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4).  
All 25 patients received a single course of therapy. One patient attained partial 
response after the 1st cycle and received an additional 4 dose course after the 

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protocol was amended with FDA and IRB approval. Twelve patients treated at 
doses ranging from 0.5 ug/kg/day to 20 ug/kg/day exhibited no or minimal adverse 
reactions (Table 1). All 13 patients treated at dose levels ≥40 ug/kg/day experienced 
adverse events (AE) attributed to drug treatment. No infusional toxicity was 
observed. The most common transient grade 1-2 AEs included weight gain (range 
5-14% of baseline), peripheral edema, and hypoalbuminemia consistent with 
capillary leak syndrome, grade 1-2 fever and fatigue (Table 1). Most AEs were 
recognized during routine monitoring before the 2nd or 3rd dose of DT2219. All 
AEs were brief and resolved completely within one week. TABLE 1. Treatment 
detail and adverse events 
Cohort 
Escalation 
detail 
DT2219 dose 
µg/kg/day 
Doses 
received 
Total dose per 
cycle (µg) 
N 
Drug related adverse effects  
(CTCAE v4.03 toxicity grade) 
DLT 
1 
Rapid 
escalation 
0.5 
4 
2.0 
1 
None 
No 
2 
1.25 
4 
5.0 
1 
None 
No 
3 
2.5 
4 
10 
1 
Gr 1 fever (n=1) 
No 
4 
Standard 
escalation 
5.0 
4 
20 
3 
None 
No 
5 
10.0 
4 
40 
4a 
None 
No 
6 
20.0 
4 
80 
3 
Gr 1 ALT elevation (n=1) 
Gr 2 ALT, AST elevation (n=1) 
No 
7 
40.0 
4b 
160 
3 
Gr 1 AST, Gr 2 hypoalbuminemia (n=1) 
Gr 2 capillary leak syndrome (n=1) 
Gr 1 fatigue (n=1) 
Gr 3 legs weakness (n=1) 
1 
7 
Continual 
Reassessment 
40.0 
4 
160 
2 
Gr 2 hypoalbuminemia (n=1) 
Gr 2 capillary leak syndrome (n=1) 
Gr 1 hypokalemia (n=1) 
No 
8 
 
60.0 
4 c,d 
240 
5 
Gr 1-2 capillary leak syndrome (n=2) 
Gr 3 capillary leak syndrome (n=1) 
Gr 2 anemia (n=1) Gr 3 or 
thrombocytopenia (n=2) 
Gr 2 fever (n=2) 
Gr 4 neutropenia (n=1) 
Gr 3 capillary leak sy (n=1)  
Gr 3 neutropenic fever (n=1) 
Gr 2 hearing loss (n=1) 
Gr 1 hypocalcemia (n=1) 
1 
9 
 
80.0 
4 
320 
3 
Gr 1 hypokalemia (n=1) 
Gr 1-2 capillary leak syndrome (n=2) 
Gr 1 vomiting (n=1) 
Gr 3 hypokalemia (n=1) 
Gr 1 AST ALT elevation (n=2) 
Gr 2 fatigue (n=2) 
No 
a1 patient at the 10 µg/kg/day was less than 12 years old and enrolled after receiving permission from the local IRB b patient with DLT received 3 
doses of DT2219 c1 patient at the 60 µg/kg/day was retreated 8 weeks later with 2nd cycle at dose 40 µg/kg/day.  
d 1 patient was dose reduced for 4th injection to 40 µg/kg/day due to capillary leak syndrome 
Two patients experienced DLTs: the first DLT occurred at the 40 µg/kg dose level 
in a 71-year-old patient with ALL who developed back pain along with acute lower 

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extremity weakness after the 3rd dose of study drug. While the patient had a recent 
history of CNS leukemia prior to enrollment, brain magnetic resonance imaging 
and cerebrospinal fluid studies at the time of AE were negative for leukemic CNS 
involvement. This patient died of rapidly progressive disease. No neurologic 
adverse effects of any grade occurred in the next 10 patients treated at this or higher 
doses (40-80 ug/kg). The second DLT event occurred at the 60 µg/kg dose level in 
a 55-year-old patient who developed grade 3 capillary leak manifested as 
hypoxemia, hypotension, pulmonary edema, and hypoalbuminemia in combination 
with febrile neutropenia. The patient was hospitalized and treated with oxygen, IV 
antibiotics, hydration and diuresis. Her symptoms improved with supportive care 
to grade 2 after 2-3 days and completely resolved in 10 days.   
Twenty-five patients were evaluable for response, recognizing that only 9 patients 
in the highest dose cohorts had measurable drug levels. Treatment produced an 
objective tumor response in two of these patients. After a single course of DT2219 
at dose level 40 µg/kg/day x 4, a 77-year-old patient with chemotherapy-refractory 
CLL experienced a 40% reduction in cervical and axillary adenopathy with 
decrease of an abdominal tumor mass at day 28 after treatment. A second response 
occurred in a 53-year-old patient with relapsed CD19+CD22+ diffuse large B cell 
lymphoma (dose level 60 µg/kg) who experienced a 75% reduction in size of 
lymphoma lesion after a single course complicated by a grade 3 capillary leak 
syndrome. Eight weeks later, after FDA approval, this patient received a second 
DT2219 course at a reduced dose of 40 µg/kg/dose x 4 which resulted in a complete 
resolution of a subcutaneous mass and pelvic lymphadenopathy. Both patients are 
alive and in remission, currently at 7 and 8 months after therapy.  
2.5 
Pharmacology 
The diphtheria toxin component of DT2219 is a genetically engineered fusion toxin 
protein consisting of the amino acid sequences for the enzymatically-active portion 
of diphtheria fused to the sequence of the single chain Fv fragments of the 
antibodies targeting the CD19 and CD22 cell surface receptors.  
The anti-CD19 and anti-CD22 sFv fragments replaced the native binding domain 
of diphtheria toxin and allow for the specificity of DT2219. The anti-CD19 sFv 
fragment recognizes an epitope present on the CD19 antigen. CD19 is a 95 KD 
glycosylated Type I integral membrane protein, highly expressed on B-cells at all 
stages of their maturation including B-precursor lymphoblasts and ALL patient 
blasts and mature B cell lymphoma cells. The anti-CD22 sFv fragment recognizes 
an epitope present on the CD22 antigen. CD22 is a 135 KD glycoprotein present 
on normal Pre-B and resting B cells, as well as a spectrum of B-cell tumors. It is 

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expressed on the majority of ALL lymphoblasts and some mature B cell lymphoma 
cells.  
DT2219 pharmacokinetic data in rats showed a two compartment behavior with a 
first distribution half-life of 2 hours and a second phase half-life of 14 hours. 
At the time of enrollment in our previous phase I study, most patients exhibited low 
peripheral blood (PB) B-cells counts (median B cell count 3.5% (<0.1 x106 
cells/µL); range 0-52%; n=10) often associated with prior rituximab, 
corticosteroids and chemotherapy. The effect of DT2219 on B lymphocytes in a 
patient with an extramedullary ALL relapse shortly after allogeneic HCT was 
observed with gradual decline in number of PB CD19- and CD22-expressing cells 
after 4 doses of DT2219 (Figure 1A). The possibility that DT2219 may interfere 
with fluorochrome-labeled anti-CD19 and anti-CD22 was excluded by examining 
CD20-positive cells, which also declined over time. The B cell depletion was 
specific as CD3-positive T cell levels remained constant during the testing interval.  
The circulating concentration of DT2219 was also measured in a functional 
pharmacokinetic bioassay. Patients treated at dose levels 0.5-20 µg/kg/day had no 
detectable drug in serum when sampled on day 1 and 8 at 15, 30, 45, 60, and 120 
minutes post-infusion. All evaluable patients at the University of Minnesota treated 
with ≥40 µg/kg/dose (n=10) demonstrated detectable levels of DT2219 with the 
exception of one with preexisting antibodies to DT. The median area under the 
curve (AUC) after the 1st dose (4 hours infusion) was lower at a median of 285 
µg/mL x minutes; (range 0-2020; n=8) compared to drug levels after the 4th dose (2 
hours infusion; AUC median 1249 µg/ml x minutes; range 0-1692; n=7). A 
representative AUC is shown in Figure 1B. The drug half-life ranged from 59-110 
minutes (n=4).  
Because the recombinant immunotoxin contains a bacterial toxin, immunogenicity 
is expected and can be a major barrier to the potential activity of bacterial toxin-
based drugs. We measured serum neutralizing antibodies (NAs) in all patients 
treated with ≥40 µg/kg/dose at days 1,8,15,29,35 and 42 (n=9). NAs developed in 
3 evaluable patients (30%) at dose levels between 40-80 ug/kg at median of one 
week (range 1-2 weeks) after the 1st dose of DT2219. One patient had pre-formed 
anti-diphtheria toxin antibody which we detected at screening and attributed to prior 
DT immunization. In some patients the presence of NA inversely correlated with 
the serum concentration of DT2219 (Figure 1C), however no consistent pattern was 
recognized.  
 
 

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A.                                                                                            
 
 
 
 
 
 
 
 
 
 
 
Figure 1 
2.6 
Study Rationale 
In our previous phase I study we established the safety and dosing feasibility of 
DT2219. We also demonstrated that the current dosing schedule and route of 
administration achieves drug levels capable of biological and clinical response 
against CD19/22-expressing lymphoid malignancies refractory to standard 
therapies with a surprisingly low incidence of neutralizing antibody responses. The 
previous study also showed that, although MTD was not reached, the drug can be 
administered safely up to 80 ug/kg/day on a every other day schedule (day 1, 3, 5 
and 8) for total of 4 doses. The first dose was infused over 4 hours as a safety 
precaution was always well tolerated. All other doses were administered over 2 
hours. Interestingly, the AUC measured for the first dose was almost always lower 
than the AUC measured for the 4th dose suggesting the importance of shorter 
B 
C 

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infusion time for immunotoxins with brief half-life. Early on-target saturation also 
may play a role in  low AUC at the onset of therapy, yet the DT2219 dosing in 4 
infusions 1-2 days apart resulted to adequate drug levels, biological effectiveness, 
and tolerable toxicity. Although clinical responses to DT2219 were observed at 
doses of 40 and 60 ug/kg/day, the 4 doses as administered in this trial maybe 
inadequate to induce deeper remissions. In one patient who achieved partial 
remission after 1 cycle, an additional cycle led to complete tumor elimination. The 
rationale for improved efficacy with repetitive dosing is supported by others who 
are developing immunotoxin conjugates using bacterial toxins, such as the anti-
CD22 moxetumomab pasudotox for hairy cell leukemia or SL-401, an interleukin 
3 receptor-diphteria toxin fusion protein for myeloid malignancies [13-15].  
In our experience, increasing the number of consecutive doses per cycle is unlikely 
to be tolerated; however the treatment schedule as proposed in this study with 
repetitive cycles of four every other day doses at least a week apart is worthy of 
exploration.  
 
This study will begin at the lowest dose of DT2219 where clinical response was 
observed (60 ug/kg/day) and apply an 8 dose schedule over the same 28 day 
treatment cycle tested during the previous phase I study. If no dose limiting toxicity 
is encountered, a second cohort of patients will be treated at 80 ug/kg/day. The 
maximum tolerated dose from the phase I component will be used for an expansion 
disease based (NHL vs Leukemia) two stage phase II component as it is felt based 
on the previous phase I study a higher number of disease responses will be seen in 
NHL.  
3 
Study Design 
This is a phase I/II study of DT2219 for the treatment of relapsed or refractory CD19 (+) 
and/or CD 22 (+) B-lineage leukemia and lymphoma. The study consists of two phases - a 
phase I dose/schedule finding component and a two-stage phase II component to confirm 
safety and make a preliminary determination of the activity level by diagnosis using the 
dose identified in phase I. 
Patients will receive a minimum of one cycle of DT2219 given as a 1-2 hour infusion days 
1, 3, 5, 8 and days 15, 17, 19 and 22. A disease reassessment will be done at day 29. If a 
patient has clinical benefit up to two additional cycles of DT2219 may be given until 
disease progression, unacceptable toxicity and/or development of antibodies. A final post-
treatment visit will occur 30 days (approximately day 50) after the final dose of DT2219. 
Patients in a response at the time treatment is discontinued will be followed until disease 
progression or the start of a new therapy for a maximum of 1 year.   

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All patients, regardless of disease status will be followed for survival for 1 year from the 
1st dose of study therapy.  
The primary goal of the dose/schedule finding component is to determine if the maximum 
tolerated dose (MTD) of DT2219 identified in our previous dose escalation study can be 
repeated after a short break. Enrollment will begin at the DT2219 dose of 60 µg/kg/dose 
using an eight dose schedule with the ability to move up or down a dose level (40 or 80 
µg/kg/dose) in subsequent patients based on the tolerance of 60 µg/kg. Tolerance is 
evidenced by an inability to receive at least 6 out of 8 planned doses at the assigned dose 
level. If toxicity develops, an individual patient may move to a lower dose-level to allow 
administration of 8 doses. A minimum of 6 patients will be enrolled to confirm that the 
previous MTD is tolerable when used on an eight dose schedule. 
Once the MTD is determined, the final dose will be carried forward into a two-stage phase 
II component to confirm safety and make a preliminary determination of the activity level 
for Non-Hodgkin Lymphoma (NHL) patients (Arm 1) and B-cell lineage leukemia 
(Leukemia) patients (Arm 2). We will employ Simon’s Optimum two-stage design [16] 
with the possibility to discontinue after the 1st stage if the response rate is low.  
With the March 2017 revision, DT2219 at 60 µg/kg/dose was declared the maximum 
tolerated dose (MTD) and the study moved to phase II enrollment. 
4 Patient Selection 
Study entry is open to persons 12 years and older regardless of gender, race or ethnic 
background. While there will be every effort to seek out and include females and minority 
patients, the patient population is expected to be no different than that of a similar studies 
at the University of Minnesota. 
Inclusion Criteria 
4.1 
Histologic verification of B-cell lineage leukemia or B cell non-Hodgkin lymphoma 
and evidence of relapse/refractory disease with the presence of CD19 and/or CD22 
by flow cytometry or immunohistochemistry of bone marrow aspirate, peripheral 
blood or node/tumor biopsy 
4.2 
Relapsed/refractory disease that has failed conventional therapy and other therapies 
of higher priority 
4.3 
Age ≥ 12 years  
4.4 
Karnofsky Performance status of ≥ 60% or, if less than 16 years of age Lansky Play 
Score of ≥ 60 (appendix II) 
4.5 
At least 2 weeks should have elapsed since the last dose of chemotherapy and must 
have recovered from the acute effects of prior therapy (grade 1 or better); however 
patients who have a >50% rise in peripheral blast count (confirmed twice) or > 50% 

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growth of lymph nodes are immediately eligible. Patients who have relapsed 
following autologous or allogeneic BMT are eligible  
4.6 
In order to prevent tumor lysis syndrome, acute leukemia patients must have a 
peripheral blast count under 50 x 109/L. This may be achieved with hydroxyurea 
cytoreduction, prior to starting DT2219  
4.7 
Adequate organ function within 14 days (30 days for cardiac and pulmonary) of 
treatment start defined as: 
o Creatinine: ≤ 1.5 x upper limit of institutional normal (ULN) 
o Hepatic: SGOT (AST) and SGPT (ALT) ≤1.5 x ULN and total bilirubin ≤ 1.5 x 
ULN 
o General health: Serum albumin ≥ 3.0g/dL 
o Pulmonary: DLCOcorr > 50% if symptomatic or prior known impairment  
o Cardiac: LVEF by ECHO or MUGA or MRI ≥ 40% 
4.8 
Women of childbearing potential and men should be advised and agree to practice 
effective methods of contraception during the course of study 
4.9 
Voluntary written consent with appropriate parent/guardian consent and minor 
information sheet for participants < 18 years of age 
 
Exclusion Criteria 
4.10 
Presence of leukemic or infectious pulmonary parenchymal disease  
4.11 
Presence of active CNS leukemia  
4.12 
Presence of any untreated systemic infection 
4.13 
Documented uncontrolled seizure disorder – a seizure disorder controlled with 
medication (i.e. no seizures in the previous 6 months) will not exclude a patient 
4.14 
Active neurologic disorder (i.e. weakness, altered mental status) – peripheral 
neuropathy alone does not exclude a patient 
4.15 
Active Hepatitis B or Hepatitis C (virus detectable by PCR) 
4.16 
Documented penicillin or cephalosporin allergies 
4.17 
Pregnant or lactating – Women of child bearing potential must have a negative 
pregnancy test within 14 days of study treatment start 
5 
Patient Registration/DT2219 Dose Level Assignment 
Registration will occur after the patient has signed the treatment consent and eligibility is 
confirmed but prior to the first dose DT2219. To be eligible for registration to this study, 
the patient must meet each criteria listed on the eligibility checklist based on the eligibility 
assessment documented in the patient’s medical record. A copy of the eligibility checklist 
(appendix I) is under attachments within the study in OnCore. 
 
 

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5.1 
Registration with the Masonic Cancer Center Clinical Trials Office 
Upon completion of the screening evaluation, eligibility confirmation and obtaining 
written consent, the Study Coordinator or designee will register the patient.  
In the phase II component, patients will be assigned to the disease specific arm 
(Arm 1 – NHL or Arm 2 – Leukemia). 
5.2 
DT2219 Dose Level Assignment 
The Study Coordinator or designee will assign each patient to the current dose level 
of DT2219. Refer to section 6.2. 
5.3 
Patient Re-Treatment (Compassionate) 
If a patient completes treatment with DT2219 in a response and later progresses, 
there may be an opportunity for re-treatment provide the patient continues to meet 
the original eligibility criteria and tests negative for study drug antibody. Refer to 
section 6.6 for complete details.  
After confirmation of eligibility and signing of a re-treatment consent, the patient 
will be registered in Oncore on the compassionate treatment study arm. 
5.4 
Patients Who Are Registered and Do Not Receive Study Treatment 
If a patient is registered to the study, and is later found not able to begin DT2219, 
for whatever reason, the patient will be removed from study and treated at the 
physician’s discretion.  
The Study Coordinator or designee will update OnCore of the patient’s non-
treatment status and notify the Principal Investigator. Study data will be collected 
until the time the patient is off study. The reason for removal from study will be 
clearly documented in OnCore. The patient will be replaced. 
6 
Treatment Plan 
In order to provide optimal patient care and to account for individual medical conditions, 
investigator discretion may be used in the prescribing of all supportive care drug therapy 
(i.e. acetaminophen, diphenhydramine, antimicrobials, etc.).  
6.1 
DT2219 Administration 
Patients may begin on prophylactic allopurinol 300 mg po the day of the 1st dose of 
DT2219 and continue daily until 24 hours after the last dose of DT2219 or as 
medically indicated. Use of allopurinol is at the discretion of the treating physician 
as part of good medical care and is not required for this study. 
 

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DT2219 will be administered at the assigned dose via a syringe pump piggy backed 
onto an established normal saline 1L IV (20mL/kg for weight < 50 kg) on days 1, 
3, 5, 8 and days 15, 17, 19 and 22. Dosing will be based on a weight obtained day 
1 (-3 days) of each treatment cycle. 
 
The day 1, 3, 5, 8 and day 15, 17, 19 and 22 dosing schedule is based on a Monday 
start day; however this is not always feasible. Therefore, general dosing rules will 
be followed within a 4 dose set: 1) each dose will be separated by a minimum 48 
hours but 2) no more than 72 hours will lapse between doses except in cases where 
it is unavoidable (e.g. Monday holidays). Situations where the dosing falls outside 
of these guidelines will be discussed with and approved by the PI or her designee. 
No deviation will be filed for these cases. 
 
The 1st dose of treatment cycle 1 will be given over 2 hours (+/- 45 minutes) 
beginning approximately 30 to 60 minutes after the normal saline is started (run at 
200ml/hour) and pre-meds (see below) have been given.  
 
For those who tolerate the 1st dose without incidence, subsequent doses may be 
infused via a syringe pump over 1 hour beginning approximately 30 minutes after 
the normal saline infusion has been started (run at 200ml/hour with adjustments as 
needed for peds) and the pre-meds (see below) have been given.  
Pre-meds: 30 minutes prior to each infusion, patients will receive acetaminophen 
325 mg po, diphenhydramine 25mg PO/IV (12.5mg PO/IV for weight <25kg), 
hydrocortisone 25-50 mg IV (25 mg IV for weight <25kg), rantidine 50 mg IV 
(1mg/kg for weight <50kg) 
Patient Monitoring: Vital signs including blood pressure, pulse, temperature, 
respirations, and pulse oximetry will be measured as follows: 
• every 15 minutes (+/- 10 minutes) during the 1st hour of the DT2219 infusion 
• every 30 minutes (+/- 10 minutes) during the 2nd hour, if applicable (and 
subsequent hours, if infusion runs longer) of the DT2219 infusion 
 
A final set of vitals will be recorded 30 minutes (+/- 10 minutes) after the end of 
the infusion (end of required post-DT2219 monitoring).  
 
Targeted toxicities (appendix IV) and unexpected adverse events will be collected 
at the time points listed in section 9.2. 
If receiving treatment as an outpatient, upon discharge from clinic after each dose, 
a member of the research staff will review the time of the next visit with the patient 

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and the caregiver(s) reiterating the need to contact the study staff during clinic hours 
or physician on call with any questions or concerns. If there is any concern 
regarding the patient’s general status, a hospital admission will be arranged. 
Supportive measures will include acetaminophen for fevers, meperidine for chills, 
anti-emetics for nausea and vomiting, normal saline or furosemide to maintain fluid 
balance/blood pressure/pulmonary function, electrolyte replacement, albumin to 
maintain serum albumin at 3 g/dL or greater.   
Anaphylactoid reactions will be treated with 100 mg methylprednisolone IV, 
diphenhydramine 25 mg IV, or 0.3cc epinephrine (1:1000) IV and transfer to an 
ICU or inpatient setting for monitoring if clinically indicated.  
If grade 2 hypersensitivity reaction occurs, we will use methylprednisolone 100mg 
pre-med prophylactically prior to subsequent doses. If a grade 2 or greater 
hypersensitivity reaction re-occurs despite pre-medication, the patient will be 
permanently discontinued from DT2219. 
Any patient experiencing a Grade 3 or greater hypersensitivity reaction related to 
the DT2219 infusion despite pre-medication will be permanently discontinued from 
DT2219.  
Dose Level Reduction for Toxicity: A one level dose reduction is permitted within 
a treatment cycle on an individual patient basis if a lower dose allows 
administration of all 8 doses. This dose reduction is at the discretion of the treating 
physician in discussion with the PI or designee. For the -1 dose level (if tested), a 
one level reduction would be 30 µg/kg/dose. 
 
If the event meets the definition of DLT (phase I) or the early stopping rule (phase 
II), treatment may continue only if the following conditions are met: 1) clinical 
benefit is observed, 2) the patient is interested in continuing treatment and 3) the 
DLT or stopping event has resolved to grade 1 or better. In such situations two 
senior hematology/oncology faculty members must concur with the decision to 
resume treatment decreasing by 1 dose level. Subsequent toxicity in these patients 
will not count toward additional DLTs or stopping rule events; however if a second 
DLT/stopping rule event occurs in the same patient, treatment will be permanently 
discontinued.  
 
As a guideline, the dose of DT2219 will be decreased by 1 dose level for a grade 3 
treatment related event (except for hypersensitivity as detailed above) either within 
the treatment cycle or at the start of next treatment cycle. No more than 1 dose level 
reduction is permitted within an individual.  

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Up to 2 Additional Treatment Cycles may be given if a patient: 
• experiences clinical benefit (CR, PR, or stable disease per disease specific 
response criteria – refer to appendix III) AND 
• toxicity from previous treatment cycle has resolved to a grade 1 or 0 and 
has not experience a grade 3 or higher hypersensitivity reaction to DT2219 
despite pre-medication or re-occurrence of a grade 2 hypersensitivity 
reaction despite pre-medication 
• patient continues to meet study eligibility criteria for kidney function 
(serum creatinine ≤ 1.5 x ULN) and liver function SGOT (AST) and 
SGPT (ALT) ≤ 1.5 x ULN and total bilirubin ≤ 1.5 x ULN 
• Neutralizing antibody against DT2219 was not detected after the current 
cycle 
 
The above criteria must be met for each subsequent cycle. Subsequent cycles will 
be given no sooner than 7 days after the last DT2219 dose on the same schedule 
and at the same or a lower per kg dose of DT2219 as the 1st cycle. The start of a 
new treatment cycle may be delayed for up to 8 additional weeks.  
6.2 
DT2219 Dose Level Assignment 
6.2.1 Phase I – DT2219 Dosing Confirmation (Completed March 2017) 
The phase I component will follow standard 3 or 6 patients per dose level. 
Enrollment will begin at dose level 1. Dose level -1 will be used only if dose 
limiting toxicity is encountered with the 1st group. A total of 6 patients will be 
enrolled at the maximum tolerated dose (MTD) before moving to the expansion 
component. 
Dose Cohort 
DT2219 Dose 
-1 
40 µg/kg/dose 
1 
60 µg/kg/dose 
2 
80 µg/kg/dose 
 
Patients will receive a minimum of one cycle of DT2219 using an 8 dose schedule 
(day 1, 3, 5, 8 and day 15, 17, 19 and 22) over 4 weeks. Dose escalation will proceed 
within each cohort according to the scheme found in section 11.1. Escalation to 
dose level 2 may not occur until no sooner than 7 days after the last DT2219 
treatment of the last patient in dose level 1 to rule out dose limiting toxicity (DLT).  
Dose limiting toxicity (DLT) is defined as any of the following occurring from 
day 1 through 7 days after the last dose of DT2219 of the 1st cycle and not attributed 
to primary malignancy or intercurrent illness:  
• any Grade 5 adverse event 
• any Grade 4 neutropenia or thrombocytopenia lasting more for than 7 days 

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• any Grade 3 thrombocytopenia with bleeding 
• any Grade 4 non-hematologic adverse event during DT2219 infusion  
• any Grade 3 non-hematologic adverse event occurring after completion of 
DT2219 infusion  
No single patient can trigger more than one DLT event. If a DLT occurs in a patient, 
further DT2219 should be only administered if the investigator, in discussion with 
the PI or designee, feels the benefit of continuing treatment.  
6.2.2 Phase II – Simon’s Optimum Two-Stage Design  
With the March 2017 protocol revision, enrollment moved to phase II using the 
DT2219 at 60 µg/kg/dose.  
 
Once the MTD for DT2219 using an eight dose schedule is determined, the study 
will move to a two stage phase II. Patients will be assigned to Arm 1 (NHL) or Arm 
2 (Leukemia) based on their diagnosis. Enrollment will proceed independently by 
diagnosis.  
 
Stage 1: Enroll a total of 9 patients (including all with the relevant diagnosis treated 
at the MTD in phase I and evaluable after 1st cycle of DT2219). If 1 or more 
responds, the trial will continue to stage 2 for that diagnosis. 
Stage 2: Enroll an additional 8 patients.  
 
If 3 or more patients out of total 17 patients respond then DT2219 will be 
considered promising for further investigation. 
6.3 
Guidelines for the Management of Selected Toxicities 
See section 8.6 for a complete list of expected toxicities. 
Chills associated with study drug administration may be treated with meperidine 
or morphine sulfate.  
Nausea and vomiting may be treated with anti-emetics and IV fluids.  
Diarrhea may be treated with loperamide and fluids after stool testing.  
Hyperuricemia may be treated with allopurinol, rasburicase and fluids as clinically 
indicated.  
Anaphylaxis and hypersensitivity reactions associated with rash, fever, urticaria, 
bronchospasm, and angioedema will be treated with IV methylprednisolone (may 
substitute for dexamethasone or hydrocortisone at equipotent doses), IV 
diphenhydramine, or, if more severe, epinephrine once. Any patient experiencing a 

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grade 3 or greater hypersensitivity reaction despite pre-medication or reoccurrence 
of a grade 2 hypersensitivity reaction despite pre-medication will be permanently 
discontinued from DT2219. 
Vascular leak syndrome is associated with vascular endothelial injury related to 
fusion protein administration and occurs 3-8 days after initiation of treatment. 
Patients note symptoms of hypotension, weight gain, edema, nausea, anorexia, 
shortness of breath, and, at times, confusion and muscle injury. Exam findings 
include hypoalbuminemia, reductions in blood oxygen saturation, and chest x-ray 
pulmonary edema. Patients with grade 3 respiratory compromise or grade 4 
vascular leak toxicity due to the study drug, will be permanently discontinued from 
the study drug and will be admitted to the hospital, if indicated, for monitoring and 
treatment. 
Symptomatic hypotension will be treated with boluses of normal saline and a hold 
on further drug infusion until resolution. If the BP fails to improve with two normal 
saline boluses, the drug infusion will not be resumed. If low BP persists through 
the next day, no further drug will be given. 
Elevated prothrombin times (PT; INR >1.2) in the absence of other 
abnormalities consistent with DIC may receive vitamin K IV daily x3. Greater 
elevations of PT (INR>1.5) may be treated with fresh frozen plasma after the last 
DT2219 infusion on day 22. If the PT is prolonged to INR >2, the patient may 
receive fresh frozen plasma daily. 
Elevated liver function tests (ALT, AST and/or total bilirubin) guidelines based 
on CTCAE grading: 
Grade 1 or 2: continue therapy per protocol 
Grade 3: hold therapy until drops to Grade 1 and resume at lower dose (40mcg/kg) 
Grade 4: permanently discontinue therapy 
6.4 
Supportive Care and Prohibited Therapies 
Supportive care will be provided per institutional guidelines. Guidelines may be 
updated based on current data/drugs without requiring a protocol amendment or be 
considered a protocol deviation.  
Hematopoietic growth factors (e.g., erythropoietin, G-CSF) will be permitted as per 
institutional pathways. 
Appropriate antibiotics, blood products, fluids, electrolytes and general supportive 
care may be used as medically appropriate.  

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No other cancer chemotherapy or radiation therapy is permitted during the study 
period (through day 29 or disease progression).  
Use of intravenous immunoglobulin through day 29 is not permitted.  
6.5 
Duration of Treatment 
Treatment may continue on DT2219 for up to 3 treatment cycles unless the patient 
experiences one or more of the following. 
• Has grade 3 or higher hypersensitivity reaction related to DT2219 
administration or re-occurrence of a grade 2 or greater hypersensitivity 
reaction despite pre-medication with methylprednisone  
• Develops neutralizing antibody against DT2219  
• Has unacceptable toxicity  
• Requires more than 1 dose level reduction due to toxicity 
• Refuses further treatment or is non-compliant 
• Continuing DT2219 is not in the best interest of the patient in the opinion 
of the treating physician 
• More than 8 weeks elapse between treatment cycles 
Patients receiving fewer than 6 doses for reasons other than dose limiting toxicity 
will be replaced. 
6.6 
Duration of Study Participation 
A final study visit will occur at day 50 or 30 days after the last dose (whichever is 
shorter) of their last treatment cycle. If at the 50 day visit, drug related toxicities 
have not resolved to < grade 2, follow-up will continue weekly until resolution or 
stabilization or the start of a new treatment.  
If in remission at the time of treatment end, patients will be followed every 3 months 
for standard of care disease assessment until relapse or progression or the start of a 
new treatment or for a maximum of 1 year. 
Opportunity for Re-Treatment: If a patient completes DT2219 treatment per 
protocol in a disease response and later relapses, re-treatment may be an option to 
be discussed with Dr. Bachanova. The subject has to fulfill the eligibility criteria in 
Section 4. In addition the patient will be tested for the anti-DT2219 antibody and 
will not be eligible for re-treatment if anti-drug antibody is detected.  
Eligible patients will receive DT2219 at the same or a lower dose level and on the 
same schedule (8 doses over 22 days) as initially treated. Treatment guidelines will 
be followed per section 6.1. Tests and evaluations during and after treatment would 
follow those in section 7. This includes frequent assessments for toxicity and 
survival follow-up through 1 year from the 1st dose off the re-treatment. 

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Such situations would be considered compassionate and would not be included in 
the statistical analysis. 
7 Schedule of Patient Activities 
Scheduled evaluations after screening and up to day 29 of each treatment cycle may be performed 
+/-1 day from the targeted date; assessments to be performed day 29 and later may be performed 
+/-3 days from the targeted date. Ongoing follow-up for disease response may be performed +/- 
30 days. 
If Day 1 Does Not Fall on a Monday:  
The day 1, 3, 5, 8 and day 15, 17, 19 and 22 dosing schedule is based on a Monday start day; 
however this is not always feasible. Therefore, general dosing rules will be followed within a 4 
dose set: 1) each dose will be separated by a minimum 48 hours but 2) no more than 72 hours (+2 
hours) will lapse between doses except in cases where it is unavoidable (e.g. Monday holidays). 
Situations where the dosing falls outside of these guidelines will be discussed with and approved 
by the PI or her designee. No deviation will be filed for these cases. 
 
 
 

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7.1 
Standard of Care 
 
Pre-Treatment 
within 14 days of 
treatment start 
(within 30 days if 
marked by *)  
During each DT2219 Treatment Cycle 
Day 50 
(+/-3 days) 
or 30 days 
after last 
DT2219 
infusion 
Follow-up 
through 1 
year from 
1st dose2 
Prior to each 
DT2219 dose 
(days 1,3,5,8 and 
15,17,19,22) – 
refer to previous 
page if day 1 is 
not a Monday 
Day 
104 
Day 244 
 
Day 29 
(+/-3 
days) 
consent 
X 
 
 
 
 
 
 
medical history 
X 
 
 
 
 
 
 
physical exam  
X 
X 
X 
X 
X 
X 
 
neurological assessment3 
X 
day 1, 8, 15, 22 
X 
X 
X 
X 
 
toxicity assessment 
X 
X 
X 
X 
X 
X 
 
Monitor for stopping 
rules per section 11.5 
(expansion only) 
 
 
 
 
 
 
 
Monitor for DLT per 
section 11.1 (dose finding 
only) 
 
X 
 
 
vital signs (including 02 
sat) 
X 
per section 6.1 
X 
X 
X 
X 
 
weight 
X 
X 
 
 
X 
X 
 
performance status 
X 
day1, 15 
 
 
X 
X 
 
CBC, diff, plt 
X 
X 
X 
X 
X 
X 
 
basic metabolic plus uric 
acid, mg, phos, LDH 
X 
on days 
comprehensive 
metabolic is not 
done 
X 
X 
 
 
 
comprehensive metabolic 
plus uric acid, mg, phos, 
LDH 
X 
day 1, 8, 15, 22 
 
 
X 
X 
 
PT, PTT, fibrinogen 
X 
day 1, 15  
 
 
 
 
 
hepatitis B and C 
screening  
X* 
 
 
 
 
 
 
Pregnancy test, serum or 
urine for females of child 
bearing potential 
X* 
 
 
 
 
 
 
EKG 
X* 
 
 
 
 
 
 
Ejection Fraction by 
MUGA or echo or MRI 
X* 
 
 
 
 
 
 
PFT’s if symptomatic or 
known impairment 
X* 
 
 
 
 
 
 
Bone marrow aspirate +/- 
biopsy (per SOC)1 
X*1 
 
 
 
X1 
 
every 3 
months1 
PET/CT OR CAP CT 
X* 
 
 
 
X (CT 
only) 5 
 
 
Lumbar Puncture if 
clinically indicated  
X* 
 
 
 
 
 
 
* within 30 days of treatment start  
1- For ALL and CLL patients only; however it maybe skipped if there is evidence of progression based upon peripheral blasts count rise or 
lymph node growth. See section 7.2 – collect additional sample for research purposes at the time of each BM done for SOC. 
2- Patients who end treatment while in disease response will be followed per standard of care until relapse, progression, or start of new 
treatment or for a maximum of 1 year, otherwise follow for survival only at 1 year per section 6.6  
3- Neurological assessment weekly including basic motor (gait), coordination (steadiness) and cognitive function (alert and oriented) - any 
abnormalities should be followed up with a detailed neurologic exam. 
4- Day 10 and Day 24 evaluation needed for patients on Phase 1 cycle 1 only 
5- PET will be obtained only in NHL patients with no detectable disease on CT scan  at C1D29 only OR at time of progression 
 
 

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7.2 
Research Related Procedures and Activities 
 
Pre-
treatment 
within 14 days 
of treatment 
start 
Day 8 and 22  
cycle 1 only 
 
Day 22 or 24 
End of 
Treatment 
(Cycle 1, D29 
only)* 
Toxicity Notation 
 
per section 9.2 
 
DT2219 serum levels (PKs) – 
one 2ml red top tube per time 
point  
 
X3 
 
 
Neutralizing antibody against -
DT2219 Ig - red top tube(s) 
X1 
(10 ml) 
 
X (5 m1 per time 
point) - cycle 1, 2 
and 3)4 
 
peripheral blood 
immunophenotyping –  
two 10 ml green top tubes 
X 
 
X (cycle 1 only) 
X 
peripheral blood  for immune 
environment assessment 
two 10 ml green top tubes  
X 
 
X (cycle 1 only) 
X 
10 ml green top bone marrow 
for CD19 and CD22 by flow 
cytometry 
At time of SOC BM Bx 
tumor or lymph node biopsy 
X2 
 
 
X5 
* only for patients who have completed 1 full cycle 
1 
Antibody testing will occur prior to treatment, and in the event of antibody presence, it will be 
determined on a case by case basis whether the patient will receive DT2219.  
2 
Pre-treatment tumor or lymph node biopsy – if patient refuses, a planned deviation will be filed. 
3 
PK time points: Prior to infusion start, at mid-infusion (i.e. 30 minutes if given over 1 hour) and at 
the end of the infusion (a ± 5 min window is permitted with the actual time of the sample collected 
recorded.) 
4 
Presence of neutralizing antibody will deem the patient ineligible for additional treatment cycles or 
re-treatment per sections 6.5 and 6.6 
5 
Optional post-treatment tumor or lymph node biopsy – requires a separate consent – adults only 
 
All samples to will go to TTL except tumor or lymph node biopsies which are processed 
through BioNet. 
 
It is recognized that with novel therapies as used in this study, the timing of protocol directed 
research samples may miss important patient specific events. For this reason, up to 3 extra 
samples for a total of 60 ml of blood may be drawn at additional time points that are not 
specified above.  
 
 
 

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7.2.1 Circulating DT2219 in the Blood 
Measurement of the Cmax and half-life of DT2219 in the blood of patients will 
permit correlation of drug levels and leukemia cell exposure (time x concentration) 
with clinical toxicities and response. Further, different patient leukemia and 
lymphoma burdens may influence drug pharmacodynamics. 
 
A 2 mL venous blood sample (red top tube) will be drawn on cycle 1 day 8 and 22 
(4th and 8th dose) of DT2219 at the following time points: prior to infusion start at 
mid-infusion (i.e. 30 minutes if given over 1 hour) and at the end of the infusion (a 
± 5 min window is permitted) with the actual time of the sample collected recorded. 
 
Samples will be processed in TTL and stored frozen until batch transfer to the 
Vallera Lab. 
7.2.2 Neutralizing Antibody Against DT2219 
At study screening: Antibody testing will be done and the results reviewed prior to 
beginning DT2219 but its result is not part of the inclusion/exclusion criteria. In the 
event of antibody presence, it will be determined on a case by case basis whether 
the patient will receive DT2219.  
 
During treatment: a sample will be collected on day 22 (+2 days) of each treatment 
course and tested in TTL with the results available before the start of the next 
treatment cycle. Per section 6.5, the antibody result must be negative prior to the 
start of a new treatment cycle or re-treatment per section 6.6.  
7.2.3 Pre-Treatment Tumor/Lymph Node Biopsy 
A fresh biopsy of tumor or lymph node will be performed during screening. Part 
will go to the Fairview Clinical Flow Lab for CD19 and CD22 expression (bill to 
research) with the remainder retained in BIONET for frozen tissue storage. If a 
patient does not have accessible tumor or refuses, a planned deviation will be filed. 
7.2.4 Post-Treatment Tumor/Lymph Node Biopsy (optional) 
A post-treatment tumor/lymph node biopsy of palpable node will be optional for 
patients with accessible tumor or lymph nodes. Part will go to the Fairview clinical 
Flow Lab for CD19 and CD22 expression (bill to research) with the remainder 
retained in BIONET for frozen tissue storage. 
 
 

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8 
DT2219 
8.1 
Procurement 
DT2219 is an experimental drug produced by Dr. Daniel A. Vallera at the 
University of Minnesota Masonic Cancer Center, Minneapolis, Minnesota with 
approval of the FDA for the purpose of this study (IND #100780). 
 
DT2219 will be supplied by Dr. Vallera for the purposes of this study. 
 
8.2 
Formulation 
DT2219 protein is supplied frozen in sterile 1 mL colorless, type I glass vials with 
an 11mm rubber stopper and an aluminum seal ring and is formulated at 1 mg drug 
in 1 mL of 0.15 M NaCl/10 mM sodium phosphate + 0.5% Polysorbate 80, pH 7.4. 
Vials used in drug preparation were sterile pyrogen-free, 1 mL (Hollister Stier, 
Miles Inc. #280090-M01). 
 
8.3 
Reconstitution 
Vials are to be thawed at room temperature for 15 minutes. Do not shake the vial 
during thawing. Vials may be gently swirled. The solution must be clear, colorless 
and without visible particulate matter. Immediately draw the thawed drug into a 3 
cc syringe and filter sterilize using a 0.22 um filter (PALL Life Sciences #PN 4192). 
The drug is transferred to a sterile 5 mL vial and the correct dose volume for the 
patient aspirated with a 18 x 1-½ “(BD305196) needle into a 30 ml disposable 
plastic sterile syringe adding enough sterile saline to reach a total volume of 20 ml.  
 
Ideally the drug will be administered within one hour of thawing.  
 
8.4 
Storage and Stability 
Intact vials should be stored at -80oC and are stable for over 12 months.  
 
8.5 
Administration 
DT2219 is injected via a syringe pump into a free flowing normal saline 1L IV 
(20mL/kg for weight < 50 kg) over the prescribed infusion time per section 6.1 on 
days 1, 3, 5, 8 and day 15, 17, 19 and 22 of a 28 day treatment cycle.  
 
8.6 
Toxicity 
In the previous first in human phase I study 25 patients were given a one 4-dose 
treatment course (on days 1, 3, 5, and 8). The first 12 patients were treated at doses 
ranging from 0.5 ug/kg/day to 20 ug/kg/day exhibited no or minimal adverse 
reactions (lower than what is used in this study). All 13 patients treated at dose 
levels ≥40 ug/kg/day experienced adverse events (AE) attributed to drug treatment. 
A patient by patient summary of events can be found in table 1 of section 2.4. 

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No infusional toxicity was observed.  
 
The most common transient grade 1-2 AEs included weight gain (range 5-14% of 
baseline), peripheral edema, and hypoalbuminemia consistent with capillary leak 
syndrome, grade 1-2 fever and fatigue. Seven patients experienced isolated mild 
elevation of liver function tests (1.1-2.1 x ULN) without hyperbilirubinemia, which 
resolved within 3-7 days. Thrombocytopenia and anemia occurred in 5 patients; 
however, marrow involvement by underlying lymphoma or leukemia often 
contributed to cytopenias. Whereas lactate dehydrogenase (2-2.3-fold) transiently 
increased in 4 patients after the 1st dose; clinical tumor lysis or acute cytokine 
release syndrome did not occur. Most AEs were recognized during routine 
monitoring before the 2nd or 3rd dose of DT2219. All AEs were brief and resolved 
completely within one week.  
 
Two patients experienced DLTs.  
1) 
The first DLT occurred at the 40 µg/kg dose level in a 71-year-old patient 
with ALL who developed back pain along with acute lower extremity weakness 
after the 3rd dose of study drug. While the patient had a recent history of CNS 
leukemia prior to enrollment, brain magnetic resonance imaging and cerebrospinal 
fluid studies at the time of AE were negative for leukemic CNS involvement. This 
patient died of rapidly progressive disease. No neurologic adverse effects of any 
grade occurred in the next 10 patients treated at this or higher doses (40-80 ug/kg).  
2) 
The second DLT event occurred at the 60 µg/kg dose level in a 55-year-old 
patient who developed grade 3 capillary leak manifested as hypoxemia, 
hypotension, pulmonary edema, and hypoalbuminemia in combination with febrile 
neutropenia. The patient was hospitalized and treated with oxygen, IV antibiotics, 
hydration and diuresis. Her symptoms improved with supportive care to grade 2 
after 2-3 days and completely resolved in 10 days. 
 
In March 2017, the MTD for DT2219 was declared as 60 µg/kg/dose when given 
as an 8 dose block (day 1, 3, 5, and 8 and day 15, 17, 19, and 22). Two patients at 
80 µg/kg/dose experienced elevated liver function tests that met the criteria for dose 
limiting. The 6th patient at this level experienced grade 3 capillary leak syndrome 
with the 1st dose.  
  
   
9 
Adverse Event Reporting 
Toxicity and adverse events will be classified according to NCI's Common Terminology 
Criteria for Adverse Events V 4.0 (CTCAE). A copy of the CTCAE can be downloaded 

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from the CTEP home page http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_8.5x11.pdf8.1   
 
9.1 
Definitions 
Note: throughout this section the generic term “drug” refers to the DT2219. 
The following definitions are based on the Code of Federal Regulations Title 21 
Part 312.32 (21CFR312.32(a)). 
Adverse Event: Any untoward medical occurrence associated with the use of a 
drug in humans, whether or not considered drug related.  
Suspected Adverse Reaction: Any adverse event for which there is a reasonable 
possibility that the drug caused the adverse event.  
Treatment-Emergent Adverse Event: Any event not present prior to the initiation 
of the treatment or any event already present that worsens in either intensity or 
frequency following exposure to the treatment. A treatment emergent AE refers to 
an event temporally related to the study treatment regardless of the causality 
assessment by the investigator. 
Life-Threatening Adverse Event Or Life-Threatening Suspected Adverse 
Reaction: 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. 
Serious Adverse Event Or Serious Suspected Adverse Reaction: An adverse 
event or suspected adverse reaction is considered “serious” if, in the view of either 
the investigator or sponsor, it results in any of the following outcomes:  
• Death 
• A life-threatening adverse event 
• Inpatient hospitalization or prolongation of existing hospitalization 
• A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions 
• A congenital anomaly/birth defect 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the patient or subject and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition. Note: 
a grade 4 CTCAE toxicity does not necessarily equate to serious. 

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If either the IND sponsor or the investigator believes the event is life-threatening 
or serious, the event must be evaluated by the sponsor for expedited reporting 
(21CRF 312.32(a)).  
Unexpected adverse event or unexpected suspected adverse reaction: An 
adverse event or suspected adverse reaction is considered “unexpected” if it is not 
listed in the investigator brochure or is not listed at the specificity or severity that 
has been observed; or, if an investigator brochure is not required or available, is not 
consistent with the risk information described in the general investigational plan or 
elsewhere in the current application, as amended. Thus, adverse events that occur 
as part of the disease process or underlying medical conditions are considered 
unexpected; however, they will not be reportable per section 9.3. 
Unanticipated (unexpected) problems/events as defined by the University Of 
Minnesota IRB are those that are not already described as potential risks in the 
consent form, not listed in the Investigator’s Brochure or not part of an underlying 
disease. 
Note: The major discord between the FDA and IRB definitions is whether or not 
the underlying disease is included when considering expectedness. 
Expedited (Rapid) Reporting: Certain events may require rapid notification to 
entities providing patient safety oversight (e.g. IRB, FDA) as detailed in section 
9.3. For the IRB this is within 5 business days of discovery. For studies under an 
IND, it is 7 or 15 calendar days. 
9.2 
Adverse Event Monitoring and Documentation 
For the purposes of this study adverse event monitoring will begin with the 1st dose 
of DT2219 and continue through 30 days after the last infusion, disease 
progression, or the start of a new therapy, whichever occurs first.  
 
A toxicity assessment will be done at each time point in section 7 including prior 
to each dose of DT2219 and at each follow-up visit. Each assessment will cover the 
time period from the previous assessment with the worse grade of the toxicity 
noted. All toxicities (regardless of grade, attribution and expectedness) will be 
recorded in OnCore in the AE log case report form for the duration of the treatment 
period and for 30 days after the last infusion or the start of a new therapy, whichever 
occur first.  
 
In addition, for the 1st cycle only, the targeted toxicity form (appendix IV) will be 
collected at the following time points. The advantage of this form is that it requires 

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an assessment for each event of interest with a “0” indicating not present or no 
compliant. 
• Before the each dose of DT2219 during cycle 1 
• 30 minutes after the each dose of DT2219 during cycle 1 
• Day 10, 24 and 29 of cycle 1  
All of the above time points are based on the assumption the patient receives 
treatment as planned. The assessment day(s) may be altered or eliminated if the 
standard of care visit(s) for a specific time point in section 7.1 is altered or does not 
occur.   
 
After the final treatment visit approximately 30 days after the last DT2219 infusion, 
formal AE documentation will end, however; the investigator must report upon 
knowledge any study treatment related event meeting the criteria for expedited 
reporting in section 9.3. 
Events that potentially meet the definition of serious (SAE): Upon identifying or 
being notified of a potential serious adverse event (SAE), the Study Coordinator or 
designee will review the current IRB approved protocol to determine the protocol 
definition of an SAE and the reporting requirements. The Study Coordinator will 
notify the study PI and IND sponsor and initiate an SAE report in OnCore within 
24 hours of knowledge. The Study Coordinator will forward the partially completed 
SAE report and the IND specific spreadsheet of “Similar Suspected Adverse 
Events” to the Principal Investigator who will assign attribution, expectedness, risk 
and expand upon the clinical information as needed and sign/date the report. The 
IND sponsor will review the SAE report and if in agreement with the report (if not, 
a discussion between the PI and Sponsor will occur to resolve any differences and 
the report edited appropriately), the Study Coordinator will forward the SAE report 
to the Regulatory Specialist. The Regulatory Specialist will determine if the SAE 
meets the criteria for expedited reporting to the University of Minnesota 
Institutional Review Board (IRB) and/or FDA within the required timeframe per 
section 9.3.  In addition, a copy will be forwarded to the Masonic Cancer Center 
SAE Coordinator at the time it is submitted to the IRB and/or FDA per section 9.3. 
 
Dose Limiting Toxicity (During phase I only): The following events occurring 
from study day 1 through 7 days after the last dose of DT2219 of the 1st cycle and 
not clearly attributed to the primary malignancy or intercurrent illness meet the 
definition of dose limiting toxicity during the phase I (dose escalation component): 
• any Grade 5 adverse event 
• any Grade 4 neutropenia or thrombocytopenia lasting more for than 7 days 
• any Grade 3 thrombocytopenia with bleeding 

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• any Grade 4 non-hematologic adverse event during DT2219 infusion  
• any Grade 3 non-hematologic adverse event occurring after completion of 
DT2219 infusion  
 
Within 24 hours of identifying or being notified of a potential DLT event, the 
study’s Study Coordinator will gather the relevant clinical data to initiate the Event 
Form in OnCore. With the study PI and biostatistician, if applicable, the current 
DLT event, all previously reported DLTs and the protocol dose escalation schema 
will be reviewed to determine if the dose escalation schema is impacted.  
 
A copy of the completed Event Form will be provided to the study’s Regulatory 
Specialist for submission within 24 hours of receipt to the Masonic Cancer Center’s 
SAE Coordinator (Data and Safety Monitoring Committee) and other entities with 
study oversight (i.e. IRB, FDA) if applicable. A copy will be filed in the study’s 
regulatory binder. If enrollment to the study is impacted, the Regulatory Specialist 
or designee, will update the study status in OnCore.  
 
Stopping Rule Events (Phase II only):   The following events count towards the 
study stopping rule during cycle 1 of the phase II (extension) component per section 
11.5. Arm 1 and Arm 2 will be monitored separately. 
 
Excess toxicity defined as grade 4 non-hematologic or grade 4 neutropenia or 
thrombocytopenia lasting for more than 7 days or treatment related toxicity 
attributed to the study drug occurring within 7 days of the last dose.   
 
If any grade 5 toxicity (death) possibly, probably or definitely related to DT2219 
occurs accrual will be temporarily suspended in order to allow comprehensive case 
review.  
 
Within 24 hours of identifying or being notified of a potential stopping rule event, 
the Study Coordinator will gather the relevant clinical data to initiate the Event 
Form in OnCore. With the study PI and biostatistician, the current event, all 
previously reported stopping rule events for the rule and the current IRB approved 
protocol will be reviewed to determine if a stopping rule event has occurred and if 
it results in the early stop of the study.  
 
A copy of the completed Event Form will be provided to the study’s Regulatory 
Specialist for submission within 24 hours of receipt to the Masonic Cancer Center’s 
SAE Coordinator (Data and Safety Monitoring Committee) and other entities with 
study oversight (i.e. IRB, FDA) if applicable. A copy will be filed in the study’s 

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regulatory binder. If enrollment to the study is impacted, the Regulatory Specialist 
or designee, will update the study status in OnCore.  
 
Events that count toward dose limiting toxicity or the early stopping rule do not 
necessarily constitute a serious adverse event requiring expedited reporting and 
should be reported as such only if they meet the criteria for expedited reporting to 
the IRB as defined in section 9.3. 
 
In addition, although not always an event requiring expedited reporting, deaths with 
cause will be recorded in OnCore upon knowledge in the follow-up tab. 
 
 

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9.3 
Required Reporting: FDA, IRB, and MCC’s SAE Coordinator 
 
In each IND safety report, the sponsor must identify all IND safety reports 
previously submitted to the FDA concerning a similar suspected adverse reaction 
and must analyze the significance of the suspected adverse reaction in light of the 
previous, similar reports. 
The SAE Coordinator will provide the Masonic Cancer Center’s Data and Safety 
Monitoring Council (DSMC) with the SAE in an appropriate format depending on 
the individual SAE (as reported or in a summary format). 
 
 
Agency 
Criteria for Reporting 
Time-frame 
Form to 
Use 
Submission 
address/ fax 
numbers 
U of MN IRB 
Events requiring prompt reporting including, but not 
limited to unanticipated death of a locally enrolled 
subject(s); new or increased risk; any adverse event  
that require a change to the protocol or consent form 
or any protocol deviation that resulting in harm  
refer to 
http://www.research.umn.edu/irb/guidance/ae.html#
.VC7xraI0-sh  
Within 5 business 
days of event 
discovery 
 
Report 
Form 
irb@umn.edu 
 
FDA 
 
Unexpected and fatal or life threatening suspected 
adverse reaction 
As soon as 
possible but no 
later than 7 
Calendar-Days 
MCC 
SAE 
Submit as an 
amendment to 
IND 
 
1) Serious and unexpected suspected adverse 
reaction or  
2) increased occurrence of serious suspected adverse 
reactions over that listed in the protocol or 
investigator brochure or  
3) findings from other sources (other studies, animal 
or in vitro testing) 
As soon as 
possible but no 
later than 15 
Calendar-Days 
All other events per CRF 312.33 
At time of IND 
annual report 
Summary 
format 
Submit as part 
of the IND 
annual report 
Note: Events clearly determined to be unrelated to DT2219 and felt due to the disease under treatment 
or an underlying medical condition will not require expedited reporting to the FDA for the purposes 
of this study 
Masonic 
Cancer Center 
Regulatory 
Specialist 
Events that count toward a dose limiting toxicity or 
stopping rule 
within 24 hours  
Event 
Form 
SAE 
Coordinator 
mcc-
saes@umn.edu 

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10 
Study Data Collection and Monitoring 
10.1 
Data Management 
This study will report clinical data using The Online Enterprise Research 
Management Environment (OnCoreTM), a web based Oracle® database utilizing 
study specific electronic case report forms. Key study personnel are trained on the 
use of OnCore and will comply with protocol specific instructions embedded within 
the OnCore. Patient demographics, patient specific study treatment calendars, 
adverse events and other information required for IND annual reporting will be 
placed in OnCore and other databases maintained by the Cancer Center. 
10.2 
Case Report Forms 
Participant data will be collected using protocol specific electronic case report 
forms (e-CRF) developed within OnCore based on its library of standardized forms. 
The e-CRF will be approved by the study’s Principal Investigator and the 
Biostatistician prior to release for use. The Study Coordinator or designee will be 
responsible for registering the patient into OnCore at time of study entry, 
completing e-CRF based on the patient specific calendar, and updating the patient 
record until patient death or end of required study participation.  
10.3 
Data and Safety Monitoring Plan (DSMP) 
The study’s Data and Safety Monitoring Plan will be in compliance with the 
University of Minnesota Masonic Cancer Center's Data & Safety Monitoring Plan 
(DSMP), which can be accessed at http://z.umn.edu/dmsp. 
For the purposes of data and safety monitoring, this study is classified as high risk 
(under a locally held IND). Therefore the following requirements will be fulfilled: 
 The Masonic Cancer Center Data and Safety Monitoring Council (DSMC) will 
review the study’s progress at least quarterly. 
 The PI will comply with at least twice yearly monitoring of the project by the 
Masonic Cancer Center monitoring services. 
 The PI will oversee the submission of all reportable adverse events per the 
definition of reportable in section 9.3 to the Masonic Cancer Center’s SAE 
Coordinator, the University of Minnesota IRB, and the FDA.  
In addition, at the time of the continuing review with the University of Minnesota 
IRB, a copy of the report with any attachments will be submitted to the Cancer 
Protocol Review Committee (CPRC). 
 
IND Annual Reports 
In accordance with regulation 21 CFR § 312.33, the sponsor/investigator (Dr. 
Bachanova) with assistance from the MCC Clinical Trials Office (CTO) will submit 

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a progress report annually. The report will be submitted within 60 days of the 
anniversary date that the IND went into effect.   
10.4 
Study Monitoring and Audits 
The investigator will permit study-related monitoring, audits, and inspections by 
the sponsor and/or sponsor designee, IRB, government regulatory bodies, and 
University of Minnesota compliance groups. The investigator will make available 
all study related documents (e.g. source documents, regulatory documents, data 
collection instruments, study data, etc.). The investigator will ensure the capability 
for inspections of applicable study-related facilities (e.g. pharmacy, diagnostic 
laboratory, etc.) will be available for trial related monitoring, audits, or regulatory 
inspections. 
10.5 
Record Retention 
The investigator will retain study records including source data, copies of case 
report form, consent forms, HIPAA authorizations, and all study correspondence in 
a secured facility for at 6 years after the study file is closed with the IRB and FDA.  
In addition, the Clinical Trials Office (CTO) will keep a master log of all patients 
participating in the study with sufficient information to allow retrieval of the 
medical records for that patient.  
Please contact the CTO before destroying any study related records. 
11 
Statistical Considerations 
11.1 
Study Design  
A phase I/II design will be used to determine the maximum tolerated dose (MTD) 
of the DT2219 when administered using an 8 dose schedule for the treatment of 
relapsed or refractory CD19 (+) and/or CD 22 (+) B-lineage leukemia and 
lymphoma.  
The phase I component will follow a standard 3 or 6 patients per dose level. 
Enrollment will begin at dose level 1. Dose level -1 will be used only if dose 
limiting toxicity is encountered with the 1st group. 
 
 

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Dose Cohort 
DT2219 Dose 
-1 
40 µg/kg/dose 
1 
60 µg/kg/dose 
2 
80 µg/kg/dose 
 
Patients will receive a minimum of one cycle of DT2219 using an 8 dose schedule 
(day 1, 3, 5, 8 and day 15, 17, 19 and 22). A disease reassessment will be done at 
day 29+/- 3 days. Each dose cohort must be separated by at least 7 days to rule out 
dose limiting toxicity (DLT). Dose escalation will proceed within each cohort 
according to the following scheme: 
 
Number of Patients 
with DLT 
at a Given Dose Level 
Escalation Decision Rule 
0 out of 3 
Enter 3 new patients at the next higher dose level 
> 2 out of 3 
This dose level is declared to be above the maximum tolerated dose (MTD) and dose 
escalation is stopped.  
Declare the next lower dose the MTD if 6 patients have already been treated at that 
dose.  
Enter 3 additional patients at the next lower dose level if only 3 patients have been 
treated at that dose, and if  ≤ 1 out of 6 patients has DLT then declare this dose the 
MTD. If > 2 out of 6 patients have DLT then dose de-escalation continues according to 
the same scheme.  
1 out of 3 
Enter 3 additional patients at this dose level. 
• If 0 of these 3 patients (i.e. 1 out of all 6 patients) experience DLT, proceed to the 
next higher level. 
• If ≥ 1 of these 3 patients (i.e.≥ 2 out of all 6 patients) experience DLT, then this 
dose is declared to be above the MTD and dose escalation is stopped. Declare the 
next lower dose the MTD if 6 patients have already been treated at that dose. Enter 
3 additional patients at the next lower dose level if only 3 patients have been treated 
at that dose, and if ≤ 1 out of 6 patients has DLT then declare this dose the MTD. If 
≥ 2 out of 6 patients have DLT then dose de-escalation continues according to the 
same scheme.  
 
Dose limiting toxicity (DLT) is defined as any of adverse events occurring from 
study day 1 through 7 days after the last dose of DT2219 of the 1st treatment cycle 
and not clearly attributed to the primary malignancy or intercurrent illness: 
• any Grade 5 adverse event 
• any Grade 4 neutropenia or thrombocytopenia lasting more for than 7 days 
• any Grade 3 thrombocytopenia with bleeding 
• any Grade 4 non-hematologic adverse event during DT2219 infusion 
• any Grade 3 non-hematologic adverse event occurring after completion of 
DT2219 infusion  

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Each dose cohort must be separated by at least 7 days after the last dose of the last 
patient in the current dose level.  
 
Evaluable for response: Patients receiving fewer than 6 doses of DT2219 for 
reasons other than dose limiting toxicity will be replaced.  
 
The design will continue until the MTD is declared or until the first dose is declared 
to be above the MTD.  
 
Once the MTD is determined, the final dose will be carried forward into a two-stage 
phase II component to confirm safety and make a preliminary determination of the 
activity level for Non-Hodgkin Lymphoma (NHL) patients (Arm 1) and Leukemia 
(Leukemia) patients (Arm 2). We will employ Simon’s Optimum two-stage design 
[16] with the possibility to discontinue after the 1st stage if the response rate is low. 
The 6 patients treated under MTD in phase I will be included in the phase II 
component if they are evaluable after the 1st cycle of treatment. They will be 
assigned to Arm 1 or Arm 2 based on their diagnosis.  
• Stage 1: Enroll a total of 9 patients (including all treated at the MTD in 
phase I and evaluable after 1st cycle of treatment). If 1 or more responds, 
the trial will continue to stage 2. 
• Stage 2: Enroll an additional 8 patients. If 3 or more patients out of total 17 
patients respond then DT2219 will be considered promising for further 
investigation.  
Based on the historical data, we expect to complete the enrollment within 12-18 
months. 
11.2 
Rationale for Sample Size 
For Phase I Component, 6 to 12 patients will be enrolled. An additional 28-34 
patients will be enrolled in the phase II component to obtain 17 lymphoma patients 
(Arm 1) and 17 leukemia patients (Arm 2) treated at MTD including the 6 patients 
treated at MTD in phase I and evaluable after the 1st cycle of treatment. For each 
arm, the phase II trial using Simon’s two-stage Optimum design will require 17 
patients to test the null hypothesis that the Complete Response (CR) and Partial 
Response (PR) at day 29 is ≤5% versus the alternative that the CR and PR rate is 
≥30% after assuming 90% power and a significance level of 0.05 and using 
maximum of 17 patients.  
 
Based on the historical data, we expect to complete the enrollment within 12-18 
months. 

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11.3 
Study Endpoints 
Primary Endpoints 
Phase I component is to determine safety and tolerability of the DT2219 for the 
treatment of relapsed or refractory CD19 (+) and/or CD 22 (+) B-lineage leukemia 
and lymphoma.  
 
The primary endpoint for Phase II is the overall response at day 29.  
 
Secondary Endpoints 
• 
To determine incidence of serious adverse events through day 29 
• 
To determine duration of response for up to 1 year 
• 
To evaluate 1 year disease-free survival  
• 
To evaluate 1 year overall survival  
• 
To determine time to relapse/progression for up to 1 year 
 
Correlative Endpoints 
• 
To determine the pharmacokinetic (PK) profile (Cmax, T1/2, AUC, Cl, Vd) of 
DT2219 
• 
To document presence and measure levels of human anti-DT2219 antibodies 
and correlate with response  
• 
To determine if there is a correlation between PK parameters and toxicity or 
response 
• 
To determine if the expression of the CD19 and CD22 cell surface antigens is 
affected by treatment with DT2219 using flow cytometric analysis of 
lymphoblasts in peripheral blood and bone marrow. B-lymphocytes in 
peripheral blood  
• 
To correlate CD19 and CD22 surface antigen expression on patient blasts or 
lymphoma cells with response 
11.4 
Statistical Analysis 
The MTD of DT2219 will be determined by the design. The primary trial endpoint 
of response will be estimated by simple proportions with confidence intervals 
calculated from asymptotic standard errors. Kaplan-Meier curves will estimate PFS 
and log-rank test will be used to compare PFS between disease groups (lymphoma 
vs. leukemia) and disease status groups (relapsed/refractory vs. post-allogeneic 
transplant). [17] Competing rusk analysis will be used to estimate 
relapse/progression rate and Gray-Fine test will be used to test disease effect and 
disease status effect.[18]  Other secondary endpoints will be described with simple 
descriptive statistics such as medians, ranges, interquartile ranges, proportions, 

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charts and plots. Correlation between various biomarkers will be estimated with 
Spearman’s rank-order correlation coefficient along with correlation plots. 
 
All analyses will be conducted using SAS software (version 9.3; SAS Institute Inc., 
Cary, NC). Results will be deemed statistically significant at the 0.05 significance 
level unless otherwise specified. 
11.5 
Early Stopping Rules for Excessive Toxicity During Expansion Component 
Stopping rules will be employed to monitor excess toxicity outside of the phase I 
trial. The stopping rule was developed using Pocock stopping boundaries. [18] The 
stopping rule will be monitored for Arm 1 and Arm 2 separately.  
If any grade 5 toxicity (death) possibly, probably or definitely related to 
DT2219 occurs accrual will be temporarily suspended in order to allow 
comprehensive case review.  
Excess toxicity will be defined as grade 4 non-hematologic or grade 4 
neutropenia or thrombocytopenia lasting for more than 7 days treatment 
related toxicity attributed to the study drug occurring within 7 days of the last 
dose. The goal is to construct a boundary based on toxicity such that the probability 
of early stopping is at most 50% if the true rate of toxicity is equal to 15% and our 
sample size is 17 for each disease cohort (lymphoma vs. leukemia). The stopping 
rule will be monitored for each cohort separately. This means the enrollment will 
be stopped and the study re-evaluated if there are 2 out of first 3 subjects, 3 out of 
8 subjects, 4 at any time. If the true toxicity rate is 30% then the chance of early 
stopping is 90% and the expected sample size is 5.68. 
12 
Conduct of the Study 
12.1 
Good Clinical Practice 
The study will be conducted in accordance with the appropriate regulatory 
requirement(s). Essential clinical documents will be maintained to demonstrate the 
validity of the study and the integrity of the data collected. Master files should be 
established at the beginning of the study, maintained for the duration of the study 
and retained according to the appropriate regulations.  
12.2 
Ethical Considerations 
The study will be conducted in accordance with ethical principles founded in the 
Declaration of Helsinki. The IRB will review all appropriate study documentation 
in order to safeguard the rights, safety and well-being of the patients. The study will 
only be conducted at sites where IRB approval has been obtained. The protocol, 
consent, written information given to the patients, safety updates, annual progress 

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CPRC #2014LS093 
reports, and any revisions to these documents will be provided to the IRB by the 
investigator.  
12.3 
Informed Consent 
All potential study participants will be given a copy of the IRB-approved consent 
to review. The investigator or designee will explain all aspects of the study in lay 
language and answer all questions regarding the study. If the participant decides to 
participate in the study, he/she will be asked to sign and date the consent document. 
Patients who refuse to participate or who withdraw from the study will be treated 
without prejudice. 
13 
References 
1. Pui CH, Evans WE. Treatment of acute lymphoblastic leukemia. New England J Med 2006; 354: 166-
178. 
2. Rowe JM, Goldstone AH. How I treat lymphocytic leukemia in adults. Blood 2007; June 27, Epub. 
3. Wong L, Suh DY, Frankel AE. Toxin conjugate therapy of cancer. Sem Oncol 2005; 32: 591-595. 
4. Todhunter DA, Hall WA, Rustamzadeh E, Shu Y, Doumbia SO, Vallera DA. A bispecific immunotoxin 
(DTAT13) targeting human IL-13 receptor (IL-13R) and urokinase-type plasminogen activator receptor 
(uPAR) in a mouse xenograft model. Protein Eng Des Sel 2004; 17: 157-164. 
5. Liu TF, Cohen KA, Willingham MC, Tatter SB, Puri RK, Frankel AE. Combination fusion protein 
therapy of refractory brain tumors: demonstration of efficacy in cell culture. J Neurooncol 2003; 65: 77-
85. 
6. Flavell DJ, Boehm DA, Noss A, Warnes SL, Flavell SU. Therapy of human T-cell acute lymphoblastic 
leukaemia with a combination of anti-CD7 and anti-CD38-SAPORIN immunotoxins is significantly 
better than therapy with each individual immunotoxin. Br J Cancer 2001; 84: 571-578. 
7. Herrera L, Farah RA, Pellegrini VA, Aquino DB, Sandler ES, Buchanan GR, Vitetta ES. Immunotoxins 
against CD19 and CD22 are effective in killing precursor-B acute lymphoblastic leukemia cells in vitro. 
Leukemia 2000; 14: 853-858. 
8. Herrera L, Yarbrough S, Ghetie V, Aquino DB, Vitetta ES. Treatment of SCID/human B cell precursor 
ALL with anti-CD19 and anti-CD22 immunotoxins. Leukemia 2003; 17: 334-338. 
9. Frankel AE, Surendranathan A, Black JH, White A, Ganjoo K, Cripe LD. Phase II clinical studies of 
denileukin diftitox diphtheria toxin fusion protein in patients with previously treated chronic 
lymphocytic leukemia. Cancer 2006; 106: 2158-2164. 
10. Frankel AE, Weir MA, Hall PD, Holguin M, Cable C, Rizzieri DA, Hogge DE. Induction of remissions 
in patients with acute myeloid leukemia without prolonged myelosuppression using diphtheria toxin-
interleukin 3 fusion protein. J Clin Oncol 2007; 25: 7068. 
11. Frankel AE, Powell BL, Hall PD, Case D, Kreitman RJ. Phase I trial of a novel diphtheria 
toxin/granulocyte macrophage colony-stimulating factor fusion protein (DT388GMCSF) for refractory 
or relapsed acute myeloid leukemia. Clin Cancer Res 2002; 8: 1004-1013. 
12. Yuan Y, Yin G. Bayesian hybrid dose-finding design in phase I oncology clinical trials. Stat Med 
2011;30(17):2098-108. 
13. Kreitman RJ, Tallman MS, Robak T, Coutre S, Wilson WH, Stetler-Stevenson M, et al. 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):1822-8.  

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14. Frankel AE, Woo JH, Ahn C, Pemmaraju N, Medeiros BC, Carraway HE, et al. Activity of SL-401, a 
targeted therapy directed to interleukin-3 receptor, in blastic plasmacytoid dendritic cell neoplasm 
patients. Blood 2014;124(3):385-92.  
15. Kreitman RJ, Pastan I. Antibody fusion proteins: Anti-CD22 recombinant immunotoxin moxetumomab 
pasudotox. Clin Cancer Res 2011;17(20):6398-405.  
16. Simon R. Optimal two-stage designs for phase II clinical trials. Controlled Clinical Trials 1989. 10; 1-
10. 
17. Kaplan EL. Meier P. Nonparametric estimation from incomplete observations. Journal of the American 
Statistical Association 1958; 53: 457-481. 
18. Fine JP, Gray RJ. A proportional hazards model for the subdistribution of a competing risk. J Am 
Statistic Assoc. 1999;94:496-509. 
19. Ivanova I, Qaqish BF, Schell MJ. Continuous toxicity monitoring in phase II trials in Oncology. 
Biometrics 2005, 61: 540-545. 
20. Cheson, BD. New Response criteria for lymphomas in clinical trials. Ann Oncol. 2008 Jun;19 Suppl 
4:iv35-8. 

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Appendix I – Eligibility Checklist  
DT2219 Immunotoxin for the Treatment of Relapsed or Refractory CD19 (+) 
and/or CD 22 (+) B-Lineage Leukemia or Lymphoma  
HM2014-26 
Eligibility Checklist – page 1 of 2 
Patient initials   
      
 
Patient ID  
 
 
 
 
1st 2 initials of first name + 1st 2 initials of last name 
        Seq # (i.e. 01, 02, 03, etc.)  
 
INCLUSION CRITERIA  
A "NO" response to any of the following disqualifies the patient from study entry. 
 
 
Yes      No 
1. 
Histologic verification of B-cell lineage leukemia or B cell non-Hodgkin lymphoma and evidence 
of relapse/refractory disease with the presence of CD19 and/or CD22 by flow cytometry or 
immunohistochemistry of bone marrow aspirate, peripheral blood or node/tumor biopsy 
 
 
2. Relapsed/refractory disease that has failed conventional therapy and other therapies of higher 
priority 
 
 
3. Age ≥ 12 years   
 
 
4. Karnofsky Performance status of ≥ 60% or, < 16 years of age, Lansky Play Score of ≥ 60                
 
 
5. 
At least 2 weeks should have elapsed since the last dose of chemotherapy and must have 
recovered from the acute effects of prior therapy (Grade 1 or better); however patients who have 
a >50% rise in peripheral blast count (confirmed twice) or > 50% growth of lymph nodes are 
immediately eligible -  Patients who have relapsed following autologous or allogeneic BMT are 
eligible 
 
 
6. In order to prevent tumor lysis syndrome, leukemia patients must have a peripheral blast count 
under 50 x 109/L. This may be achieved with hydroxyurea cytoreduction, prior to starting DT2219  
 
 
7. 
Adequate organ function within 14 days (30 days for cardiac and pulmonary) of enrollment 
defined as: 
test 
requirement 
SGOT  
≤1.5 x UNL 
SGPT 
≤1.5 x UNL 
total bilirubin 
≤ 1.5 x ULN 
creatinine 
≤ 1.5 mg/dl 
serum albumin 
≥ 3.0g/dL 
Pulmonary, if sxs or 
known impairment 
DLCOcorr > 50%   
 check if n/a 
Cardiac 
LVEF ≥ 40% 
 
 
8. Women of childbearing potential and men should be advised and agree to practice effective 
methods of contraception during the course of study 
 
 
9. Voluntary written consent  
 
 

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DT2219 Immunotoxin for the Treatment of Relapsed or Refractory CD19 (+) 
and/or CD 22 (+) B-Lineage Leukemia or Lymphoma  
HM2014-26 
Eligibility Checklist – page 2 of 2 
Patient initials   
     
 
EXCLUSION CRITERIA 
A "YES" response to any of the following disqualifies the patient from study entry. 
 
 
Yes      No 
10.  Presence of leukemic or infectious pulmonary parenchymal disease 
 
 
11.  Active CNS leukemia.  
 
 
12.  Presence of any untreated systemic infection 
 
 
13.  Documented seizure disorder or abnormal neurological examination 
 
 
14.  Active neurologic disorder (i.e. weakness, altered mental status) – peripheral neuropathy 
alone does not exclude a patient 
 
 
15.  Active Hepatitis B or Hepatitis C (virus detectable by PCR) 
 
 
16.  Documented penicillin or cephalosporin allergies 
 
 
17.  Pregnant or lactating – Women of child bearing potential must have a negative pregnancy 
test within 14 days of study treatment start 
 
 
 
 
 
Diagnosis if enrolled in Phase II: 
  lymphoma 
  leukemia 
 
 
Having obtained consent and reviewed each of the inclusion/exclusion criteria, I verify that this patient is 
eligible. 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of enrolling investigator 
 
 
 
 
 
 

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Appendix II – Performance Status Criteria 
 
For patients 16 years of age and older: 
Karnofsky Performance Scale 
Percent 
Description 
100 
Normal, no complaints, no evidence of disease. 
90 
Able to carry on normal activity; minor signs or symptoms of disease. 
80 
Normal activity with effort; some signs or symptoms of disease. 
70 
Cares for self, unable to carry on normal activity or to do active work. 
60 
Requires occasional assistance, but is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and frequent medical care. 
40 
Disabled, requires special care and assistance. 
30 
Severely disabled, hospitalization indicated. Death not imminent. 
20 
Very sick, hospitalization indicated. Death not imminent. 
10 
Moribund, fatal processes progressing rapidly. 
0 
Dead. 
 
For patients < 16 years of age: 
Lansky 
Score 
Play Score 
100 
Fully active, normal 
90 
Minor restrictions in physically strenuous activity 
80 
Active, but tires more quickly 
70 
Both greater restriction of and less time spent in play activity 
60 
Up and around, but minimal active play; keeps busy with quieter activities 
50 
Gets dressed but lies around much of the day, no active play but able to 
participate in all quiet play and activities 
40 
Mostly in bed; participates in quiet activities 
30 
In bed; needs assistance even for quiet play 
20 
Often sleeping; play entirely limited to very passive activities 
10 
No play; does not get out of bed 
0 
Unresponsive 
 
 

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Appendix III – Disease Specific Response Criteria 
 
ACUTE LYMPHOCYTIC LEUKEMIA (ALL) RESPONSE CRITERIA 
 
Bone Marrow: 
A1.Maturation of all cell lines: and <5% blasts. 
A2. Same as A1, except blasts ≥ 5% and < 25%. 
A3. Failure to meet the criteria for A1 or A2. 
 
Peripheral Blood:  
B1. Neutrophils > 1,000/mcl; and platelets > 100,000/mcl; and no leukemia blasts in the peripheral blood. 
B2. Failure to meet the criteria for B1. 
 
Extramedullary Disease: 
C1. None 
C2. Any  
 
CR 
Attainment of A1 marrow status and B1 peripheral blood status and C1 extramedullary disease 
status for a period of at least 28 days. 
CRi 
CR with incomplete blood count recovery: Same as CR but platelets ≤ 100,000/mcl and/or 
neutrophils ≤ 1,000/mcl. 
PR 
Partial Response: All of the above criteria for CR must be met, except that the bone marrow may 
contain ≥ 5% but less than 25% blasts,  
or 
≤ 5% blasts with  abnormal morphology 
Failure – 
resistant 
disease 
Resistant Disease: Patient survives ≥ 7 days following completion of initial treatment course with 
persistent leukemia in the last peripheral blood smear or bone marrow, or with persistent 
extramedullary disease. 
Failure – 
aplasia 
Aplasia: Patient survives ≥ 7 days following completion of initial treatment course then dies 
while cytopenic, with the last post-induction bone marrow aplastic or hypoplastic (i.e. < 20% 
cellularity) and without leukemia blasts. 
Failure - 
indeterminate 
Indeterminate:  
(a) Patient survives < 7 days after completion of initial treatment course;  
or 
(b) patient survives ≥ 7 days following completion of initial treatment course then dies with no 
persistent leukemia in the peripheral smear but no post-induction bone marrow examination. 
relapse from 
CR 
Relapse: Reappearance of leukemia blasts in the peripheral blood; or > 5% blasts in the bone 
marrow not attributable to another cause (e.g., recovery of normal cells following chemotherapy-
induced aplasia); or appearance or reappearance of extra-medullary disease. 
 
 
 
 
 

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CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) RESPONSE CRITERIA 
 
Complete Remission 
CR requires all of the following criteria as assessed at least 3 months after completion of therapy: 
• 
Absence of clonal lymphocytes in the peripheral blood. 
• 
Absence of significant lymphadenopathy (e.g., lymph nodes > 1.5 cm in diameter) by physical examination or 
CT scan. 
• 
No hepatomegaly or splenomegaly by physical examination or by CT scan. 
• 
Absence of constitutional symptoms. 
• 
Blood counts above the following values: 
o Polymorphonuclear leukocytes 1.5 x 109/L or more. 
o Platelets more than 100 x 109/L 
o Hemoglobin more than 11.0 g/dL; untransfused. 
A bone marrow aspirate and biopsy should be performed at least 3 months after the last treatment if clinical and 
laboratory results demonstrate a CR. The marrow should be analyzed by flow cytometry and/or 
immunohistochemistry to demonstrate that the marrow is free of clonal B-CLL cells. Cases with residual CLL cells by 
conventional flow cytometry or immunohistochemistry are defined as partial remission (PR). 
 
In some cases, lymphoid nodules can be found (formerly used to define nodular PR), which often reflect residual 
disease. Therefore, these nodules should be assessed by immunohistochemistry to define whether they are comprised 
of CLL cells. 
 
CR with Incomplete Bone Marrow Recovery (CRi) 
For the definition of this category, CRi, the marrow evaluation should be performed with scrutiny and not show any 
clonal infiltrate. 
 
Partial Remission 
PR is defined by at least one of these parameters and needs to be documented for a minimal duration of 2 months: 
• A decrease in the number of blood lymphocytes by less than 50% or more from the value before therapy. 
• A decreased lymph node size by 50% or more in the sum products of up to 6 lymph nodes, or in one lymph node 
diameter if only a single lymph node was present before therapy, as assessed by CT scan. 
• No increase in any lymph node, and no new enlarged lymph node. In small lymph nodes (<2 cm), an increase of 
less than 25% is not considered to be significant. 
• A decrease in the size of the liver and/or spleen by 50% or more as defined by CT scan. 
• The blood count should show one of the following results: 
• 
Polymorphonuclear leukocytes at 1.5 x 109/L or more or 50% improvement over baseline without 
granulocyte colony-stimulating factor (G-CSF) support. 
• 
Platelet counts greater than 100 x 109/L or 50% improvement over baseline. 
• 
Hemoglobin greater than 11.0 g/dL or 50% improvement over baseline without red blood cell transfusions 
or erythropoietin support. 
 
Progressive Disease 
Progressive disease is characterized by at least one of the following: 
• 
Constitutional symptoms persisting for more than 1 month. 
• 
Progression of lymphadenopathy. 
• 
Appearance of any new lesion, such as enlarged lymph nodes (>1.5 cm), splenomegaly, hepatomegaly or 
other organ infiltrates. 
• 
An increase by 50% or more in greatest determined diameter of any previous site. 
• 
A lymph node of 1 to 1.5 cm must increase by 50% or more to a size greater than cm in the longest axis. A 
lymph node of more than 1.5 cm must increase to more than 2.0 cm in the longest axis. 
• 
An increase of 50% or more in the sum of the product of diameters of multiple nodes. 
• 
An increase in the liver or spleen size by 50% or more or the de novo appearance of hepatomegaly or 
splenomegaly. 

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CPRC #2014LS093 
• 
An increase in the number of blood lymphocytes by 50% or more with at least 5000 B lymphocytes per 
microliter. 
• 
Transformation to a more aggressive histology (e.g., Richter syndrome). 
Whenever possible, this diagnosis should be established by lymph node biopsy. 
After treatment: The progression of any cytopenia (unrelated to autoimmune cytopenia), as documented by a 
decrease of Hb levels by more than 2 g/dL or to less than 10 g/dL, or by a decrease of platelet counts by more than 
50% or to less than 100 x 109/L, which occurs at least 3 months after treatment, defines disease progression, if the 
marrow biopsy demonstrates an infiltrate of clonal CLL cells. 
 
Stable Disease 
Patients who have not achieved a CR or a PR, and who have not exhibited progressive disease, will be considered to 
have stable disease. 
 
 

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CPRC #2014LS093 
REVISED RESPONSE CRITERIA FOR MALIGNANT LYMPHOMA [19] 
 
Response 
Definition 
Nodal Masses 
Spleen, Liver 
Bone Marrow 
CR 
Disappearance 
of all evidence 
of disease 
(a) FDG-avid or PET positive prior to 
therapy; mass of any size permitted if PET 
negative (b) Variably FDG-avid or PET 
negative; regression to normal size on CT  
Not palpable, 
nodules disappeared 
Infiltrate cleared on 
repeat biopsy; if 
indeterminate by 
morphology, 
immunohistochemistry 
should be negative 
PR 
Regression of 
measurable 
disease and no 
new sites 
≥ 50% decrease in SPD of up to 6 largest 
dominant masses; no increase in size of 
other nodes (a) FDG-avid or PET positive 
prior to therapy; one or more PET positive 
at previously involved site (b) Variably 
FDG-avid or PET negative; regression on 
CT  
≥ 50% decrease in 
SPD of nodules (for 
single nodule in 
greatest transverse 
diameter); no 
increase in size of 
liver or spleen 
Irrelevant if positive 
prior to therapy; cell 
type should be 
specified 
SD 
Failure to 
attain CR/PR 
or PD 
(a) FDG-avid or PET positive prior to 
therapy; PET positive at prior sites of 
disease and no new sites on CT or PET 
 
 
 
 
(b) Variably FDG-avid or PET negative; 
no change in size of previous lesions on 
CT 
 
 
Relapsed 
disease or 
PD 
Any new lesion 
or increase by 
≥ 50% of 
previously 
involved sites 
from nadir 
Appearance of a new lesion(s) > 1.5 cm in 
any axis, ≥ 50% increase in SPD of more 
than one node, or ≥ 50% increase in 
longest diameter of a previously identified 
node > 1 cm in short axis  
> 50% increase from 
nadir in the SPD of 
any previous lesions 
New or recurrent 
involvement 
 
 
Lesions PET positive if FDG-avid 
lymphoma or PET positive prior to 
therapy 
 
 
Abbreviations: CR, complete remission; FDG, [18F]fluorodeoxyglucose; PET, positron emission tomography; CT, 
computed tomography; PR, partial remission; SPD, sum of the product of the diameters; SD, stable disease; PD, 
progressive disease.  
 

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Appendix IV –Targeted Toxicity Form (CTCAE 4.0)   
See section 9.2 for time points 
Cycle 1 only 
 
 
 
 
 
 
 Patient Initials: _______ Date of Assessment: _________ Assessment Time Point: _________      
Toxicity 
Grade 0 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Hyper-
sensitivity 
reaction 
None 
Mild transient reaction; 
infusion 
interruption not indicated; 
intervention not 
indicated……………… 
Therapy or infusion 
interruption indicated but 
responds promptly to 
symptomatic treatment; 
prophylactic medications 
indicated for ≤24 hrs 
Prolonged (e.g., not rapidly responsive to 
symptomatic medication and/or brief 
interruption of infusion); recurrence of 
symptoms following initial improvement; 
hospitalization indicated for clinical 
sequelae 
Life-threatening and 
urgent intervention 
indicated 
Capillary 
leak 
syndrome 
None 
……………… 
Symptomatic; medical 
intervention indicated 
Severe symptoms; intervention indicated 
Life-threatening 
consequences; urgent 
intervention indicated 
Dyspnea 
None 
Shortness of breath with 
moderate exertion 
Shortness of breath with 
minimal exertion; limiting 
instrumental ADL 
Shortness of breath at rest; 
limiting self care ADL 
Life-threatening 
consequences; urgent 
intervention indicated 
Hypoxia 
None 
……………… 
Decreased O2 saturation 
with exercise (e.g., pulse 
oximeter < 88%) 
intermittent supplemental 
oxygen 
Decreased oxygen saturation at rest (e.g., 
pulse oximeter < 88% or PaO2 ≤ 55 mm 
Hg) 
Life-threatening airway 
compromise; urgent 
intervention indicated  
Fever  
None 
38.0 - 39.0 degrees C 
(100.4 -102.2 degrees F) 
> 39.0 - 40.0 degrees C 
(102.3 - 104.0 degrees 
F) 
> 40.0 degrees C (>104.0 
degrees F) for ≤ 24 hours 
> 40.0 degrees C (>104.0 
degrees F) for > 24 hours 
Chills 
None 
Mild sensation of cold; 
shivering; chattering of 
teeth 
Moderate tremor of the 
entire body; narcotics 
indicated 
Severe or prolonged, not 
responsive to narcotics 
……………… 
Nausea 
None 
Loss of appetite without 
alteration in eating habits 
Oral intake decreased 
without significant weight 
loss, dehydration or 
malnutrition 
Inadequate oral caloric or fluid intake; tube 
feeding, TPN, or hospitalization indicated 
……………… 
Vomiting 
None 
1- 2 episodes (separated 
by 5 minutes) in 24 hours 
3 - 5 episodes 
(separated by 5 minutes) 
in 24 hours 
>=6 episodes (separated by 5 minutes) in 
24 hours; tube feeding, TPN or 
hospitalization indicated 
Life-threatening and 
urgent intervention 
indicated 
Hypotension 
None 
Asymptomatic, 
intervention 
not indicated 
Non-urgent medical 
intervention indicated 
Medical intervention or 
hospitalization indicated 
Life-threatening and 
urgent intervention 
indicated 
Edema 
None 
Localized to dependent 
areas, no disability or 
functional impairment 
Moderate localized 
edema 
and intervention 
indicated; 
limiting instrumental ADL 
Severe localized edema and intervention 
indicated; limiting self care ADL 
……………… 
Rash 
None 
Covering < 10% body 
surface area (BSA) 
Covering 10-30% body 
surface area (BSA) 
>30% body surface area (BSA) 
Generalized exfoliative, 
ulcerative, or bullous 
dermatitis 
Weight Gain 
None  
5 - <10% from baseline  
10 - <20% from baseline  
≥20% from baseline 
……………… 
Record all other adverse events on the AE log eCRF in OnCore 
 Person Completing Form:  
 
 
 
 
 
 
 
ADL = activities of daily living