Conditions: Precursor Cell Lymphoblastic Leukemia-Lymphoma
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 47
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the efficacy of daratumumab in addition to standard chemotherapy in pediatric participants with relapsed/refractory B-cell acute lymphoblastic leukemia (ALL)/lymphoblastic lymphoma (LL) and T-cell ALL/LL as measured by the complete response (CR) rate.

Detailed description:
Screening for eligible participants will be performed within 21 days before administration of the study drug. Participants with B-cell ALL/LL will receive treatment until disease progression, unacceptable toxicity or achievement of CR followed by hematopoietic stem cell transplant (HSCT). Participants with T cell ALL/LL will receive treatment for up to 2 cycles. If disease progression is confirmed, then the participant will discontinue study treatment, complete the End of Treatment Visit, and enter the Posttreatment Period. For those participants who discontinue study drug prior to disease progression, disease evaluations will continue to be performed every 8 weeks until subsequent anticancer therapy is initiated.

Arms:
arm 1: Cohort 1 will include participants with B cell ALL/LL in second or greater relapse or refractory to at least 2 prior induction regimens. Participant will receive daratumumab in combination with vincristine and prednisone. arm 2: Cohort 2 will include participants with T-cell ALL/LL in first relapse or refractory to at least 1 prior induction/consolidation regimen. Participant will receive daratumumab in combination with vincristine, prednisone, doxorubicin and peg-asparaginase in Cycle 1 and daratumumab in combination with cyclophosphamide, cytarabine, 6- mercaptopurine and methotrexate in Cycle 2.

Interventions: intervention 1: Daratumumab intervention 2: Vincristine intervention 3: Prednisone intervention 4: Doxorubicin intervention 5: Peg-asparaginase intervention 6: Cyclophosphamide intervention 7: Cytarabine intervention 8: 6-mercaptopurine intervention 9: Methotrexate
Intervention descriptions: intervention 1: Participant will receive daratumumab 16 milligram per kilogram (mg/kg) in cohort 1 and cohort 2. intervention 2: Participant will receive vincristine 1.5 milligram per meter square (mg/m\^2) in cohort 1 and cohort 2. intervention 3: Participant will receive prednisone 40 mg/m\^2 in cohort 1 and cohort 2. intervention 4: Participant will receive doxorubicin 60 mg/m\^2 in cohort 2. intervention 5: Participant will receive peg-asparaginase 2500 units per meter square (U/m\^2) in cohort 2. intervention 6: Participant will receive cyclophosphamide 1 gram per meter square (g/m\^2) once in cohort 2. intervention 7: Participant will receive cytarabine 75 mg/m\^2 in cohort 2. intervention 8: Participant will receive 6-mercaptopurine 60 mg/m\^2 orally daily in cohort 2. intervention 9: Participant will receive methotrexate 5 g/m\^2 intravenously (IV) in cohort 2.

Protocol document:
Prot_000.pdf: 
1
Status: Approved,  Date: 22 January 2019
Janssen Research & Development *
Clinical Protocol
An Open-label, Multicenter, Phase 2 Study Evaluating the Efficacy and Safety of 
Daratumumab in Pediatric and Young Adult Subjects ≥1 and ≤30 Years of Age With 
Relapsed/Refractory Precursor B-cell or T-cell Acute Lymphoblastic Leukemia or 
Lymphoblastic Lymphoma
Protocol 54767414ALL2005; Phase 2
AMENDMENT 3
JNJ-54767414 (daratumumab)
*Janssen Research & Development is a global organization that operates through different legal entities in 
various countries. Therefore, the legal entity acting as the sponsor for Janssen Research & Development 
studies may vary, such as, but not limited to Janssen Biotech, Inc.; Janssen Products, LP; Janssen 
Biologics, BV; Janssen-Cilag International NV; Janssen Pharmaceutica NV; Janssen, Inc; Janssen 
Sciences Ireland UC; or Janssen Research & Development, LLC. The term “sponsor” is used throughout 
the protocol to represent these various legal entities; the sponsor is identified on the Contact Information 
page that accompanies the protocol. 
This study will be conducted under US Food & Drug Administration IND regulations 
(21 CFR Part 312).
EudraCT NUMBER:  2017-003377-34
Status:
Approved  
Date:
22 January 2019
Prepared by:
Janssen Research & Development, LLC 
EDMS number:
EDMS-ERI-142296624, 5.0
GCP Compliance: This study will be conducted in compliance with Good Clinical Practice, and applicable regulatory 
requirements. 
Confidentiality Statement
The information in this document contains trade secrets and commercial information that are privileged or confidential and 
may not be disclosed unless such disclosure is required by applicable law or regulations. In any event, persons to whom the 
information is disclosed must be informed that the information is privileged or confidential and may not be further disclosed
by them. These restrictions on disclosure will apply equally to all future information supplied to you that is indicated as 
privileged or confidential.


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TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
LIST OF ATTACHMENTS............................................................................................................................ 5
LIST OF IN-TEXT TABLES AND FIGURES................................................................................................ 5
PROTOCOL AMENDMENTS....................................................................................................................... 6
SYNOPSIS.................................................................................................................................................. 21
ABBREVIATIONS ...................................................................................................................................... 32
DEFINITIONS OF TERMS.......................................................................................................................... 33
1.
INTRODUCTION................................................................................................................................ 34
1.1.
Acute Lymphoblastic Leukemia and Lymphoblastic Lymphoma................................................... 34
1.1.1.
Treatment of Acute Lymphoblastic Leukemia and Lymphoblastic Lymphoma .......................... 34
1.2.
Daratumumab for Intravenous Infusion.......................................................................................... 36
1.2.1.
Nonclinical Studies ..................................................................................................................... 37
1.2.2.
Clinical Studies ........................................................................................................................... 39
1.2.2.1.
Monotherapy Studies............................................................................................................... 39
1.2.2.2.
Combination Therapy Studies ................................................................................................. 40
1.2.2.3.
Pharmacokinetics .................................................................................................................... 40
1.3.
Overall Rationale for the Study...................................................................................................... 41
2.
OBJECTIVES, ENDPOINTS, AND HYPOTHESIS........................................................................... 42
2.1.
Objectives and Endpoints .............................................................................................................. 42
2.1.1.
Objectives ................................................................................................................................... 42
2.1.2.
Endpoints.................................................................................................................................... 42
2.2.
Hypothesis ..................................................................................................................................... 43
3.
STUDY DESIGN AND RATIONALE ................................................................................................. 44
3.1.
Overview of Study Design.............................................................................................................. 44
3.2.
Study Design Rationale.................................................................................................................. 45
3.3.
Dose Rationale............................................................................................................................... 47
3.4.
Dose-Limiting Toxicity.................................................................................................................... 47
3.5.
Dose Tolerability Evaluation Guidelines ........................................................................................ 48
4.
SUBJECT POPULATION.................................................................................................................. 50
4.1.
Inclusion Criteria ............................................................................................................................ 50
4.2.
Exclusion Criteria ........................................................................................................................... 52
4.3.
Prohibitions and Restrictions ......................................................................................................... 55
5.
TREATMENT ALLOCATION AND BLINDING................................................................................. 55
6.
DOSAGE AND ADMINISTRATION .................................................................................................. 55
6.1.
Study Drug Administration for Each Cohort................................................................................... 55
6.1.1.
B-cell ALL/LL Cohort................................................................................................................... 55
6.1.2.
T-cell ALL/LL Cohort................................................................................................................... 57
6.1.2.1.
T-cell ALL/LL Cycle 1 .............................................................................................................. 57
6.1.2.2.
T-cell ALL/LL Cycle 2 .............................................................................................................. 58
6.1.3.
Daratumumab Continuation Phase Prior to Transplant.............................................................. 59
6.2.
Daratumumab Preparation and Administration.............................................................................. 60
6.2.1.
Daratumumab Preparation ......................................................................................................... 60
6.2.2.
Daratumumab Administration ..................................................................................................... 60
6.3.
Guidelines for Prevention and Management of Infusion-related Reactions .................................. 61


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6.3.1.
Preinfusion Medications.............................................................................................................. 61
6.3.2.
Postinfusion Medications............................................................................................................ 62
6.3.3.
Management of Infusion-related Reactions................................................................................ 62
6.4.
Delay and Modifications................................................................................................................. 63
6.4.1.
Daratumumab............................................................................................................................. 63
6.4.2.
Intrathecal Methotrexate/Triple Intrathecal Therapy................................................................... 65
6.4.3.
Vincristine ................................................................................................................................... 65
6.4.4.
Glucocorticoid (Prednisone) ....................................................................................................... 66
6.4.5.
Doxorubicin (Anthracycline)........................................................................................................ 66
6.4.6.
Asparaginase (Pegaspargase [PEG-Asparaginase] or Erwinia)................................................ 66
6.4.7.
Cyclophosphamide ..................................................................................................................... 68
6.4.8.
Cytarabine (ARA-C).................................................................................................................... 68
6.4.9.
Mercaptopurine........................................................................................................................... 68
6.4.10.
High-dose Methotrexate (HD MTX)............................................................................................ 68
7.
TREATMENT COMPLIANCE............................................................................................................ 69
8.
PRESTUDY AND CONCOMITANT THERAPY ................................................................................ 69
8.1.
Prestudy Therapy........................................................................................................................... 69
8.2.
Concomitant Therapy..................................................................................................................... 69
8.2.1.
Recommended Concomitant Therapies..................................................................................... 69
8.2.1.1.
Prophylaxis for Tumor Lysis Syndrome................................................................................... 69
8.2.1.2.
Prophylaxis for Infection .......................................................................................................... 70
8.2.1.3.
Prophylaxis for Nausea ........................................................................................................... 70
8.2.1.4.
Prophylaxis for Herpes Zoster Reactivation............................................................................ 70
8.2.1.5.
Prophylaxis for Glucocorticoid-Induced Gastritis..................................................................... 70
8.2.1.6.
Management of Hepatitis B Virus Reactivation....................................................................... 70
8.2.2.
Permitted Concomitant Therapies .............................................................................................. 70
8.2.3.
Prohibited Concomitant Therapies ............................................................................................. 71
9.
STUDY EVALUATIONS .................................................................................................................... 71
9.1.
Study Procedures........................................................................................................................... 71
9.1.1.
Overview..................................................................................................................................... 71
9.1.2.
Screening Period ........................................................................................................................ 71
9.1.3.
Treatment Period........................................................................................................................ 72
9.1.4.
Posttreatment Period (Follow-Up) .............................................................................................. 72
9.2.
Efficacy Evaluations....................................................................................................................... 73
9.2.1.
Response Categories ................................................................................................................. 73
9.2.1.1.
Acute Lymphoblastic Leukemia............................................................................................... 73
9.2.1.2.
Central Nervous System Disease............................................................................................ 74
9.2.1.3.
Mediastinal Mass..................................................................................................................... 74
9.2.1.4.
Lymphoblastic Lymphoma....................................................................................................... 75
9.2.2.
Bone Marrow Evaluation............................................................................................................. 75
9.2.3.
Lumbar Puncture ........................................................................................................................ 77
9.3.
Pharmacokinetics and Immunogenicity ......................................................................................... 78
9.3.1.
Evaluations ................................................................................................................................. 78
9.3.2.
Analytical Procedures................................................................................................................. 78
9.3.3.
Pharmacokinetic Assessments................................................................................................... 78
9.3.4.
Immunogenicity Assessments .................................................................................................... 79
9.3.5.
Pharmacokinetic/Pharmacodynamic Evaluations ...................................................................... 79
9.4.
Biomarkers ..................................................................................................................................... 79
9.5.
Safety Evaluations ......................................................................................................................... 80
9.6.
Sample Collection and Handling.................................................................................................... 83
10.
SUBJECT COMPLETION/DISCONTINUATION OF STUDY TREATMENT/ WITHDRAWAL 
FROM THE STUDY ........................................................................................................................... 83
10.1.
Completion ..................................................................................................................................... 83
10.2.
Discontinuation of Study Treatment/Withdrawal from the Study ................................................... 83


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10.3.
Withdrawal From the Use of Research Samples........................................................................... 84
11.
STATISTICAL METHODS................................................................................................................. 84
11.1.
Subject Information ........................................................................................................................ 85
11.2.
Sample Size Determination ........................................................................................................... 85
11.3.
Efficacy Analyses ........................................................................................................................... 86
11.3.1.
Primary Endpoint ........................................................................................................................ 86
11.3.2.
Secondary Endpoints.................................................................................................................. 86
11.4.
Pharmacokinetic Analyses............................................................................................................. 86
11.5.
Immunogenicity Analyses .............................................................................................................. 87
11.6.
Biomarker Analyses ....................................................................................................................... 87
11.7.
Safety Analyses ............................................................................................................................. 87
11.8.
Safety Evaluation Team................................................................................................................. 88
12.
ADVERSE EVENT REPORTING ...................................................................................................... 89
12.1.
Definitions ...................................................................................................................................... 89
12.1.1.
Adverse Event Definitions and Classifications ........................................................................... 89
12.1.2.
Attribution Definitions.................................................................................................................. 90
12.1.3.
Severity Criteria .......................................................................................................................... 91
12.2.
Special Reporting Situations.......................................................................................................... 91
12.3.
Procedures..................................................................................................................................... 91
12.3.1.
All Adverse Events...................................................................................................................... 91
12.3.2.
Serious Adverse Events ............................................................................................................. 92
12.3.3.
Pregnancy................................................................................................................................... 93
12.4.
Contacting Sponsor Regarding Safety........................................................................................... 94
13.
PRODUCT QUALITY COMPLAINT HANDLING.............................................................................. 94
13.1.
Procedures..................................................................................................................................... 94
13.2.
Contacting Sponsor Regarding Product Quality ............................................................................ 94
14.
STUDY DRUG INFORMATION......................................................................................................... 94
14.1.
Physical Description of Study Drugs.............................................................................................. 94
14.2.
Packaging ...................................................................................................................................... 94
14.3.
Labeling.......................................................................................................................................... 95
14.4.
Preparation, Handling, and Storage............................................................................................... 95
14.5.
Drug Accountability ........................................................................................................................ 95
15.
STUDY-SPECIFIC MATERIALS....................................................................................................... 96
16.
ETHICAL ASPECTS ......................................................................................................................... 96
16.1.
Study-Specific Design Considerations........................................................................................... 96
16.2.
Regulatory Ethics Compliance....................................................................................................... 97
16.2.1.
Investigator Responsibilities ....................................................................................................... 97
16.2.2.
Independent Ethics Committee or Institutional Review Board ................................................... 98
16.2.3.
Informed Consent and Assent Form........................................................................................... 99
16.2.4.
Privacy of Personal Data .......................................................................................................... 100
16.2.5.
Long-Term Retention of Samples for Additional Future Research .......................................... 100
16.2.6.
Country Selection ..................................................................................................................... 101
17.
ADMINISTRATIVE REQUIREMENTS ............................................................................................ 101
17.1.
Protocol Amendments.................................................................................................................. 101
17.2.
Regulatory Documentation .......................................................................................................... 101
17.2.1.
Regulatory Approval/Notification .............................................................................................. 101
17.2.2.
Required Prestudy Documentation........................................................................................... 101
17.3.
Subject Identification, Enrollment, and Screening Logs .............................................................. 102
17.4.
Source Documentation................................................................................................................. 103
17.5.
Case Report Form Completion .................................................................................................... 103
17.6.
Data Quality Assurance/Quality Control ...................................................................................... 104
17.7.
Record Retention ......................................................................................................................... 104


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17.8.
Monitoring .................................................................................................................................... 105
17.9.
Study Completion/Termination..................................................................................................... 105
17.9.1.
Study Completion/End of Study................................................................................................ 105
17.9.2.
Study Termination..................................................................................................................... 105
17.10.
On-Site Audits .............................................................................................................................. 106
17.11.
Use of Information and Publication.............................................................................................. 106
REFERENCES.......................................................................................................................................... 108
INVESTIGATOR AGREEMENT ............................................................................................................... 123
LIST OF ATTACHMENTS
Attachment 1:
Karnofsky and Lansky Performance Status Scales ................................................. 111
Attachment 2:
Conversion Table for Glucocorticoid Dose............................................................... 112
Attachment 3:
Serum Creatinine Guidelines.................................................................................... 113
Attachment 4:
Asthma Guidelines ................................................................................................... 114
Attachment 5:
High-Dose Methotrexate (HD MTX) Infusion Guidelines ......................................... 116
Attachment 6:
The Family of Antihistamine Medications................................................................. 119
Attachment 7:
Estimated Total Blood Volume Collected During the Study..................................... 120
Attachment 8:
Doxorubicin Equivalent Conversion ......................................................................... 122
LIST OF IN-TEXT TABLES AND FIGURES 
TABLES
Table 1:
Time and Events Schedule – Overview.................................................................................... 23
Table 2:
Time and Events Schedule – Detailed Procedures and Study Drug Administration................ 27
Table 3:
Time and Events Schedule –Pharmacokinetics and Immunogenicity...................................... 31
Table 4:
Percent of CD38+ Tumors in Pediatric and Adult Patient ALL Samples.................................. 37
Table 5:
Efficacy of Daratumumab in ALL Cell Lines ............................................................................. 38
Table 6:
Daratumumab Infusion Rates ................................................................................................... 61
Table 7:
Daratumumab-Related Toxicity Management .......................................................................... 64
Table 8:
Local and Central Bone Marrow Evaluations ........................................................................... 76
FIGURES
Figure 1:
Efficacy of Daratumumab in ALL PDX models ......................................................................... 39
Figure 2:
Schematic Overview of the Study............................................................................................. 45


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PROTOCOL AMENDMENTS
Protocol Version 
Issue Date
Original Protocol
11 October 2017
Amendment 1
12 January 2018
Amendment 2
04 September 2018
Amendment 3
22 January 2019
Amendment 3 (22 January 2019)
The overall reason for the amendment: the overall reason for the amendment is in response to identification of a 
new important risk (hepatitis B virus [HBV] reactivation). 
Applicable Section(s)
Description of Change(s)
Rationale: The text for identification of HBV reactivation, testing, and management of subjects with the 
potential for HBV reactivation was added or modified in response to identification of a new important risk (HBV 
reactivation).
Table 1 Time and Events 
Schedule – Overview
Added rows for HBV serology and HBV DNA test, and identified the timepoints at 
which HBV serology and HBV DNA test would be conducted.
4.2 Exclusion Criteria 
(#10.1)
Clarified language to exclude subjects who are seropositive for HBV. 
8.2.1.6 Management of 
Hepatitis B Virus 
Reactivation
Added a new section providing information for the management of HBV
reactivation.
9.1.1 Overview; 
Attachment 7 Estimated 
Total Blood Volume 
Collected During the Study
Corrected the maximum blood volume to be collected during the Screening Visit to 
approximately 17 mL, thus accounting for HBV serology.
9.5 Safety Evaluations
Added information detailing the conduct of HBV serology and DNA tests.
Rationale: Clarified timepoints and procedures.
Table 1 Time and Events 
Schedule – Overview
Clarified that disease evaluations have a visit window of +7 days. 
Table 2 Time and Events 
Schedule – Detailed 
Procedures and Study 
Drug Administration; 6.1.3 
Daratumumab 
Continuation Phase Prior 
to Transplant
Clarified timepoints for daratumumab administration and CBC assessment in the 
optional daratumumab continuation phase prior to transplant.
6.1.1 B-cell ALL/LL 
Cohort; 6.1.2 T-cell 
ALL/LL Cohort
Clarified that on daratumumab dosing days, methylprednisolone 2 mg/kg 
(maximum 100 mg) pre-infusion medication should be substituted for prednisone 
40 mg/m2.
Rationale: Clarified that the primary and secondary endpoints will be analyzed for the pediatric ALL 
population only. Subjects aged 18 to 30 years of age and subjects with LL will not be included in the analyses of 
the primary/secondary endpoints for this study; rather, the data gathered will be summarized descriptively.  
Synopsis; 2.1.1 
Objectives; 2.1.2 
Endpoints
Clarified that the primary and secondary endpoints will be analyzed for the 
pediatric ALL population only.


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Applicable Section(s)
Description of Change(s)
Rationale: Clarified inclusion and exclusion criteria. 
4.1 Inclusion Criteria 
(#5.2)
Corrected inadvertent omission of greater than or equal to sign (≥) in inclusion 
criterion regarding renal function.
4.2 Exclusion Criteria 
(#18.2)
Correction per French country-specific amendment:
Subject is not affiliated to, or a beneficiary of, a social security category, per local 
regulatory requirements, if applicable.
4.2 Exclusion Criteria 
(New #19)
Added text:
Subjects with infant leukemia (defined as under 1 year old at the time of initial 
diagnosis). These subjects will not be eligible for this study, even if they are 
greater than 1 year old at the time of relapse.
Rationale: Clarified criteria for disease response and progression categories. 
9.2.1.1 Acute 
Lymphoblastic Leukemia
Revised text:
Refractory disease: failure to achieve CR at end of induction therapy and does 
not meet criteria for progressive disease
Rationale: Clarified requirements for local vs. central bone marrow evaluation.
9.2.2 Bone Marrow 
Evaluation
Revised text:
Bone marrow aspirate is required for central bone marrow evaluations; bone 
marrow biopsy is not acceptable for central testing.  If the aspirate procedure 
is deemed inadequate, biopsy is required for local testing.
Rationale: Minor errors were noted.
Throughout the protocol
Minor grammatical, formatting, or spelling changes were made.


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Amendment 2 (04 September 2018)
The overall reason for the amendment: To incorporate changes from country-specific amendments and to provide 
additional details and clarifications regarding study procedures.
Applicable Section(s)
Description of Change(s)
Rationale: Clarified the population in which objectives and endpoints will be assessed.
Synopsis; 2.1.1 Objectives; 
2.1.2 Endpoints
Clarified that secondary objectives and endpoints regarding efficacy, safety, PK, 
and immunogenicity will be assessed in subjects with ALL only. Clarified that 
efficacy and safety of daratumumab in combination with standard chemotherapy 
will be assessed.
11.3.1 Primary Endpoint
For subjects 1 to <18 years of age, the number and percentage of subjects who 
achieve a CR including 90% exact CI will be calculated for each cohort. The exact
p-value to test the hypothesis, H0: CR rate ≤15% in the B cell ALL cohort and H0: 
CR rate ≤30% in the T-cell ALL cohort, will also be calculated.
Rationale: Clarified requirements for screening procedures.
Table 1 (Time and Events 
Schedule – Overview); 
9.1.2 Screening Period
Clarified that results from standard of care procedures obtained within 21 days 
before Cycle 1 Day 1 may be used without these tests being repeated.
Rationale: Provided a visit window for the End-of-Treatment Visit.
Table 1 (Time and Events 
Schedule – Overview); 
9.1.3 Treatment Period
It was clarified that the End-of-Treatment Visit is to occur 30 days (+7 days) after 
last dose.
Rationale: Revised the timing of follow-up procedures.
Table 1 (Time and Events 
Schedule – Overview); 
9.1.4 Posttreatment Period 
(Follow-Up)
It was clarified that for all subjects who discontinue study drug prior to CR or PD, 
disease evaluations will continue every 8 weeks until CR, PD, subsequent 
anticancer therapy is initiated, or study completion. After CR or PD, follow up will 
occur every 12 weeks to record information on subsequent anticancer therapy, 
second primary malignancies, documentation of progressive disease or relapsed 
disease, and survival status. 
For all subjects proceeding to transplant, the following information will be 
collected and documented in the eCRF: date of transplant, type of transplant, time 
to engraftment, and any graft failures. In addition, any maintenance chemotherapy 
given after discontinuation of study treatment and prior to transplant must be 
documented in the eCRF.
Rationale: Clarified the procedures and timing of disease evaluations and laboratory assessments. 
Table 1 (Time and Events 
Schedule – Overview); 
9.2.1 Response Categories
Added a window of ±7 days for all disease evaluations. Clarified that if disease 
evaluations are delayed, treatment should also be delayed.
Table 1 (Time and Events 
Schedule – Overview); 
9.2.3 Lumbar Puncture; 
9.5 Safety Evaluations
Clarified that cerebrospinal fluid will be used for cytology evaluations for 
lymphoblasts as well as RBC and WBC counts, and that methods may include 
cytospin or flow cytometry.


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Applicable Section(s)
Description of Change(s)
Table 1 (Time and Events 
Schedule – Overview); 
Attachment 7: Estimated 
Total Blood Volume 
Collected During the Study
Clarified that for subjects with B-cell ALL/LL who are Ph+, blood will be collected 
on Day 1 of Cycles 1 and 2, and then on Day 28 of every other cycle from Cycle 4 
until complete response or progressive disease. Clarified that this evaluation is not 
required for subjects with T-cell ALL/LL.
Table 1 (Time and Events 
Schedule – Overview)
Clarified that bone marrow aspirate/biopsy is to be collected for subjects with 
B-cell ALL/LL on Day 28 of every other cycle from Cycle 4 until complete 
response or progressive disease. 
Table 1 (Time and Events
Schedule – Overview); 
9.2 Efficacy Evaluations;
9.2.1.3 Mediastinal Mass
Clarified the following regarding chest and abdomen/pelvis CT or MRI:

Chest scans can include either CT or MRI.

Chest CT or MRI is required for subjects with ALL with mediastinal mass and 
all subjects with LL during screening. Screening chest CT or MRI may be 
delayed until the subject is stable.

Abdomen/pelvis CT or MRI is only required for subjects with LL at screening 
and on treatment if positive at screening and the subject has not yet achieved 
CR. 

The same imaging modality performed at screening should be used during the 
treatment period as indicated.
Table 1 (Time and Events 
Schedule – Overview); 
9.2 Efficacy Evaluations; 
9.2.1.3 Mediastinal Mass; 
9.2.1.4 Lymphoblastic 
Lymphoma
Removed the optional PET or gallium scans from the planned procedures.
Table 1 (Time and Events 
Schedule – Overview)
Added collection of hematology and chemistry samples at the End-of-Treatment 
Visit, and hematology samples during follow-up prior to progressive disease. It was 
also clarified that at screening, serum chemistry should be performed prior to IT 
methotrexate treatment.
Rationale: Clarified procedures for the evaluation of vital signs.
Table 2 (Time and Events 
Schedule – Detailed 
Procedures and Study 
Drug Administration); 
9.5 Safety Evaluations; 
11.7 Safety Analyses
Removed vital signs assessment on Day 28 of Cycles 1 and 2. Added respiration 
rate to vital signs. Clarified that statistical evaluations of vital signs will include 
only post baseline changes.


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Applicable Section(s)
Description of Change(s)
Rationale: Clarified procedures for administration of study drugs.
Table 2 (Time and Events 
Schedule – Detailed 
Procedures and Study 
Drug Administration); 
6.1.1 B-cell ALL/LL 
Cohort; 6.1.2 T-cell 
ALL/LL Cohort; 6.1.2.1 
T-cell ALL/LL Cycle 1; 
6.1.2.2 T-cell ALL/LL 
Cycle 2; 
6.1.3 Daratumumab 
Continuation Phase Prior 
to Transplant
Clarified that the order of administration of study medications may vary and that a 
window of ±1 day is allowed in order to meet local requirements. However, on 
daratumumab dosing days, IT therapy should be given first, then daratumumab 
should be administered prior to any other study drugs. Routine transfusions should 
be avoided on daratumumab dosing days.
Clarified that for both B-cell and T-cell ALL/LL, acceptable substitutes for IT 
MTX include both IT ARA-C and triple IT therapy. Removed statement regarding 
skipping the IT MTX dose if IT therapy was given within 7 days of Cycle 1 Day 1 
as part of previous therapy.
Clarified that Erwinia asparaginase may be substituted for peg-asparaginase. 
Added allowance for prednisone taper as clinically indicated per local standard 
practice. 
Clarified that for subjects with T-cell ALL/LL, Cycle 2 Day 15 therapy should be 
held until ANC is >0.75x109/L and platelets are >75x109/L.
Clarified procedures for both cohorts for the optional daratumumab continuation 
phase prior to transplant. If daratumumab is given post completion of Cycles 2 to 4, 
administration of drug and CBC should be done on Day 1 and Day 15. If 
daratumumab is given post completion of Cycle 5+, administration of drug and 
CBC should be done on Day 1 only. A maximum of 1 cycle of continuation therapy 
is allowed prior to transplant. 
Rationale: Clarified guidelines regarding DLT evaluation.
3.4 Dose-Limiting 
Toxicity
During the safety run-in, 3 subjects in each cohort will be evaluated for dose-
limiting toxicities (DLTs). A Safety Evaluation Team (SET) (see Section 11.8) will 
review the DLT data and determine whether a modification to the dose or schedule 
of study drugs is needed for any of the treatment cohorts. The DLT Evaluation 
Period is defined as the first 28 days from the start of the first dose of 
daratumumab. If a subject receives any amount of daratumumab during the DLT 
evaluation period, they will be considered evaluable for DLT. DLTs will be 
evaluated in each cohort separately at the end of Cycle 1. Only toxicities that occur 
during the DLT evaluation period will be used for the purpose of defining DLT and 
for subsequent dose or dosing schedule modifications or safety-run in expansion. 
However, toxicities that occur in all cycles will be considered in the overall 
decisions of the SET. If a subject receives less than 75% of the planned dose of 
daratumumab for reasons other than toxicity (eg, disease progression, subject 
withdrawal, etc.), that subject will be considered non-evaluable for DLTs and may 
be replaced, but the safety profiles of these subjects will be included in the SET 
review. Additional safety reviews will be conducted by the SET after Stage 1 of the 
study in each cohort and as deemed necessary during the conduct of the study. 
If 1 or more subjects in a cohort experience a DLT, then the safety run in for that 
cohort will be expanded to 6 subjects. After the additional 3 subjects complete 1 
cycle of therapy, safety will be re evaluated. If 2/6 or more subjects experience a 
DLT, the dose or schedule of study drugs may be adjusted in the remaining 
treatment cycles, and an additional 3 subjects may be treated at a lower dose or 
adjusted schedule for a given combination regimen. A new safety evaluation will 
begin with 3 new subjects with the adjusted dosing regimen and will follow the 
guidelines noted below.


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The following DLT guidelines will apply to each cohort separately:

If DLT is not observed in the initial 3 subjects treated with 16 mg/kg of 
daratumumab for a given combination regimen, then that combination regimen 
will be considered safe and well tolerated and the cohort may continue to 
enroll to pre-specified numbers.

If DLT is observed in ≥33% 1 of the initial 3 subjects, then the safety-run in 
will be expanded to 6 subjects. 
o
If 1/6 subjects treated with 16 mg/kg of daratumumab for a given 
combination regimen experience a DLT, then that combination regimen 
will be considered safe and well tolerated and the cohort may continue 
to enroll to pre-specified numbers.
o
If ≥2/6 subjects experience a DLT, then that combination regimen will be 
considered not safe unless the events are due to unexpected circumstances 
clearly not related to a study procedure or treatment (eg, a passenger in an 
automobile accident). The dose or schedule of study drugs may be 
adjusted and a new safety run-in may begin or the cohort may be 
closed. in the remaining treatment cycles, and an additional 3 Three new
subjects may be treated at a lower dose or adjusted schedule for a given 
combination regimen. If no further toxicities are observed, then the study 
may continue to enroll to pre specified numbers. The safety run-in will 
follow the rules above.

If DLT is observed in ≥2 of the initial 3 subjects, then that combination 
regimen will be considered not safe unless the events are due to 
unexpected circumstances clearly not related to a study procedure or 
treatment (eg, a passenger in an automobile accident). The dose or 
schedule of study drugs may be adjusted and a new safety run-in may 
begin or the cohort may be closed. Three new subjects may be treated at a 
lower dose or adjusted schedule for a given combination regimen. The 
safety run-in will follow the rules above.
Rationale: Clarified that for Cohort 2 (the T-cell cohort) only, certain non-hematologic Grade 4 toxicities are not 
considered DLTs.
3.5 Dose Tolerability 
Evaluation Guidelines

Non-hematologic toxicity of Grade 4 that occurs after the first dose of 
daratumumab and is considered related to daratumumab with the following 
exceptions for Cohort 2 only:
o
Fever or infection
o
Gastrointestinal symptoms (anorexia, vomiting, dehydration, mucositis)
o
Hypofibrinogenemia
o
Metabolic/laboratory abnormalities that resolve to ≤Grade 2 within 7 
days
o
Tumor lysis syndrome or hyperuricemia
Rationale: Clarified entry criteria regarding renal and liver function.
4.1 Inclusion Criteria (#5.1 
and #6.2)
Clarified that adequate renal and liver function are required prior to enrollment 
rather than on Cycle 1 Day 1.
4.2 Exclusion Criteria
If a subject's clinical status changes (including any available laboratory results or 
receipt of additional medical records) after screening but before the first dose of 
study drug is given such that he or she no longer meets all eligibility criteria, then 
the subject should be excluded from participation in the study, with the exception 
of subjects who meet screening liver function criteria but have elevation of 
liver function tests (≤Grade 3) on Cycle 1 Day 1 after IT methotrexate.


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Description of Change(s)
Rationale: Clarified definition of female subjects of childbearing potential. Clarified requirements for sexual 
abstinence to be considered an acceptable method of birth control. Extended the posttreatment contraception 
duration requirements for female subjects, as well as the time period when female subjects must agree not to 
donate eggs, to 12 months after the last administration of any component of the treatment regimen.
4.1 Inclusion Criteria 
(#7.1)
Female subjects of reproductive
childbearing
potential (defined
as a
post-menarchal and sexually active female who is sexually active prior to 
initiation of the study or during the study should reproductive potential change 
during the study until becoming post-menopausal unless permanently sterile) 
must commit either to abstain continuously from heterosexual sexual intercourse or 
to use 2 methods of reliable birth control simultaneously during the Treatment 
Period, during any dose interruptions, and for 6 12 months after the last dose of any 
component of the treatment regimen. Permanent sterilization methods include 
hysterectomy, bilateral salpingectomy and bilateral oophorectomy. Sexual 
abstinence is considered a highly effective method only if defined as refraining 
from heterosexual intercourse during the entire period of risk associated with the 
study drug. The reliability of sexual abstinence needs to be evaluated in 
relation to the duration of the study and the preferred and usual lifestyle of 
the subject. Birth control methods must include one highly effective method of 
contraception (tubal ligation, intrauterine device, hormonal [birth control pills, 
injections, hormonal patches, vaginal rings or implants], or partner’s vasectomy) 
and one additional effective contraceptive method (male latex or synthetic condom, 
diaphragm, or cervical cap). Contraception must begin 4 weeks prior to dosing. 
Reliable contraception is indicated even where there has been a history of 
infertility, unless due to hysterectomy.
4.1 Inclusion Criteria 
(#8.1)
During the study and for 6 12 months after receiving the last dose of any 
component of the treatment regimen, female subjects must agree not to donate eggs 
(ova, oocytes) for the purposes of assisted reproduction.
4.2 Exclusion Criteria 
(#14.1)
Pregnant, breastfeeding, or planning to become pregnant while enrolled in this 
study or within 6 12 months after the last dose of any component of the treatment 
regimen.
Rationale: Clarified exclusion criteria regarding prior cancer immunotherapy.
4.2 Exclusion Criteria 
(#8.1)
Prior cancer immunotherapy (ie, CAR-T, inotuzumab) within 4 weeks prior to start 
of daratumumab treatment enrollment or blinatumomab within 2 weeks prior to 
the start of daratumumab treatment enrollment.   
Rationale: Clarified exclusion criteria regarding prior anthracycline exposure.
4.2 Exclusion Criteria 
(#9.1)
For subjects with T-cell ALL/LL only: prior cumulative anthracycline exposure 
must not exceed 400 mg/m2 of doxorubicin or equivalent (each 10 mg/m2 of 
idarubicin should be calculated as the equivalent of 30 mg/m2 of doxorubicin see 
Attachment 8 for conversion).
New Attachment 8: 
Doxorubicin Equivalent 
Conversion; References

Daunorubicin: multiply total dose in m2 x 1

Mitoxantrone: multiply total dose in m2 x 4

Idarubicin: multiply total dose in m2 x 5

Epirubicin: multiply total dose in m2 x 0.67
For doses in mg/kg, first multiply dose x 30 for mg/m2 then apply conversion 
above.
Source: Feijen 2015


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Rationale: Clarified that exclusion due to known allergies to certain treatments applies only to subjects with T-
cell ALL/LL.
4.2 Exclusion Criteria 
(#12.1)
Known allergies, hypersensitivity, or intolerance to mannitol, glucocorticoid, 
doxorubicin, 
cytarabine,
methotrexate, 
vincristine, 
cyclophosphamide, 
6 merceaptopurine, mAb (IRR is not considered hypersensitivity) or human 
proteins, or their excipients (refer to respective package inserts and Investigator’s 
Brochure), or known sensitivity to mammalian-derived products.  For subjects 
with T-cell ALL/LL only, known allergies to doxorubicin, cytarabine, 
cyclophosphamide, or 6-mercaptopurine.
Rationale: Revised exclusion criteria to include an affiliation to a social security system.
4.2 Exclusion Criteria 
(#18.1)
Added the following requirement for exclusion from the study: Subject is affiliated 
to, or a beneficiary of, a social security category, per local regulatory requirements, 
if applicable.
Rationale: Clarified options for daratumumab continuation phase.
6.1.3 Daratumumab 
Continuation Phase Prior 
to Transplant
Clarified that other standard maintenance chemotherapy may also be given after 
the discontinuation of study treatment and prior to transplant, at the discretion of 
the investigator. All maintenance therapy must be documented in the eCRF.
Rationale: Increased the dose of preinfusion paracetamol in an effort to prevent IRRs.
6.3.1 Preinfusion 
Medications
Increased the dose of preinfusion paracetamol from 650 mg to 1000 mg PO.
Rationale: Revised the instructions for the management of IRRs for consistency with other daratumumab study 
protocols.
6.3.3 Management of 
Infusion-related Reactions
Subjects should be observed carefully during daratumumab infusions. Trained 
study staff at the clinic should be prepared to intervene in case of an infusion 
reaction any IRRs, and resources necessary for resuscitation (eg, agents such as 
epinephrine and aerosolized bronchodilator, also medical equipment such as 
oxygen tanks, tracheostomy equipment, and a defibrillator) must be available 
at the bedside. Attention to staffing should be considered when multiple subjects 
will be dosed at the same time. 
For infusion related reactions of any grade/severity, immediately interrupt the 
daratumumab infusion and manage symptoms. Management of infusion reactions 
may further require reduction in the rate of infusion, or treatment discontinuation 
of daratumumab.
If an IRR develops, then daratumumab administration should be temporarily 
interrupted. Please see the IPPI for further details. Subjects who experience 
adverse events during daratumumab administration must be treated for their 
symptoms. Subjects should be treated with acetaminophen, antihistamine, or 
corticosteroids, as needed. Intravenous saline may be indicated. For 
bronchospasm, urticaria, or dyspnea, subjects may require antihistamines, 
oxygen, corticosteroids, or bronchodilators. For hypotension, subjects may 
require vasopressors. In the event of a life-threatening IRR (which may 
include pulmonary or cardiac events) or anaphylactic reaction, daratumumab 
should be discontinued and no additional daratumumab should be 
administered to the subject.

Grade 1-2 (mild to moderate) IRRs:  Once reaction symptoms resolve, resume 
the infusion at no more than half the rate at which the reaction occurred. If the 
subject does not experience any further reaction symptoms, infusion rate 
escalation may resume at increments and intervals as appropriate as outlined 
in Table 6. If the investigator assesses a Grade 1-2 IRR adverse event to be 


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related to administration of study drug, then the daratumumab 
administration should be paused. When the subject's condition is stable, 
daratumumab administration may be restarted at half of the rate at the 
investigator's discretion.
If the subject experiences a Grade 2 or higher event of laryngeal edema, 
or a Grade 2 or higher event of bronchospasm that does not respond to 
systemic therapy and does not resolve within 6 hours from onset, then the 
subject must be permanently discontinued from daratumumab 
treatment.

Grade 3 (severe) or higher IRRs: Once reaction symptoms resolve, consider 
restarting the infusion at no more than half the rate at which the reaction 
occurred. If the subject does not experience additional symptoms, resume 
infusion rate escalation at increments and intervals as outlined in Table 6. 
Repeat the procedure above in the event of recurrence of Grade 3 symptoms. 
Permanently discontinue daratumumab upon the third occurrence of a Grade 3 
or greater infusion related reaction. For IRR adverse events (other than 
laryngeal edema or bronchospasm) that are Grade 3, the daratumumab 
administration must be stopped and the subject must be observed 
carefully until resolution of the adverse event or until the intensity of the 
event decreases to Grade 1, at which point the daratumumab 
administration may be restarted at half of the rate at the investigator’s 
discretion. If the intensity of the adverse event returns to Grade 3 after 
restart of the daratumumab administration, then the subject must be 
withdrawn from daratumumab treatment. For IRR adverse events that 
are Grade 4, the daratumumab administration must be stopped and the 
subject withdrawn from daratumumab treatment.

Grade 4 (life threatening): Permanently discontinue daratumumab treatment.

Recurrent IRRs: If a Grade 3 IRR (or ≥Grade 2 event of laryngeal edema 
or bronchospasm) recurs during or within 24 hours after a subsequent 
daratumumab administration, the daratumumab treatment must be 
discontinued.
Rationale: Clarified procedures for daratumumab dose delays.
6.4.1 Daratumumab
Only if any of the following criteria are met and the event cannot be ascribed to 
components of the chemotherapy regimen or if the causality is unclear, then the 
daratumumab infusion must be held to allow for recovery from toxicity.
If daratumumab administration does not commence within the prespecified 
window (Table 2 Table 7) of the scheduled administration date, then the dose will 
be considered a missed dose. Administration may resume at the next planned 
dosing date. A missed dose will not be made up.
Table 7: Daratumumab-Related Toxicity Management
Cycles Frequency
Dose Missed
Dosing Resumption
1-2
Weekly
>3 days
next planned weekly dosing date
3-6
Every 2 weeks
>7 days
next planned every-2-weeks dosing date
7+
Every 4 weeks
>14 days
next planned every-4-weeks dosing date
If Day 1 of a cycle is delayed, then Day 1 of subsequent cycles should be adjusted 
accordingly to maintain the cycle duration. However, if a within-cycle dose is 
delayed, then the dates of the subsequent within-cycle doses should not be 
adjusted. If a dose delay occurs, then PK assessments should be performed on 
the actual administration day of daratumumab, not on the original scheduled 
administration day. A daratumumab dose that is held for more than the permitted 


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time (Table 2) from the per protocol administration date for any reason other than 
toxicities suspected to be related to daratumumab should be brought to the attention 
of the Sponsor at the earliest possible time.
For Cohort 1 (B cell cohort): any Any adverse event deemed to be related to 
daratumumab that requires a dose hold of more than 4 weeks (Cycle 1 to Cycle 6) 
or more than 6 weeks (Cycle 7 and beyond) will result in permanent 
discontinuation of daratumumab, unless, upon consultation with the sponsor and 
the review of safety and efficacy, continuation is agreed upon. If a dose delay 
occurs, then PK assessments should be performed on the actual administration day 
of daratumumab, not on the original scheduled administration day.
Rationale: Updated recommendations for prophylaxis of herpes zoster reactivation in accordance with 
daratumumab prescribing information.
8.2.1.4 Prophylaxis for 
Herpes Zoster Reactivation
Prophylaxis for herpes simplex/zoster reactivation is recommended during the 
Treatment Period, in accordance with as per institutional guidelines, and for 
3 months following treatment.
Rationale: Revised the list of permitted concomitant therapies.
8.2.2 Permitted 
Concomitant Therapies

Antivirals

Prevention of constipation (eg, adequate hydration, high-fiber diet, and stool 
softeners if needed)

Prophylactic antiemetics, with the exception of glucocorticoids and 
aprepitant/fosaprepitant

Colony stimulating factors, erythropoietin, and transfusion of platelets and 
red blood cells; except routine transfusions should not be given on 
daratumumab dosing days

Loperamide is recommended for the treatment of diarrhea, starting at the time 
of the first watery stool. The loperamide dose and regimen is according to 
institutional guidelines. Prophylactic loperamide is not recommended
Rationale: Expanded the list of prohibited concomitant therapies.
8.2.3 Prohibited 
Concomitant Therapies
Concomitant administration of the following therapies is prohibited during 
the study:

Concomitant administration of Any antineoplastic therapy for the intention of 
treating ALL or LL is prohibited, including conventional chemotherapy 
agents, investigational agents, and approved or investigational medications 
that target CD38 

Aprepitant/fosaprepitant

Strong CYP3A4 and P glycoprotein inhibitors, such as ketoconazole or 
itraconazole, is prohibited. For an ongoing list of CYP3A inhibitors and 
inducers, see http://medicine iupui.edu/flockhart/  

Live vaccines during the study and for 3 months after the last dose of 
vincristine 
The sponsor must be notified in advance (or as soon as possible thereafter) of any 
instances in which prohibited therapies are administered.
8.2.1.3 Prophylaxis for 
Nausea
Subjects should be given antiemetics during each chemotherapy course 
individualized to the subject’s best response. However, glucocorticoids and 
aprepitant/fosaprepitant should not be used as antiemetics.


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Rationale: Clarified the definition of “MRD negative.”
9.2.1.1 Acute 
Lymphoblastic Leukemia
MRD negative is defined as <0.01% abnormal population counts to total event 
counts nucleated mononuclear cells when measured by flow.
Rationale: Clarified the definition of CNS relapse and added guidelines for discontinuation.
9.2.1.2 Central Nervous 
System Disease
Relapse: development of new M3 CNS status or development of new symptoms of 
CNS leukemia
Subjects with M2 or M3 CNS status who do not improve to M1 CNS status 
after 1 cycle of treatment should permanently discontinue all study treatment.
Rationale: Provided additional details on the procedures for local and central bone marrow evaluations.
9.2.2 Bone Marrow 
Evaluation
Fresh bone marrow aspirate will be collected according to the Time and Events 
Schedule (Table 1 and Table 2). Local and central bone marrow evaluations will 
be performed as described in Table 8. Bone marrow at screening will be 
evaluated locally for morphology and cytogenetic analysis and centrally for MRD. 
During treatment, bone marrow aspirate will be collected as per the Time and 
Events Schedule for both local morphology to evaluate clinical response and 
central testing for MRD assessment as well as biomarkers predictive of clinical 
response. If the aspirate procedure is deemed inadequate, biopsy is required. 
Added the following table:
Table 8: Local and Central Bone Marrow Evaluations
Timepoint
Local Testing
Central Testing
Screening
Disease characterization

Morphology (evaluate percentage 
of tumorous leukemia/lymphoma 
cells and cellularity)

Immunohistochemistry, 
immunofluorescence, or flow 
cytometry (evaluate presence of 
tumorous leukemia/lymphoma 
cells present by 
immunophenotyping and indicate 
probes used for 
immunophenotyping)
Cytogenetics

Either by FISH or conventional 
karyotype
MRD: a portion of fresh bone 
marrow aspirate collected at 
Screening will be sent to a central 
laboratory for assessment of MRD 
by flow cytometry and PCR
Biomarkers: baseline assessment 
of biomarkers predictive of clinical 
response or resistance to therapy
Disease 
evaluations prior 
to PD or CR, and 
prior to start of 
subsequent 
anticancer 
therapya
Disease characterization

Morphology (evaluate percentage 
of tumorous leukemia/lymphoma 
cells and cellularity)
MRD: a portion of fresh bone 
marrow aspirate collected at each 
disease evaluation time point will 
be sent to a central laboratory
Biomarkers: assessment of 
biomarkers predictive of clinical 
response or resistance to therapy
End of Treatment 
(if feasible)
Disease characterization

Morphology (evaluate percentage 
of tumorous leukemia/lymphoma 
cells and cellularity)
MRD: a portion of fresh bone 
marrow aspirate collected will be 
sent to a central laboratory
Biomarkers: assessment of 
biomarkers predictive of clinical 
response or resistance to therapy
Abbreviations: CR=complete response; FISH=fluorescence in situ hybridization; 
LL=lymphoblastic lymphoma; MRD=minimal residual disease; PCR=polymerase chain 
reaction; PD=progressive disease. 
a.
For subjects with LL, on-treatment bone marrow evaluations are only required if bone 
marrow disease is present at Screening.


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Applicable Section(s)
Description of Change(s)
Rationale: Revised instructions for hematology and chemistry evaluations.
9.5 Safety Evaluations
Added instructions that if WBC is too low for automated assessment, a manual 
differential should be performed to document absolute lymphocyte count, absolute 
neutrophil count, and peripheral blast count. Clarified that the serum chemistry 
panel includes amylase or lipase.
Rationale: Added reasons for discontinuation for consistency with other sections of the protocol and for 
consistency with other daratumumab study protocols.
10.2 Discontinuation of 
Study Treatment/
Withdrawal from the 
Study; 9.1.3 Treatment 
Period; Synopsis 
A subject's study treatment must be discontinued for any of the following reasons:

The investigator believes that for safety reasons or tolerability reasons 
(eg, adverse event) it is in the best interest of the subject to discontinue study 
treatment

The subject becomes pregnant, unless the subject (or the subject's legally 
acceptable representative), investigator, and sponsor agree the benefits 
outweigh the risks to the fetus and continuation of study treatment is in the 
best interest of the subject

Progression of disease or relapse as defined in Section 9.2.1

Subjects with CNS M2 or CNS M3 status at baseline who do not achieve 
CNS M1 status (ie, 2 successive negative CSF evaluations) after 
completion of Cycle 1

Withdrawal of consent

Subject initiates treatment with any prohibited medication

Subject experiences unacceptable toxicity, including IRRs, as described 
in Section 6.3.3

Subject’s daratumumab dose is held for more than 4 weeks due to a 
daratumumab-related toxicity as described in Section 6.4.1 (unless 
sponsor approves continuation)

Subject experiences a second primary malignancy that cannot be treated 
by surgery or radiotherapy alone

Subjects who achieve CR and proceed to allogeneic HSCT
If a subject discontinues study treatment for any reason before the end of the 
treatment period, end-of-treatment and posttreatment assessments should be 
obtained.
Rationale: Updated the study population definitions for consistency with the Statistical Analysis Plan.
11.1 Subject Information
The study analysis populations are defined as follows:

All enrolled population All treated population:  all enrolled subjects who 
receive any study treatment. This population will be used for efficacy and 
safety analyses. All subjects in the all treated analysis population will be 
analyzed according to the treatment that they actually received.

Response evaluable population: all enrolled treated subjects who receive 
daratumumab and have at least 1 adequate postbaseline disease assessment. 
Sensitivity analyses of CR rate and ORR will be based on the response 
evaluable population.

PK evaluable population: all enrolled
treated subjects who receive 
daratumumab and
provide at least one postinfusion sample. All PK 
parameters will be analyzed based on the PK evaluable population.
Rationale: Clarified that backbone treatment is not to be documented on the drug accountability form as these 
treatments are commercially available.
14.5 Drug Accountability
The backbone treatment administered to the subject must be documented on the 
drug accountability form.


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Applicable Section(s)
Description of Change(s)
Rationale: Added the Cockcroft-Gault formula for eGFR.
Attachment 3: Serum 
Creatinine Guidelines
Added the Cockcroft-Gault formula.
Rationale: Updated infusion guidelines for HD MTX to include options to follow local standards.
Attachment 5: High-Dose 
Methotrexate (HD MTX) 
Infusion Guidelines
Clarified that all guidelines for HD MTX are a recommendation and that local 
standards may be followed as an alternative.
Updated infusion guidelines for HD MTX to include options for administration of 
mannitol if urine output fails to continue at 80% of the fluid intake.
Rationale: Minor errors were noted.
Throughout the protocol
Minor grammatical, formatting, or spelling changes were made.


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Amendment 1 12 January 2018
The overall reason for the amendment: The overall reason for the amendment is to clarify procedures to be 
conducted during the follow-up period and to add the collection of relevant information from subjects who 
proceed to posttreatment, off-study bone marrow transplantation. 
Applicable Section(s)
Description of Change(s)
Rationale: Procedures to be conducted during the follow-up period and optional continuation phase were 
clarified. The collection of data related to posttreatment off-study bone marrow transplantation was added.
Table 1 (Time and 
Events Schedule –
Overview)
It was clarified that after EoT, subjects without PD will continue to undergo disease 
evaluations every 4 weeks until subsequent anticancer therapy is initiated.
Table 2 (Time and 
Events Schedule –
Detailed Procedures 
and Study Drug 
Administration)
For consistency with Section 9.2.2, it was added in the Time and Events Schedule that a 
bone marrow aspirate/biopsy will be performed at the end of the continuation phase for 
subjects whose prior assessment was >2 weeks from the start of the conditioning 
regimen for bone marrow transplantation.
9.1.4 Posttreatment 
Period (Follow-Up)
For those subjects who discontinue study drug prior to disease progression, disease 
evaluations will continue to be performed every 4 weeks until subsequent anticancer 
therapy is initiated. For those subjects proceeding to transplant, the following 
information will be collected: date of transplant, type of transplant, time to 
engraftment, and any graft failures. After disease progression is documented or 
subsequent anticancer therapy is initiated, follow-up will occur every 8 weeks to 
record information on subsequent anticancer therapy, second primary malignancies, 
documentation of progressive disease or relapsed disease, and survival status.
Rationale: Requirements for CT scans were clarified.
Table 1 (Time and 
Events Schedule –
Overview)
For consistency with Section 9.2, it was clarified in the Time and Events Schedule that 
CT scans of the chest and abdomen/pelvis will be performed for subjects with ALL with 
mediastinal mass and subjects with LL. 
Rationale: It was clarified that PET or gallium scans are optional due to the availability of these procedures in 
the study site countries.
Table 1 (Time and 
Events Schedule –
Overview);
9.2.1.3 Mediastinal
Mass;
9.2.1.4 
Lymphoblastic 
Lymphoma
The text was updated to clarify that PET or gallium scans are optional.
Rationale: Heart rate and oxygen saturation were added to vital signs measurements to ensure adequate safety 
monitoring in this first study of daratumumab in pediatric subjects.
Table 2 (Time and 
Events Schedule –
Detailed Procedures 
and Study Drug 
Administration);
9.5 Safety 
Evaluations;
11.7 Safety Analyses
The text was updated to include heart rate and oxygen saturation.


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Rationale: A typographical error was corrected.
4.1 Inclusion Criteria 
(#6)
Adequate liver function at Cycle 1 Day 1 pre-dosing defined as:
a. Alanine Aspartate aminotransferase level ≤2.5x the upper limit of normal (ULN),
b. Aspartate aminotransferase level ≤2.5xULN, and
c. Total bilirubin ≤2x ULN or direct bilirubin level ≤2.0xULN
Rationale: Exclusion criterion regarding immunosuppression was clarified.
4.2 Exclusion 
Criteria (#3)
Received immunosuppression post hematopoietic transplant within 1 month of study 
entry.
Rationale: Exclusion criteria related to prior treatments was updated to prohibit investigational drugs and 
medical devices within 4 weeks of first dose of study drug, as well as current treatment in other investigational 
studies.
4.2 Exclusion 
Criteria (#13)
Received an investigational drug, Vaccination was vaccinated with live attenuated 
vaccines, or used an invasive investigational medical device within 4 weeks of first 
study agent administration. before the planned first dose of study drug, or is currently 
being treated in an investigational study.
Rationale: Minor corrections were made to the instructions for daratumumab infusion.
6.2.2 Daratumumab 
Administration;
Table 6 
(Daratumumab 
Infusion Rates)
Subjects weighing ≥10 to <20 kg will have daratumumab administered in a volume of 
250 mL for the first infusion (Cycle 1 Day 1), then in a volume of 125 100 mL for all 
subsequent infusions.
7 Treatment 
Compliance
The requirement for recording (in the eCRF) the weight of the IV bag before and after 
infusion was removed.
Rationale: Procedures for substituting Erwinia asparaginase for pegaspargase in the event of anaphylaxis were 
clarified.
6.4.6 Asparaginase 
(Pegaspargase 
[PEG-Asparaginase] 
or Erwinia)
Give 6 only 3 doses of Erwinia on M/W/F schedule for each dose of pegaspargase except 
the last dose of pegaspargase; give 6 doses of Erwinia over 2 weeks on M/W/F schedule 
for the last dose of pegaspargase
Rationale: Prohibited concomitant therapies were clarified.
8.2.3 Prohibited 
Concomitant 
Therapies
Concomitant administration of any antineoplastic therapy for the intention of 
treating ALL or LL is prohibited, including conventional chemotherapy agents,
investigational agents, and including approved or investigational medications that target 
CD38, with the intention of treating ALL/LL is prohibited. The sponsor must be notified 
in advance (or as soon as possible thereafter) of any instances in which prohibited 
therapies are administered.
Rationale: Criteria for disease response were clarified.
9.2.1 Response 
Categories
Disease response should reflect response in all areas of disease (ie, bone marrow 
and mediastinal mass, or bone marrow and extramedullary disease). If a subject 
does not have a CR in an extramedullary compartment, response will be considered 
“refractory disease” as per Section 9.2.1.1.
Rationale: Minor errors were noted.
Throughout the 
protocol
Minor grammatical, formatting, or spelling changes were made.


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SYNOPSIS
An Open-label, Multicenter, Phase 2 Study Evaluating the Efficacy and Safety of Daratumumab 
in Pediatric and Young Adult Subjects ≥1 and ≤30 Years of Age With Relapsed/Refractory 
Precursor B-cell or T-cell Acute Lymphoblastic Leukemia or Lymphoblastic Lymphoma
OBJECTIVES 
The primary objective is to evaluate the efficacy of daratumumab in addition to standard chemotherapy in 
pediatric subjects with relapsed/refractory B-cell acute lymphoblastic leukemia (ALL) and T-cell ALL as 
measured by the complete response (CR) rate.
The secondary objectives include the following:

To assess the efficacy of daratumumab in addition to standard chemotherapy, including overall 
response rate (ORR), relapse-free survival (RFS), event-free survival (EFS), and overall survival 
(OS) in pediatric subjects with B-cell and T-cell ALL, and minimal residual disease (MRD) 
negative rate in subjects with B-cell and T-cell ALL

To assess the safety and tolerability of daratumumab in addition to standard chemotherapy in 
pediatric subjects with B-cell and T-cell ALL

To assess the pharmacokinetics (PK) of daratumumab in pediatric subjects with B-cell and T-cell 
ALL

To assess daratumumab immunogenicity in pediatric subjects with B-cell ALL and T-cell ALL

To assess daratumumab concentration in cerebrospinal fluid (CSF)
The exploratory objectives include the following:

To explore biomarkers predictive of response or resistance to therapy

To assess expression of CD38 at study entry and at relapse
OVERVIEW OF STUDY DESIGN
This is a Phase 2, open-label, multicenter study to evaluate the efficacy, safety, and PK of daratumumab 
in addition to standard chemotherapy in approximately
49 subjects aged ≥1 to <18 with 
relapsed/refractory ALL and a maximum of 69 total subjects ≥1 and ≤30 years of age with relapsed or 
refractory ALL/LL. Cohort 1 will evaluate daratumumab in combination with vincristine and prednisone 
in subjects with B-cell ALL/LL in second relapse or greater. Cohort 2 will evaluate daratumumab in 
combination with a standard 4-drug re-induction regimen in subjects with T-cell ALL/LL in first relapse. 
There will be an initial safety run-in period for evaluation of dose-limiting toxicities. A Safety Evaluation 
Team will be commissioned for this study. The sponsor plans to enroll a minimum of 3 subjects with 
ALL in each of the following age groups in both cohorts: 1 to 6, 7 to 12, and 13 to <18 years if that cohort 
proceeds to stage 2 of the study.
DOSAGE AND ADMINISTRATION
Subjects with B-cell ALL/LL will receive treatment continuously in 28-day cycles until disease 
progression or unacceptable toxicity. Treatment will consist of daratumumab 16 mg/kg IV weekly for 
8 doses, then every 2 weeks for 8 doses, then every 28 days thereafter; vincristine 1.5 mg/m2 (maximum 
2 mg) IV weekly for 4 doses, then every 2 weeks for 2 doses, then every 28 days thereafter; and 
prednisone 40 mg/m2 orally daily for 28 days, then pulses on the first 5 days of each cycle thereafter. 


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Subjects with T-cell ALL/LL will receive up to two 28-day cycles of therapy. Subjects who achieve CR 
should proceed to allogeneic hematopoietic stem cell transplant off study. Cycle 1 treatment consists of 
daratumumab 16 mg/kg IV weekly for 4 doses, vincristine 1.5 mg/m2 (maximum 2 mg) IV weekly for 
4 doses, prednisone 40 mg/m2 orally daily for 28 days, doxorubicin 60 mg/m2 IV once, and 
peg-asparaginase 2500 U/m2 IV twice. Cycle 2 treatment consists of daratumumab 16 mg/kg IV weekly 
for 4 doses, cyclophosphamide IV 1 g/m2 once, cytarabine 75 mg/m2 IV/subcutaneous for 8 doses, 
6-mercaptopurine 60 mg/m2 orally daily for 14 doses, and methotrexate 5 g/m2 IV once. 
Subjects in both cohorts will also receive age-adjusted treatment with intrathecal methotrexate 
(for subjects 
without 
central 
nervous 
system 
[CNS] 
involvement) 
or 
intrathecal 
methotrexate-hydrocortisone-cytarabine (for subjects with CNS involvement).
EFFICACY EVALUATIONS
Disease evaluations will include bone marrow evaluations, CSF evaluations, blood samples to evaluate 
for BCR-ABL in Philadelphia chromosome positive subjects, and imaging studies.
OTHER EVALUATIONS
Blood samples will be used to characterize the PK of daratumumab and to assess for the generation of 
anti-daratumumab antibodies. Cerebrospinal fluid samples will also be collected for assessment of 
daratumumab concentration. Biomarker assessments will focus on 3 main objectives: to evaluate the 
ability of daratumumab to induce MRD, to confirm pharmacodynamic biomarkers, and to evaluate CD38 
expression on blast cells. Safety will be measured by adverse events, laboratory test results (hematology 
and chemistry), and assessment of Karnofsky or Lansky performance status.
STATISTICAL METHODS
The study utilizes a Simon’s 2-stage design for subjects aged less than 18 years. The B-cell ALL cohort 
will enroll 7 subjects in the first stage. If there is more than 1 responder after these subjects have received 
2 cycles of treatment, then an additional 18 subjects will be enrolled in Stage 2. If 25 subjects are 
enrolled, then there is 80% power to show that the true CR rate is >15% at a one-sided alpha of 5%. The 
T-cell ALL cohort will enroll 8 subjects in the first stage. If there are more than 3 responders after these 
subjects have received at least 1 cycle of treatment, then an additional 16 subjects will be enrolled in 
Stage 2. If 24 pediatric subjects are enrolled, then there is 80% power to show that the true CR rate is 
>30% at a one-sided alpha of 5%. 
A maximum of 10 young adult subjects (aged 18 to 30 years) with ALL and a maximum of 10 subjects 
with LL (aged 1 to 30 years) will be included in Stage 2 to evaluate the safety and efficacy in this patient 
population in addition to the 49 pediatric subjects included for the Simon’s 2- stage design and the data 
from these additional young adult subjects with ALL and subjects with LL will be summarized 
descriptively. 




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Screening 
Period
(Day -21 to 
Day -1)a
Treatment 
Cycles 1-2
Treatment 
Cycles 3-4
(B-ALL/LL 
only)
Treatment 
Cycles 5+
(B-ALL/LL 
only)
EoTb
Follow-
up
Q8W 
pre- CR 
or PD 
Follow-
upc
Q12W 
Notes
Bone marrow aspirate/biopsy
X
All 
subjects*: 
C1 D28 and 
C2 D28
B-ALL/LL: 
D28 of every other cycle 
from C4 until CR or PD
T-ALL/LL: not applicable
B-ALL 
and 
T-ALL:
if 
feasible
See Section 9.2.2 for details on local and 
central evaluations.
Fresh aspirate required. 
Biopsy is only required if the aspirate 
procedure is deemed inadequate. 
For subjects with LL, on-study bone 
marrow evaluation is only required if bone 
marrow disease is present at study entry. 
*If there is no hematologic recovery, repeat 
bone marrow evaluation when count 
recovery occurs (ANC >1.0x109/L platelets 
>100x109/L) unless there is evidence of 
blasts, then continue to next cycle.
Chest X-ray
X
As clinically indicated
Not required if chest CT obtained.
CT or MRI of chest*, CT or 
MRI of abdomen/pelvis^ 
ALL and 
LL*:
X
ALL with 
mediastinal 
mass and 
LL:
C1 D28^ 
and C2 
D28^
B-ALL with mediastinal 
mass and B-LL: 
D28 of every other cycle 
from C4 until CR or PD^
T-ALL and T-LL: not 
applicable
*Chest CT or MRI required for subjects 
with ALL with mediastinal mass and all 
subjects with LL during screening. 
Screening chest CT or MRI may be 
delayed until subject is stable.
^Abdomen/pelvis CT or MRI only 
required for subjects with LL at screening 
and on treatment if positive at screening 
and subject has not yet achieved CR.
The same imaging modality performed at 
screening should be used during the 
treatment period as indicated.
Follow-up period: disease 
evaluations Q8W for subjects 
who discontinue study drug 
prior to CR or PD and who 
have not initiated subsequent 
therapy
X
















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ABBREVIATIONS
ADCC
antibody-dependent cell-mediated cytotoxicity
ALL
acute lymphoblastic leukemia
ANC
absolute neutrophil count
Anti-HBc
hepatitis B core antibody
Anti-HBs
hepatitis B surface antibody
ARA-C
cytarabine
CAR-T
chimeric antigen receptor T-cell
CDC
complement-dependent cytotoxicity
CI
confidence interval
CNS
central nervous system
COG
Children’s Oncology Group
CR
complete response
CRi
complete response with only partial hematological recovery
CRu
complete response unconfirmed
CSF
cerebrospinal fluid
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
DLT
dose-limiting toxicity
DRd
daratumumab in combination with lenalidomide and dexamethasone
DVd
daratumumab in combination with bortezomib and dexamethasone
ECG
electrocardiogram
eCRF
electronic case report form
eDC
electronic data capture
EFS
event-free survival
EU
European Union
FEV1
forced expiratory volume in 1 second
GCP
Good Clinical Practice
GFR
glomerular filtration rate
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HC
hydrocortisone
HIV
human immunodeficiency virus
HSCT
hematopoietic stem cell transplant
IAT
indirect antiglobulin test
ICF
informed consent form
ICH
International Council for Harmonisation
IEC
Independent Ethics Committee
IM
intramuscular
IMiD
immunomodulatory drug
IRB
Institutional Review Board
IRR
infusion-related reaction
IT
intrathecal 
LL
lymphoblastic lymphoma
LP
lumbar puncture
mAb
monoclonal antibody
MedDRA
Medical Dictionary for Regulatory Activities


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MRD
minimal residual disease
MRI
magnetic resonance imaging
MTX
methotrexate
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
NHL
non-Hodgkin lymphoma
NK
natural killer (cell)
ORR
overall response rate
OS
overall survival
PCR
polymerase chain reaction
PDX
patient-derived xenograft
PFS
progression-free survival
Ph
Philadelphia chromosome
PI
proteasome inhibitor
PK
pharmacokinetic(s)
PQC
product quality complaint
PR
partial response
RBC
red blood cell
Rd
lenalidomide and dexamethasone
RFS
relapse-free survival
SAE
serious adverse event
sCR
stringent complete response
SD
standard deviation
SET
Safety Evaluation Team
SPD
sum of the products of the diameter
SUSAR
suspected unexpected serious adverse reaction
SVR
sustained virologic response
TEAE
treatment-emergent adverse event
ULN
upper limit of normal
US
United States
Vd
bortezomib and dexamethasone
WBC
white blood cell
DEFINITIONS OF TERMS
AUC
area under the concentration-time curve
Cmax
maximum observed concentration
Cmin
minimum observed concentration


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1.
INTRODUCTION
1.1.
Acute Lymphoblastic Leukemia and Lymphoblastic Lymphoma
Acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LL) comprise a 
heterogeneous group of lymphoid disorders that result from a monoclonal proliferation and 
expansion of immature lymphoid cells in the bone marrow, blood, and other organs.17
Immunophenotypic analysis permits sub-classification into B-cell and T-cell lineage types. As a 
result of leukemic blast infiltration of the bone marrow, patients present with signs of bone 
marrow failure, including anemia, thrombocytopenia, and neutropenia. Clinical manifestations 
include fatigue, bleeding, and fever. Clinical signs include pallor, petechiae, weight loss, 
lymphadenopathy, and hepatosplenomegaly. Other symptoms of ALL and LL include bone pain 
and dyspnea.25 Central nervous system (CNS) involvement may include leptomeningeal disease 
or an intracranial or spinal mass.25 Testicular involvement occurs in less than 3% of boys, who 
may present with painless testicular enlargement, which is most often unilateral on initial 
presentation.25 Patients with mediastinal masses, which commonly occur in T-cell ALL and LL, 
may present with dyspnea, wheezing, or shortness of breath and possibly with superior vena cava 
syndrome.
ALL is the most common pediatric malignancy, accounting for up to 30% of newly diagnosed 
cases of cancer in children.18 The estimated annual incidence of ALL is 6,500 in the United 
States (US) and 5,000 in the European Union (EU).32,42 B-cell ALL accounts for 80 to 85% of 
cases of ALL and T-cell ALL accounts for approximately 10 to 15% cases of ALL.35,39 LL is 
considered a form of non-Hodgkin lymphoma (NHL). It accounts for 20% of NHL in 
children.4,34,40 T-cell LL accounts for 75% of the cases of LL and B-cell LL accounts for 25% of 
cases.30,40 The World Health Organization classifies LL as the same disease as ALL.43 As such, 
both diseases commonly are studied in the same treatment protocols.
1.1.1.
Treatment of Acute Lymphoblastic Leukemia and Lymphoblastic 
Lymphoma
While pediatric ALL and LL remain highly curable, 20 to 25% of patients will be refractory to or 
relapse after frontline treatment.9,15,31 In B-cell ALL, relapse is risk-stratified and treatment is 
assigned accordingly based on timing of relapse from initial diagnosis and the site of relapse 
(extramedullary vs. medullary or combined).2 For B-cell ALL, depending on the site of relapse 
and the timing of relapse, 5-year overall survival (OS) ranges from 25% for the very early 
medullary/combined relapsed patients to 60%-70% for patients with isolated extramedullary 
relapse.2 Relapsed T-cell ALL is associated with an even worse prognosis with only 7 to 23% of 
patients surviving for 3 to 5 years.16,30 Patients with B-cell LL and T-cell LL have particularly 
dismal long-term outcomes due to difficulty of achieving second remission, with reported 5-year 
OS 14% and 8-year OS of 9%.5,28 The best chance for achieving long-term survival for T-cell 
ALL and LL is to induce a second complete remission followed by hematopoietic stem cell 
transplant (HSCT).2,5


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First re-induction consists of multi-drug chemotherapy with the goal to achieve CR. 
Additionally, CNS-directed therapy is provided via intrathecal chemotherapy with methotrexate 
alone or methotrexate with cytarabine and hydrocortisone (triple intrathecal chemotherapy) to 
clear CNS leukemia or to prophylax against spread of disease to the CNS.37 For many patients 
who achieve CR, this is followed by an allogeneic HSCT. 
One re-induction regimen (prednisone, vincristine, doxorubicin, and PEG-asparaginase) was 
evaluated in a single-arm Phase 2 study of patients with relapsed B-cell and T-cell ALL in first 
relapse. The rate of CR was 68% for patients with B-cell ALL with early relapse (n=63) and 17% 
for patients with T-cell ALL with early relapse (n=6).38 The 4-month event-free survival (EFS) 
was 62% and the 12-month EFS was only 35% for all early relapses (<36 months); no subjects 
with relapsed T-cell ALL survived longer than 10 months. The most common Grade 3 or higher 
adverse events in 124 subjects overall other than hematologic toxicity (neutropenia 97.6%, 
thrombocytopenia 
79.8%, 
and 
anemia 
62.9%) 
were 
febrile 
neutropenia 
(40.3%), 
hypofibrinogenemia (32.3%), and infection with Grade 3/4 neutropenia (19.4%). Given the high 
CR rate and tolerable safety profile of this regimen, this has become the standard backbone for 
the Children’s Oncology Group (COG) with which to evaluate the addition of novel therapies. 
As such, bortezomib was combined with this standard backbone of prednisone, vincristine, 
doxorubicin, and PEG-asparaginase, in the Phase 2 COG study AALL07P1 for patients with 
B-cell ALL in early relapse or T-cell ALL/LL in first relapse.
Several new approaches to treating patients with relapsed B-cell ALL/LL have been developed 
in the last 5 years, including agents that target CD19, such as the bispecific antibody 
blinatumomab. The CR rate after single-agent blinatumomab treatment for relapsed/refractory 
B-ALL was 39%.47 This agent is now being evaluated in combination with chemotherapy for the 
treatment of patients with relapsed B-cell ALL. However, neurological toxicity is a concern with 
this agent and can lead to treatment interruptions or discontinuations. 
Another strategy being actively investigated in ALL is chimeric antigen receptor (CAR) T-cell 
immunotherapy. Among 30 subjects (25 pediatric, 5 adult) with relapsed or refractory ALL 
treated with CTL019, there was a CR rate of 90% at 1 month post-infusion.27 At 6 months, the 
EFS rate was 67% and the OS rate was 78%. Cytokine-release syndrome was seen in all subjects 
(mild to moderate in 22 subjects and severe [requiring intensive care with respiratory support] in 
8 subjects), while neurologic toxic effects were seen in 13 subjects. Long-term outcomes remain 
unclear with this novel therapy.
Inotuzumab ozogamicin, an antibody-drug conjugate targeting CD22, has been evaluated in 
adults; however, while initial response rates are high (CR of 80.7%) in the Phase 3 pivotal trial, 
the duration remains short with a median OS of only 5 months.20 Liver-related toxicity is 
common with 11% of subjects experiencing veno-occlusive disease. This agent is now being 
evaluated in children. 


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The most recent drug approved for T-cell ALL/LL is nelarabine, which was approved in 2005.23
In a phase 2 study, nelarabine treatment resulted in an overall response rate (ORR) of 55% 
(n=34) and CR rate of 47% for patients with T-cell ALL in first relapse/refractory disease and an 
ORR of 43% with a CR rate of 14% in patients with relapsed T-cell LL (n=7).1 Nelarabine has 
significant neurologic toxicity that can be irreversible. Combining nelarabine with 
cyclophosphamide and etoposide as a re-induction regimen for relapsed T-cell ALL/LL resulted 
in a 44% CR rate in subjects with T-cell ALL/LL in first relapse.48
While novel treatment modalities including BiTEs (blinatumomab), monoclonal antibodies 
(mAbs) (inotuzumab), CAR T-cell immunotherapy, and the deoxyguanosine analogue nelarabine 
have shown improved rates of complete remission in relapsed/refractory ALL/LL, these gains 
have not translated to improvements in median OS and duration of response remains limited. 
Additionally, these novel agents have significant side effects that influence their tolerability. 
New agents are needed with improved safety profiles and the ability to improve duration of 
response and long-term survival in relapsed/refractory B-cell and T-cell ALL/LL.
1.2.
Daratumumab for Intravenous Infusion
Daratumumab is a human IgG1қ monoclonal antibody (mAb) that binds with high affinity to a 
unique epitope on CD38. It is a targeted immunotherapy that attacks tumor cells that overexpress 
CD38, a transmembrane glycoprotein, in a variety of hematological malignancies including 
multiple myeloma. Daratumumab induces lysis of CD38-expressing tumor cells, including 
multiple myeloma tumor cells that were freshly isolated from patients, by a wide spectrum of 
mechanisms including complement-dependent cytotoxicity (CDC), antibody-dependent 
cell-mediated cytotoxicity (ADCC), and antibody-dependent cellular phagocytosis, through 
activation of complement proteins, natural killer (NK) cells, and macrophages, respectively.10,33
In the US, intravenously administered daratumumab is indicated for use as follows: (1) in 
combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, for the 
treatment of patients with multiple myeloma who have received at least one prior therapy; (2) in 
combination with pomalidomide and dexamethasone for the treatment of patients with multiple 
myeloma who have received at least 2 prior therapies including lenalidomide and a proteasome 
inhibitor; (3) as monotherapy, for the treatment of patients with multiple myeloma who have 
received at least 3 prior lines of therapy including a proteasome inhibitor (PI) and an 
immunomodulatory drug (IMiD) or who are double refractory to a PI and an IMiD.
In the EU, daratumumab IV is indicated for use as follows: (1) as monotherapy for the treatment 
of adult patients with relapsed and refractory multiple myeloma, whose prior therapy included a 
PI and an IMiD and who have demonstrated disease progression on the last therapy; (2) in 
combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, for the 
treatment of adult patients with multiple myeloma who have received at least one prior therapy.
For the most comprehensive nonclinical and clinical information regarding daratumumab, refer 
to the latest version of the Investigator's Brochure. The term "sponsor" used throughout this 
document refers to the entities listed in the Contact Information page(s), which will be provided 
as a separate document.


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1.2.1.
Nonclinical Studies
CD38 is expressed in many hematologic malignancies including multiple myeloma, chronic 
lymphocytic leukemia, ALL, acute myeloid leukemia, NK cell leukemia, and NK/T-cell 
lymphoma.45 For daratumumab to be an effective agent for pediatric leukemias, the CD38 target 
must be present on pediatric ALL cells. Therefore, several studies were conducted to evaluate 
CD38 expression and daratumumab efficacy in leukemia cell lines, patients’ samples, and 
xenograft mouse models. 
Quantitative flow cytometry analysis of 9 ALL cell lines showed that CD38 expression levels 
varied among cell lines, but the majority (n=8/9) had >3000 CD38 receptors per cell.11 CD38 
was also expressed on a large proportion of tumor cells from patients with pediatric and adult 
B-cell and T-cell ALL (Table 4).3 CD38 expression level was comparable in pediatric and adult 
B-cell ALL.3 CD38 expression levels were also comparable in pediatric T-cell ALL and T-cell 
LL.46 Furthermore, average CD38 receptor density in B-cell (91,000 receptors/cellb) or T-cell 
(118,000 receptors/cellb) ALL blasts from adult patient samples was comparable to that observed 
in multiple myeloma34 (125,000 receptors/cell, n=10). 
Table 4:
Percent of CD38+ Tumors in Pediatric and Adult Patient ALL Samples
Condition
Assay
Pediatric Samplesa
Adult Samplesb
T-cell ALL
Flow
100% (n=15)
91% (n=20)
B-cell ALL
Flow
85% (n=115)
78% (n=59)
MMa
Flow
Not applicable
100% (n=49)
Abbreviation: ALL=acute lymphoblastic leukemia; MM=multiple myeloma.
a. Samples with greater than 70% of the tumor expressing CD38. Positive expression was based on a threshold 
greater than 103 mean fluorescence intensity (a receptor density surrogate) established from a CD38 negative 
tumor.
b. Percent of CD38+ ALL tumors was derived based on conversion of receptors/cell to percent CD38 positive 
tumors. Positive expression was based on a threshold greater than 30,000 CD19 receptors/cell. 
Source: Bras 20163; Data on file.
In vitro studies were conducted to evaluate several of daratumumab’s mechanisms of action. 
CD38 expression was sufficient to induce daratumumab-mediated CDC, ADCC, and apoptosis 
in ALL cell lines (Table 5).11 Daratumumab induced ≥20% apoptosis in 6 of 9 cell lines in the 
presence of a cross-linking agent. Evaluation of effector cell and complement-mediated tumor 
cell-killing assays revealed limited killing by CDC (max 5%); however, >10% ADCC occurred 
in 6 of 9 cell lines. These observations support previously reported studies showing that CD38 
antibody-drug conjugates were sufficient to induce in vitro killing of ALL cell lines.13 While no 
clear threshold/correlation was observed between CD38 expression and daratumumab-induced 
killing, other factors, possibly disease related, may also influence daratumumab activity.


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Table 5:
Efficacy of Daratumumab in ALL Cell Lines
Abbreviations: ADCC=antibody-dependent cell-mediated cytotoxicity; ALL=acute lymphoblastic leukemia; 
CDC=complement-dependent cytotoxicity.
Source: Data on file
In vivo cell line xenograft and patient-derived xenograft (PDX) models were investigated to 
further qualify daratumumab efficacy. A xenograft NALM-6 cell line model treated with 
daratumumab alone or combined with vincristine exhibited prolonged survival compared with 
vehicle or vincristine alone (p<0.001).11 In adult PDX mouse models, single-agent daratumumab 
showed strong anti-tumor effects compared with control-treated animals in both B-cell ALL 
(p<0.001) and T-cell ALL (p<0.05). This therapeutic benefit was corroborated in 23 ALL 
pediatric PDX mouse models, in which strong anti-tumor effects were observed when 
daratumumab monotherapy was administered compared with control-treated animals (B-cell 
ALL, n=2/5; T-cell ALL n=10/18). Of note, daratumumab monotherapy was highly efficacious 
in aggressive subsets of early T-cell precursor ALL pediatric PDX models (n=8/9) (data on file; 
Figure 1).


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Figure 1:
Efficacy of Daratumumab in ALL PDX models
Abbreviations: ALL=acute lymphoblastic leukemia; ETP=early T-cell precursor; PDX= patient-derived xenograft.
Single-agent daratumumab efficacy was observed in both pediatric B-cell and T-cell ALL (ETP [above] and 
non-ETP) PDX models by reduction in blast counts from peripheral blood (A) and spleen (B).
Source: Data on file.
These data suggest that daratumumab significantly inhibits tumor growth and induces long-term 
tumor regression in CD38-expressing adult and pediatric ALL xenograft models. 
Expression of CD38 on ALL cell lines and primary adult and pediatric patient samples coupled 
with multiple daratumumab mechanisms of action in vitro and in vivo suggest that CD38 may be 
targeted with daratumumab for the treatment of pediatric ALL/LL. CD38 is a distinct target from 
those of other approved agents for ALL/LL therapy. Therefore, treatment with daratumumab 
offers a promising new approach to treating ALL/LL. 
1.2.2.
Clinical Studies
Daratumumab was initially developed as a treatment for multiple myeloma. There is a 
comprehensive development plan across various hematologic malignancies. As of 30 June 2017, 
approximately 2700 subjects have been treated with daratumumab monotherapy or combination 
therapy in 21 clinical studies.
1.2.2.1.
Monotherapy Studies
Daratumumab as monotherapy induces deep and durable responses in subjects with heavily 
pretreated multiple myeloma. Phase 2 Study MMY2002 and Phase 1/2 Study GEN501 Part 2 
(Part 1 was the dose-escalation phase of this first-in-human study) were both single-arm, 
open-label studies in which subjects with relapsed and refractory multiple myeloma were 
administered IV daratumumab as monotherapy weekly for 8 weeks, every 2 weeks for an 


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additional 16 weeks, and every 4 weeks thereafter until disease progression or unacceptable 
toxicity. One hundred forty-eight (148) subjects treated with IV daratumumab 16 mg/kg 
monotherapy were included in a combined analysis of efficacy in Study GEN501 and 
Study MMY2002. The ORR for the combined data set was 31% (95% confidence interval [CI], 
23.7%-39.2%). Responses included 3 subjects with stringent complete response (sCR; 2.0%), 
4 subjects with CR (2.7%), 13 subjects with very good partial response (8.8%) and 26 subjects 
with partial response (PR; 17.6%). Within the individual studies, the ORR was 35.7% 
(95% CI, 21.6%-52.0%) in Study GEN501 and 29.2% (95% CI, 20.8%-38.9%) in 
Study MMY2002. After a median duration of follow-up of 20.7 months, the Kaplan-Meier based 
median OS was 20.1 months.
Among 156 subjects treated with IV daratumumab 16 mg/kg as monotherapy in Studies 
GEN501, MMY2002, and MMY1002 (a single-arm, open-label Phase 1 study of PK and safety 
conducted in Japanese subjects), 6 subjects (4%) discontinued treatment due to a 
treatment-emergent adverse event (TEAE). Three subjects (2%) died due to TEAEs. The most 
frequently reported TEAEs were fatigue (40%), nausea (28%), anemia (28%), back pain (26%), 
cough (24%), neutropenia (23%), pyrexia (22%), upper respiratory tract infection (22%), and 
thrombocytopenia (21%). Serious adverse events (SAEs) were reported in 34% of subjects; the 
most frequently reported SAEs were pneumonia (6%), pyrexia (3%), hypercalcemia (3%), and 
general physical health deterioration (3%). 
1.2.2.2.
Combination Therapy Studies
Two Phase 3 studies examined the safety and efficacy of IV daratumumab in combination with 
other therapies in the treatment of relapsed multiple myeloma: 

In Study MMY3003, subjects with multiple myeloma received IV daratumumab in 
combination with lenalidomide and dexamethasone (DRd). At the time of the first interim 
analysis, treatment with DRd resulted in a 63% reduction in the risk of disease progression 
or death compared with Rd alone. The median progression-free survival (PFS) was not 
reached in the daratumumab group; median PFS was 18.4 months in the Rd group. The 
ORRs were 91% for the DRd group and 75% for Rd group.

In Study MMY3004, subjects with multiple myeloma received IV daratumumab in 
combination with bortezomib and dexamethasone (DVd). At the time of the first interim 
analysis, treatment with DVd showed a 61% reduction in the risk for disease progression or 
death compared with Vd alone. The median PFS was not estimable in the DVd group; 
median PFS was 7.2 months, in the Vd group. The ORRs were 79% for the DVd group and 
60% for the Vd group. 
1.2.2.3.
Pharmacokinetics
Pharmacokinetic data are not available in pediatric subjects. In adult subjects with multiple 
myeloma, over the dose range of 1 to 24 mg/kg as monotherapy or 1 to 16 mg/kg of 
daratumumab in combination with other treatments, increases in area under the 
concentration-time curve (AUC) were more than dose-proportional. Following the recommended 
dose of 16 mg/kg when daratumumab was administered as monotherapy or in combination 
therapy, the mean serum maximal concentration (Cmax) value at the end of weekly dosing was 


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approximately 2.7- to 3-fold higher compared with the mean serum Cmax following the first dose. 
The mean ± standard deviation (SD) trough serum concentration (Cmin) at the end of weekly 
dosing was 573 ± 332 µg/mL when daratumumab was administered as monotherapy and 
502 ± 196 to 607 ± 231 µg/mL when administered as combination therapy. Daratumumab 
steady-state was achieved approximately 5 months into the every 4-week dosing period (by the 
21st infusion). The mean ± SD ratio of Cmax at steady-state to Cmax after the first dose was 1.6 ± 
0.5. In the current study, subjects with B-cell ALL would expect to reach steady-state in this 
same timeframe (approximately the twenty-first daratumumab infusion) while subjects with 
T-cell ALL would stop therapy after 8 weekly doses of daratumumab and therefore not reach a 
steady-state concentration. At the recommended dose of 16 mg/kg, the mean ± SD central 
volume of distribution was 4.7 ± 1.3 L when administered as monotherapy and 4.4 ± 1.5 L when 
administered as combination therapy. Daratumumab clearance decreased with increasing dose 
and with multiple dosing. At the recommended dose of 16 mg/kg of daratumumab as 
monotherapy, the mean ± SD linear clearance was estimated to be 171.4 ± 95.3 mL/day. The 
mean ± SD estimated terminal half-life associated with linear clearance was 18 ± 9 days when 
daratumumab was administered as monotherapy and 23 ± 12 days when daratumumab was 
administered as combination therapy. 
1.3.
Overall Rationale for the Study
Patients with relapsed B-cell ALL/LL or patients with refractory disease have dismal prognoses. 
While several active agents exist for B-cell ALL/LL in first relapse, there is a subset of patients 
whose disease relapses a second time or remains resistant to these therapies. For these patients, 
with each subsequent relapse, the leukemia becomes more resistant to chemotherapy due to loss 
of antigens and other resistance mechanisms.  These patients are also accumulating organ 
toxicity with exposure to each subsequent salvage therapy.22 Thus, novel agents with novel 
targets and limited toxicity are needed for patients with relapsed or refractory B-cell ALL/LL. 
Hence, daratumumab, which targets a novel antigen for B-cell ALL/LL, will be combined with 
the less intensive regimen of vincristine and prednisone for the heavily pretreated group of 
patients who are now experiencing a second or greater relapse of disease. 
Treating relapsed T-cell ALL/LL in pediatric patients is challenging as responses to standard 
agents remain poor and no efficacious novel agents are available. Thus, daratumumab, which 
targets a novel antigen for T-cell ALL/LL, will be added to a standard intensive induction and 
consolidation regimen in this study for patients in first relapse or with refractory disease. 
CD38 provides a novel treatment approach for both B-cell and T-cell ALL/LL in settings in 
which treatment resistance to the standard chemotherapies is seen. Daratumumab may be used in 
combination with other targeted agents or standard chemotherapy with minimal additional 
toxicity, which has been done successfully in multiple myeloma studies. Thus, daratumumab has 
the potential to provide therapeutic benefit for patients with relapsed/refractory B-cell or T-cell 
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2.
OBJECTIVES, ENDPOINTS, AND HYPOTHESIS
2.1.
Objectives and Endpoints
2.1.1.
Objectives
Primary Objective
The primary objective is to evaluate the efficacy of daratumumab in addition to standard 
chemotherapy in pediatric subjects with relapsed/refractory B-cell ALL and T-cell ALL as 
measured by the CR rate.
Secondary Objectives
The secondary objectives include the following:

To assess the efficacy of daratumumab in addition to standard chemotherapy, including 
ORR, relapse-free survival (RFS), EFS, and OS in pediatric subjects with B-cell and T-cell 
ALL, and minimal residual disease (MRD) negative rate in subjects with B-cell and T-cell 
ALL

To assess the safety and tolerability of daratumumab in addition to standard chemotherapy in 
pediatric subjects with B-cell and T-cell ALL

To assess the PK of daratumumab in pediatric subjects with B-cell and T-cell ALL

To assess daratumumab immunogenicity in pediatric subjects with B-cell ALL and T-cell 
ALL

To assess daratumumab concentration in cerebrospinal fluid (CSF)
Exploratory Objectives
The exploratory objectives include the following:

To explore biomarkers predictive of response or resistance to therapy

To assess expression of CD38 at study entry and at relapse
2.1.2.
Endpoints
Primary Endpoint
The primary endpoint is CR rate within 2 cycles of therapy for B-cell ALL and at the end of 
Cycle 1 for T-cell ALL. CR is defined as:

Less than 5% blasts in the bone marrow

No evidence of circulating blasts or extramedullary disease

Full recovery of peripheral blood counts:
o
Platelets >100x109/L
o
Absolute neutrophil count (ANC) >1.0x109/L


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Secondary Endpoints
The secondary endpoints include:

ORR, defined as CR or CRi for ALL
o
CR is defined as above
o
CRi is defined as:

Less than 5% blasts in the bone marrow

No evidence of circulating blasts or extramedullary disease

Partial recovery of peripheral blood counts not meeting criteria for CR noted above

EFS, defined as the time from the date of first treatment to the first documented treatment 
failure (ie, disease progression) or date of relapse from CR or death due to any cause, 
whichever occurs first

RFS, defined as the time from CR to relapse from CR or death due to any cause, whichever 
occurs first

OS, defined as the time from the date of first treatment to the date of death due to any cause

MRD negative rate, defined as the proportion of subjects who are MRD negative 

Proportion of subjects who receive an allogeneic HSCT after treatment with daratumumab

PK of daratumumab (Cmax and Cmin)

Daratumumab immunogenicity incidence 

Concentration of daratumumab in CSF
Exploratory Endpoints
The exploratory endpoints include:

Biomarkers predictive of response or resistance to therapy

Expression of CD38 at study entry and at relapse
Refer to Section 9, Study Evaluations, for evaluations related to endpoints.
2.2.
Hypothesis
The primary hypothesis for each ALL subtype is as follows:

For relapsed/refractory precursor B-cell ALL, treatment with daratumumab in combination 
with vincristine and prednisone will result in a CR rate of 40% or higher.

For relapsed/refractor T-cell ALL, treatment with daratumumab in combination with 
doxorubicin, prednisone, vincristine, and asparaginase will result in a CR rate of 60% or 
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3.
STUDY DESIGN AND RATIONALE
3.1.
Overview of Study Design
This open-label, multicenter, Phase 2 study will enroll approximately 49 subjects aged ≥1 to 
<18 years with relapsed/refractory ALL and a maximum of 69 total subjects ≥1 and ≤30 years of 
age with relapsed/refractory ALL/LL. Cohort 1 will evaluate the safety and efficacy of 
daratumumab in combination with vincristine and prednisone in subjects with B-cell ALL/LL in 
second relapse or greater. Cohort 2 will evaluate the safety and efficacy of daratumumab in 
combination with a standard 4-drug re-induction regimen (prednisone, vincristine, doxorubicin, 
and PEG-asparaginase) in subjects with T-cell ALL/LL in first relapse. 
Subject participation will include a Screening Period, a Treatment Period, and a Posttreatment 
Period. The Screening Period will be up to 21 days before first dose. During the Treatment 
Period, cycles are 28 days. Subjects with B-cell ALL/LL will receive treatment until disease 
progression, unacceptable toxicity, or achievement of CR followed by HSCT. Subjects with 
T-cell ALL/LL will receive treatment for up to 2 cycles (induction and consolidation). There is 
an optional maintenance phase for all subjects who achieve CR and need to bridge therapy until 
an allogeneic HSCT. The Posttreatment Period begins immediately following the End-of-
Treatment Visit, and will continue until death, loss to follow-up, or consent withdrawal for study 
participation, whichever occurs first.
A diagram of the study design is provided below in Figure 2. The study has 2 stages. Stage 1 will 
evaluate the initial safety and efficacy in each cohort. Only B-cell or T-cell ALL subjects aged 
1 to <18 years will be enrolled in their respective cohorts in Stage 1. Stage 1 will include a safety 
run-in which will evaluate the initial 3 subjects with B-cell ALL and initial 3 subjects with T-cell 
ALL. Enrollment will continue after safety is confirmed in each cohort separately. After 
confirming safety (see Section 3.4), Cohort 1 (B-cell ALL) will enroll an additional 4 subjects 
aged 1 to <18 years in Stage 1 and Cohort 2 (T-cell ALL) will enroll an additional 5 subjects 
aged 1 to <18 years in Stage 1. During Stage 1, the dose of daratumumab will be evaluated with 
ongoing PK analysis to confirm the therapeutic dose of daratumumab to be used in Stage 2 of the 
study. The study will have a futility analysis for each cohort after Stage 1 is completed before 
enrolling subjects to Stage 2 (see Section 11.2).  All subjects enrolled into Stage 1, including 
subjects in the safety run-in at the confirmed safe dosing regimen will be included in the futility 
analysis.
In Stage 2, an additional 18 subjects with B-cell ALL and 16 subjects with T-cell ALL aged 1 to 
<18 years will be enrolled for a total of 25 subjects with B-cell ALL and 24 subjects with T-cell 
ALL aged 1 to <18 years. The sponsor plans to enroll a minimum of 3 subjects with ALL in each 
of the following age groups in both cohorts if an individual cohort proceeds to Stage 2: 1 to 6, 
7 to 12, and 13 to <18 years. In Stage 2 subjects with LL and young adults with ALL will also be 
enrolled. A maximum of 10 subjects aged 1 to 30 years with LL and a maximum of 10 subjects 
aged 18 to 30 years with ALL will be enrolled to the respective B-cell and T-cell cohorts. The 
data from these subjects with LL (pediatric and young adult) and young adult subjects aged 18 to 
30 years with ALL will be descriptively summarized. 




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In Cohort 1, subjects with B-cell ALL/LL will be treated with daratumumab in combination with 
vincristine and prednisone with the intent to achieve CR. There are no standard therapies for 
B-cell ALL in second relapse or greater. Treatment is generally tailored to individual patients 
based on prior therapies and residual toxicities. Vincristine and prednisone are active agents that 
are commonly used in this setting and the toxicity profile is amenable to the addition of 
daratumumab. Additionally, preclinical data with daratumumab combined with vincristine 
showed promising results in a xenograft model (see Section 1.2).  CNS-directed therapy will be 
provided according to standard of care according to CNS status (CNS 1, 2, or 3). Treatment of 
testicular disease, if present, will proceed according to institutional standards. 
In contrast, there are very few active agents or regimens for T-cell ALL/LL in first relapse. 
Response rates and long-term outcomes are dismal for any patients with T-cell ALL/LL who 
relapse or are resistant to initial therapy. Further intensification of re-induction is required to 
improve outcomes by adding novel agents to standard re-induction therapy for T-cell ALL/LL 
patients in first relapse. Thus, Cohort 2 will include subjects with T-cell ALL/LL in first relapse 
or refractory to at least 1 prior induction/consolidation regimen.
In Cohort 2, subjects with T-cell ALL/LL will be treated with daratumumab in combination with 
a standard 4-drug re-induction regimen. Several re-induction regimens have been utilized by 
various cooperative groups. However, based on the toxicity profile of these induction regimens, 
the 4-drug combination of doxorubicin, prednisone, vincristine, and PEG-asparaginase appears 
to be most amenable to the addition of a novel agent as toxic deaths and severe infections were 
lower with this regimen than other standard re-induction regimens such as the R3 regimen. The 
second cycle of therapy is optional to allow further treatment for those subjects who do not 
achieve CR after the first cycle of therapy or to consolidate the response prior to HSCT. The 
second cycle of therapy is a combination of therapy commonly utilized in the relapsed setting for 
T-cell ALL/LL. Subjects who achieve CR after Cycle 1 or 2 are expected to proceed to 
allogeneic HSCT off study. For those subjects who do not achieve CR after 2 cycles of therapy, 
treatment will be continued off study at the investigator’s discretion. CNS treatment will follow 
the standard of care for relapsed T-cell ALL/LL according to CNS status (CNS 1, 2, or 3). 
Treatment of testicular disease, if present, will proceed according to institutional standards.
There is growing evidence that EFS and OS are better when pediatric protocols are utilized in 
treating young adults.19 Therefore, a maximum of 10 young adult subjects (aged 18 to 30 years) 
will be included in Stage 2 to evaluate the safety and efficacy in this patient population to inform 
future studies and the data will be summarized descriptively by cohort as B-cell or T-cell lineage. 
Additionally, a maximum of 10 subjects with LL aged 1 to 30 years will be included in Stage 2 
of the study to establish safety in efficacy in this patient population to inform future studies. 
Patients with LL historically have a worse prognosis and different methodology for response 
assessment compared to ALL, therefore subjects with LL will be summarized descriptively by 
cohort as B-cell or T-cell lineage.


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3.3.
Dose Rationale
There are no PK data for daratumumab in pediatric subjects. The sponsor plans to analyze the 
PK of daratumumab during this Phase 2 study to confirm the pediatric dose.
As an IgG1қ mAb, daratumumab is presumably biotransformed by degradation into small 
peptides and amino acids by catabolic pathways.26,44 These biotransformation pathways are 
expected to be similar in adults and children. A comparison of PK parameters for most mAbs 
shows comparable PK for adults and the pediatric population, especially for patients older than 
12 years after adjusting for body size.49 Some differences in clearance and volume can be 
observed in children under 12 years of age, which may require a dose adjustment (typically a 
higher dose) to achieve similar concentrations as older subjects; assessment of PK exposure and 
response, as is planned in this study, is warranted to confirm the dose in these subjects.
Daratumumab exhibits target-mediated drug disposition, and therefore a complex nonlinear, 
non-stationary PK. Daratumumab binds to CD38 receptors in the body. The complex with 
daratumumab is rapidly cleared. As the dose is increased, and after repeated administration, 
CD38 becomes saturated, and the effect of target binding clearance is minimized. The PK of 
daratumumab may be similar in adult multiple myeloma and pediatric subjects, because the 
target (receptor) density is similar in adult multiple myeloma and pediatric ALL cell lines. A 
population PK model was developed for daratumumab for adult patients with multiple myeloma. 
Model-based population PK simulations have been conducted for subjects aged 1 to 18 years, 
demonstrating that based on PK considerations, the 16 mg/kg IV dose may be a feasible starting 
dose to be evaluated in this Phase 2 pediatric study. As expected, younger patients with lower 
body weight tend to have slightly lower concentrations when adult standard mg/kg dose is given. 
This is consistent with the allometric theory which suggests that CL cannot be adjusted 
proportionally with weight.49 Nonetheless, the standard 16 mg/kg dose and schedule for 
daratumumab could produce >99% and >90% target saturation after weekly dosing and every 
4 week dosing, respectively, in all age groups based on the primary simulation scenario.49
The PK samples collected during the first 2 cycles from the first 10 subjects will be evaluated to 
confirm that the exposure is within the range of the adult multiple myeloma data. Further 
evaluations of the PK, efficacy, and safety data from Stage 1 may be performed to confirm the 
dose for Stage 2 of the study.
3.4.
Dose-Limiting Toxicity
During the safety run-in, 3 subjects in each cohort will be evaluated for dose-limiting toxicities 
(DLTs). A Safety Evaluation Team (SET) (see Section 11.8) will review the DLT data and 
determine whether a modification to the dose or schedule of study drugs is needed for any of the 
treatment cohorts. The DLT Evaluation Period is defined as the first 28 days from the start of the 
first dose of daratumumab. DLTs will be evaluated in each cohort separately at the end of 
Cycle 1. Only toxicities that occur during the DLT evaluation period will be used for the purpose 
of defining DLT and for subsequent dose or dosing schedule modifications or safety-run in 
expansion. However, toxicities that occur in all cycles will be considered in the overall decisions 
of the SET. If a subject receives less than 75% of the planned dose of daratumumab for reasons 


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other than toxicity (eg, disease progression, subject withdrawal, etc.), that subject will be 
considered non-evaluable for DLTs and may be replaced, but the safety profiles of these subjects 
will be included in the SET review. Additional safety reviews will be conducted by the SET after 
Stage 1 of the study in each cohort and as deemed necessary during the conduct of the study. 
The following DLT guidelines will apply to each cohort separately:

If DLT is not observed in the initial 3 subjects treated with 16 mg/kg of daratumumab for a 
given combination regimen, then that combination regimen will be considered safe and 
well-tolerated and the cohort may continue to enroll to pre-specified numbers.

If DLT is observed in 1 of the initial 3 subjects, then the safety-run in will be expanded to 
6 subjects. 
o
If 1/6 subjects treated with 16 mg/kg of daratumumab for a given combination 
regimen experience a DLT, then that combination regimen will be considered safe 
and well-tolerated and the cohort may continue to enroll to pre-specified numbers.
o
If ≥2/6 subjects experience a DLT, then that combination regimen will be 
considered not safe unless the events are due to unexpected circumstances clearly 
not related to a study procedure or treatment (eg, a passenger in an automobile 
accident). The dose or schedule of study drugs may be adjusted and a new safety 
run-in may begin or the cohort may be closed. Three new subjects may be treated at 
a lower dose or adjusted schedule for a given combination regimen. The safety 
run-in will follow the rules above.
o
If DLT is observed in ≥2 of the initial 3 subjects, then that combination regimen will be 
considered not safe unless the events are due to unexpected circumstances clearly not related
to a study procedure or treatment (eg, a passenger in an automobile accident). The dose or 
schedule of study drugs may be adjusted and a new safety run-in may begin or the cohort 
may be closed. Three new subjects may be treated at a lower dose or adjusted schedule for a 
given combination regimen. The safety run-in will follow the rules above.
3.5.
Dose Tolerability Evaluation Guidelines
DLTs will be evaluated at the end of Cycle 1. Only toxicities that occur during the DLT 
evaluation period will be used for the purposes of defining DLT and for subsequent dose 
modifications or cohort expansion. However, toxicities that occur in all cycles will be considered 
in the overall decisions of the SET. Subjects considered non-evaluable for DLTs (ie, a subject 
who receives less than 75% of the planned dose of daratumumab for reasons other than toxicity) 
may be replaced, but the safety profiles of these subjects will be included in the SET review.
DLTs are based on daratumumab-related toxicities and defined as any of the following events in 
the DLT evaluation period. However, infusion-related reactions (IRRs) may result from either 
the first infusion or subsequent infusions. Noncompliance with the protocol-defined 
requirements for infusion of the study drug may influence the evaluation of DLTs. If 
noncompliance with the protocol-defined requirements (eg, antiviral prophylaxis) results in 
toxicities of ≥Grade 3, then these toxicities will not qualify as DLTs. 
The following are considered to be DLTs:


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
Grade 4 IRR occurring within 48 hours of the infusion of daratumumab

Grade 3 IRR occurring within 48 hours of the infusion of daratumumab that does not resolve 
after the initiation of supportive care and symptomatic therapy such as administration of 
glucocorticoid and antihistamine

Non-hematologic toxicity of Grade 4 that occurs after the first dose of daratumumab and is 
considered related to daratumumab with the following exceptions for Cohort 2 only:
o
Fever or infection
o
Gastrointestinal symptoms (anorexia, vomiting, dehydration, mucositis)
o
Hypofibrinogenemia
o
Metabolic/laboratory abnormalities that resolve to ≤Grade 2 within 7 days
o
Tumor lysis syndrome or hyperuricemia

Non-hematologic toxicity Grade 3 or higher that is considered related to daratumumab and 
results in delay of the subsequent course of chemotherapy for >7 days, with the exception of 
fever or infection

Persistent neutropenia (ANC <0.5x109/L) or thrombocytopenia (<50x109/L) without 
transfusion) lasting longer than 45 days from Cycle 1 Day 1 that is not clearly due to another 
identifiable factor such as persistent disease, leukemia progression/relapse, or infection 
The rate and severity of infections will be evaluated at the end of Stage 1 to confirm safety of the 
regimens before proceeding to Stage 2.


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4.
SUBJECT POPULATION
Screening for eligible subjects will be performed within 21 days before administration of the 
study drug. The inclusion and exclusion criteria for enrolling subjects in this study are described 
in the following 2 subsections. If there is a question about the inclusion or exclusion criteria 
below, then the investigator must consult with the appropriate sponsor representative and resolve 
any issues before enrolling a subject in the study. Waivers are not allowed. 
4.1.
Inclusion Criteria
Each potential subject must satisfy all the following criteria to be enrolled in the study: 
1.
≥1 and ≤30 years of age.
2.
Documented ALL or LL as defined by the criteria below:

B-cell cohort:
o
Stage 1: 

ALL in second or greater relapse or refractory to 2 prior induction regimens 
with ≥5% blasts in the bone marrow and aged 1 to <18 years 
o
Stage 2: 

ALL in second or greater relapse or refractory to 2 prior induction regimens 
with ≥5% blasts in the bone marrow and aged 1 to 30 years 

LL in second or greater relapse or refractory to 2 prior induction regimens 
and biopsy proven and with evidence of measurable disease by radiologic 
criteria and aged 1 to 30 years (see Section 9.2.1.4)

T-cell cohort:
o
Stage 1: 

ALL in first relapse or refractory to 1 prior induction/consolidation regimen 
with ≥5% blasts in the bone marrow and aged 1 to <18 years
o
Stage 2: 

ALL in first relapse or refractory to 1 prior induction/consolidation regimen 
with ≥5% blasts in the bone marrow and aged 1 to 30 years

LL in first relapse or refractory to 1 prior induction/consolidation regimen 
biopsy proven and with evidence of measurable disease by radiologic 
criteria and aged 1 to 30 years (see Section 9.2.1.4)
3.
Performance status ≥70 by Lansky scale (for subjects <16 years of age) or Karnofsky 
scale (for subjects ≥16 years of age) (Attachment 1).
4.
Adequate hematology laboratory values at Cycle 1 Day 1 pre-dosing defined as follows:
a.
Hemoglobin ≥7.5 g/dL (≥5 mmol/L; prior red blood cell [RBC] transfusion is 
permitted)
b. Platelet count ≥10 × 109/L (prior platelet transfusion is permitted)


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5.
Criterion modified per Amendment 2
Criterion modified per Amendment 3
5.2 Adequate renal function defined as normal serum creatinine for the subject’s age or 
creatinine clearance or radioisotope glomerular filtration rate (GFR) ≥70 mL/min/1.73 
m2 prior to enrollment (see Attachment 3).
6.
Criterion modified per Amendment 1
Criterion modified per Amendment 2
6.2 Adequate liver function prior to enrollment defined as:
a.
Alanine aminotransferase level ≤2.5x the upper limit of normal (ULN),
b. Aspartate aminotransferase level ≤2.5xULN, and
c.
Total bilirubin ≤2x ULN or direct bilirubin level ≤2.0xULN
7.
Criterion modified per Amendment 2
7.1 Female subjects of childbearing potential (defined as post-menarchal and sexually 
active until becoming post-menopausal unless permanently sterile) must commit either 
to abstain continuously from heterosexual sexual intercourse or to use 2 methods of 
reliable birth control simultaneously during the Treatment Period, during any dose 
interruptions, and for 12 months after the last dose of any component of the treatment 
regimen. Permanent sterilization methods include hysterectomy, bilateral salpingectomy 
and bilateral oophorectomy. Sexual abstinence is considered a highly effective method 
only if defined as refraining from heterosexual intercourse during the entire period of 
risk associated with the study drug. The reliability of sexual abstinence needs to be 
evaluated in relation to the duration of the study and the preferred and usual lifestyle of 
the subject. Birth control methods must include one highly effective method of 
contraception (tubal ligation, intrauterine device, hormonal [birth control pills, 
injections, hormonal patches, vaginal rings or implants], or partner’s vasectomy) and 
one additional effective contraceptive method (male latex or synthetic condom, 
diaphragm, or cervical cap). Contraception must begin 4 weeks prior to dosing. Reliable 
contraception is indicated even where there has been a history of infertility, unless due 
to hysterectomy.
8.
Criterion modified per Amendment 2
8.1 During the study and for 12 months after receiving the last dose of any component 
of the treatment regimen, female subjects must agree not to donate eggs (ova, oocytes) 
for the purposes of assisted reproduction.


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9.
Male subjects of reproductive potential who are sexually active with females of 
reproductive potential must always use a latex or synthetic condom during the study and 
for 6 months after discontinuing study treatment (even after a successful vasectomy). 
10.
Male subjects of reproductive potential must not donate sperm during the study or for 
6 months after the last dose of study treatment.
11.
The informed consent form (ICF) must be signed by a legally authorized representative 
or by the subject if at legal age of consent indicating understanding of the purpose of, 
and procedures required for, the study and willingness to participate in the study. Assent 
is also required of children capable of understanding the nature of the study according to 
country-specific or site-specific standards as described in Section 16.2.3, Informed 
Consent and Assent Form.
12.
Must be willing and able to adhere to the prohibitions and restrictions specified in this 
protocol.
4.2.
Exclusion Criteria
Any potential subject who meets any of the following criteria will be excluded from participating 
in the study: 
1.
Received an allogeneic hematopoietic transplant within 3 months of screening.
2
Active acute graft-versus-host disease of any grade or chronic graft-versus-host disease 
of Grade 2 or higher.
3.
Criterion modified per Amendment 1
3.1 Received immunosuppression post hematopoietic transplant within 1 month of study 
entry.
4.
Philadelphia chromosome positive (Ph+) B-cell ALL eligible for tyrosine kinase 
inhibitor therapy.
5.
Has either of the following:
a.
Evidence of dyspnea at rest or oxygen saturation ≤94%. 
b. Known moderate or severe persistent asthma within the past 2 years 
(see Attachment 4), or uncontrolled asthma of any classification. Note that 
subjects who currently have controlled intermittent asthma or controlled mild 
persistent asthma may participate in the study.
6.
Down syndrome, juvenile myelomonocytic leukemia, Fanconi anemia, Kostmann 
syndrome, Shwachman syndrome, or any other known bone marrow failure syndrome.


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7.
Prior exposure to daratumumab or other anti-CD38 therapies. 
8.
Criterion modified per Amendment 2
8.1 Prior cancer immunotherapy (ie, CAR-T, inotuzumab) within 4 weeks prior to 
enrollment or blinatumomab within 2 weeks prior to enrollment.
9.
Criterion modified per Amendment 2
9.1 For subjects with T-cell ALL/LL only: prior cumulative anthracycline exposure 
must not exceed 400 mg/m2 of doxorubicin or equivalent (see Attachment 8 for 
conversion).
10.
Criterion modified per Amendment 3
10.1 Subject is:

known to be seropositive for human immunodeficiency virus (HIV).

seropositive for hepatitis B (defined by a positive test for hepatitis B surface 
antigen [HBsAg]). Subjects with resolved infection (ie, subjects who are HBsAg 
negative but positive for antibodies to hepatitis B core antigen [Anti-HBc] and/or 
antibodies to hepatitis B surface antigen [Anti-HBs]) must be screened using 
real-time polymerase chain reaction (PCR) measurement of hepatitis B virus 
(HBV) DNA levels. Those who are PCR positive will be excluded. EXCEPTION: 
Subjects with serologic findings suggestive of HBV vaccination (Anti-HBs 
positivity as the only serologic marker) AND a known history of prior HBV 
vaccination, do not need to be tested for HBV DNA by PCR.

known to be seropositive for hepatitis C (except in the setting of a sustained 
virologic response [SVR], defined as aviremia at least 12 weeks after completion of 
antiviral therapy).
11.
Screening 12-lead electrocardiogram (ECG) showing a baseline QT interval >470 msec 
or Grade 3 or higher cardiac disorders (according to National Cancer Institute Common 
Terminology Criteria for Adverse Events [NCI-CTCAE] version 4.03).
12.
Criterion modified per Amendment 2
12.1 Known allergies, hypersensitivity, or intolerance to mannitol, glucocorticoid, 
methotrexate, vincristine, mAb (IRR is not considered hypersensitivity) or human 
proteins, or their excipients (refer to respective package inserts and Investigator’s 
Brochure), or known sensitivity to mammalian-derived products. For subjects with T-
cell ALL/LL only, known allergies to doxorubicin, cytarabine, cyclophosphamide, or 
6-mercaptopurine.
13.
Criterion modified per Amendment 1
13.1 Received an investigational drug, was vaccinated with live attenuated vaccines, or 


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used an invasive investigational medical device within 4 weeks before the planned first 
dose of study drug, or is currently being treated in an investigational study.
14.
Criterion modified per Amendment 2
14.1 Pregnant, breastfeeding, or planning to become pregnant while enrolled in this 
study or within 12 months after the last dose of any component of the treatment 
regimen.
15.
Plans to father a child while enrolled in this study or within 6 months after the last dose 
of any component of the treatment regimen.
16.
Subject has any concurrent medical or psychiatric condition or disease (eg, active 
systemic infection, uncontrolled diabetes, acute diffuse infiltrative pulmonary disease) 
that is likely to interfere with the study procedures or results, or that in the opinion of 
the investigator, would constitute a hazard for participating in this study.
17.
Major surgery within 2 weeks before screening, or will not have fully recovered from 
surgery, or has surgery planned during the time the subject is expected to participate in 
the study or within 2 weeks after the last dose of study drug administration. 
Note: Subjects with planned surgical procedures to be conducted under local anesthesia 
may participate.
18.
Criterion modified per Amendment 2
Criterion modified per Amendment 3
18.2 Subject is known or suspected of not being able to comply with the study protocol 
(eg, because of alcoholism, drug dependency, or psychological disorder). Subject has 
any condition for which, in the opinion of the investigator, participation would not be in 
the best interest of the subject (eg, compromise the well-being) or that could prevent, 
limit, or confound the protocol-specified assessments. Subject is taking any prohibited 
medications listed in Section 8. Subject is not affiliated to, or a beneficiary of, a social 
security category, per local regulatory requirements, if applicable.
19.
Criterion added per Amendment 3
Subjects with infant leukemia (defined as under 1 year old at the time of initial 
diagnosis).  These subjects will not be eligible for this study, even if they are greater 
than 1 year old at the time of relapse.
NOTE: Investigators should ensure that all study enrollment criteria have been met at screening. 
If a subject's clinical status changes (including any available laboratory results or receipt of 
additional medical records) after screening but before the first dose of study drug is given such 
that he or she no longer meets all eligibility criteria, then the subject should be excluded from 


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participation in the study, with the exception of subjects who meet screening liver function 
criteria but have elevation of liver function tests (≤Grade 3) on Cycle 1 Day 1 after IT 
methotrexate. Section 17.4, Source Documentation, describes the required documentation to 
support meeting the enrollment criteria.
4.3.
Prohibitions and Restrictions 
Potential subjects must be willing and able to adhere to the following prohibitions and 
restrictions during the study to be eligible for participation. 
1.
Refer to Section 8 Prestudy and Concomitant Therapy for details regarding prohibited 
and restricted therapy during the study.
2.
Agree to follow all requirements that must be met during the study as noted in the 
Inclusion and Exclusion Criteria (eg, contraceptive requirements).
5.
TREATMENT ALLOCATION AND BLINDING
As this is an open-label study, blinding procedures are not applicable. 
6.
DOSAGE AND ADMINISTRATION
6.1.
Study Drug Administration for Each Cohort
6.1.1.
B-cell ALL/LL Cohort
Subjects with B-cell ALL/LL will receive daratumumab in combination with vincristine and 
prednisone continuously in 28-day cycles as specified in the Time and Events Schedule (Table 2) 
until disease progression, unacceptable toxicity, or proceeding to HSCT after achievement of 
CR.  Subjects proceeding to HSCT may receive bridging daratumumab prior to transplant as 
described in Section 6.1.3.  
The treatment schedule for subjects with B-cell ALL/LL is as follows. Disease status definitions 
for CNS leukemia are provided in Section 9.2.3. The order of administration for study 
medications may vary and a window of ±1 day is allowed in order to meet local requirements. 
However, on daratumumab dosing days, intrathecal therapy should be given first, then 
daratumumab should be administered prior to any other study drugs. Routine transfusions should 
be avoided on daratumumab dosing days. A steroid taper may be used as clinically indicated as 
per local standard practice.  


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
Intrathecal methotrexate (MTX) on Cycle 1 Day 1 (all subjects) and Cycles 2 and later Day 1 
of each cycle for CNS negative subjects (CNS 1 or 2 at study entry). Cycle 1 Day 1 IT 
therapy may be given up to 72 hours prior as part of diagnostic lumbar puncture (LP) during 
screening. IT cytarabine (ARA-C) is an acceptable substitute for Cycle 1 Day 1 only.  
o
Age 1 to <2 years=8 mg
o
Age 2 to <3 years=10 mg
o
Age 3 to <9 years=12 mg
o
Age ≥9 years=15 mg

Intrathecal MTX/hydrocortisone (HC)/ARA-C (CNS positive subjects; CNS 3 only at study 
entry) on Cycle 1 Days 8, 15, 22, 28 (if indicated; refer to Table 2) and Cycles 2 and later 
Day 1 of each cycle
o
Age 1 to <2 years=MTX 8 mg, HC 8 mg, ARA-C 16 mg
o
Age 2 to <3 years=MTX 10 mg, HC 10 mg, ARA-C 20 mg
o
Age 3 to <9 years=MTX 12 mg, HC 12 mg, ARA-C 24 mg
o
Age ≥9 years=MTX 15 mg, HC 15 mg, ARA-C 30 mg 

Daratumumab 16 mg/kg IV weekly for 8 doses, then every 2 weeks for 8 doses, then every 
28 days thereafter 
o
Cycles 1 and 2: Days 1, 8, 15, and 22 of each cycle
o
Cycles 3 to 6: Days 1 and 15 of each cycle
o
Cycle 7 and later: Day 1 of each cycle

Vincristine 1.5 mg/m2 (maximum dose 2 mg) IV push or mini bag (according to institutional 
standards) weekly for 4 doses, then every 2 weeks for 2 doses, then every 28 days thereafter
o
Cycle 1: Days 1, 8, 15, and 22
o
Cycle 2: Days 1 and 15
o
Cycle 3 and later: Day 1 of each cycle


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
Prednisone 40 mg/m2 given as 2 doses (20 mg/m2 per dose) orally for 28 days, then pulses of 
5 days per month thereafter, 
o
Cycle 1: Days 1 to 28
o
Cycles 2 and later: Days 1 to 5 of each cycle
NOTE: On daratumumab dosing days, substitute methylprednisolone 2 mg/kg (maximum 
100 mg) pre-infusion medication for prednisone 40 mg/m2.
6.1.2.
T-cell ALL/LL Cohort
Subjects with T-cell ALL/LL will receive up to 2 cycles (28-day cycles) of therapy as specified 
in Table 2 with subjects achieving CR proceeding to allogeneic HSCT off study if available. 
Subjects who do not achieve a CR or do not proceed to transplant at the end of Cycle 2 will 
discontinue study treatment and enter the Posttreatment Period. Subjects proceeding to HSCT 
may receive bridging daratumumab prior to transplant as described in Section 6.1.3.  
6.1.2.1.
T-cell ALL/LL Cycle 1
Subjects will receive the following treatment during Cycle 1. Disease status definitions for CNS 
leukemia are provided in Section 9.2.3. The order of administration for study medications may 
vary and a window of ±1 day is allowed in order to meet local requirements. However, on 
daratumumab dosing days, intrathecal therapy should be given first, then daratumumab should be 
administered prior to any other study drugs. Routine transfusions should be avoided on 
daratumumab dosing days.  A steroid taper after Cycle 1 may be used as clinically indicated as 
per local standard practice. For subjects in the T-cell ALL/LL cohort who achieve a CR after 
Cycle 1, subjects may proceed directly to allogeneic HSCT, or receive bridging therapy to 
transplant as per Section 6.1.3 or proceed to Cycle 2 therapy prior to HSCT as clinically 
indicated.

Intrathecal methotrexate (MTX) on Cycle 1 Day 1 (all subjects) and for CNS negative 
subjects (CNS 1 or 2 at study entry) on Cycle 1 Days 15 and 22. Cycle 1 Day 1 IT therapy 
can be given up to 72 hours prior as part of diagnostic LP during screening. IT cytarabine 
(ARA-C) is an acceptable substitute for Cycle 1 Day 1 only.
o
Age 1 to <2 years=8 mg
o
Age 2 to <3 years=10 mg
o
Age 3 to <9 years=12 mg
o
Age ≥9 years=15 mg


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
Intrathecal MTX/HC/ARA-C (CNS positive subjects; CNS 3 only at study entry) on Days 8, 
15, 22, and 28 (if indicated; refer to Table 2)
o
Age 1 to <2 years=MTX 8 mg, HC 8 mg, ARA-C 16 mg
o
Age 2 to <3 years=MTX 10 mg, HC 10 mg, ARA-C 20 mg
o
Age 3 to <9 years=MTX 12 mg, HC 12 mg, ARA-C 24 mg
o
Age ≥9 years=MTX 15 mg, HC 15 mg, ARA-C 30 mg 

Daratumumab 16 mg/kg IV weekly for 4 doses on Days 1, 8, 15, and 22

Doxorubicin 60 mg/m2 IV once on Day 1

Vincristine 1.5 mg/m2 (maximum dose 2 mg) IV push or mini bag (according to institutional 
standards) once weekly for 4 doses on Days 1, 8, 15, and 22 

Prednisone 40 mg/m2 given as 2 doses (20 mg/m2 per dose) orally daily on Days 1 to 28 
NOTE: On daratumumab dosing days, substitute methylprednisolone 2 mg/kg (maximum 100 
mg) pre-infusion medication for prednisone 40 mg/m2.

Peg-asparaginase 2500 U/m2 IM or IV (IV given over 1 to 2 hours is preferred) on Days 2 
and 16 (Erwinia asparaginase may be substituted; see Section 6.4.6)
6.1.2.2.
T-cell ALL/LL Cycle 2
Subjects with M2 or M3 bone marrow status will start Cycle 2 therapy immediately following
completion of Cycle 1. If intrathecal therapy was given less than 1 week prior to start of Cycle 2, 
then the start of Cycle 2 should be delayed for one week. For subjects with M1 bone marrow 
status at the end of Cycle 1, subjects must have peripheral count recovery with ANC 
>0.75x109/L and platelets >75x109/L and at least 1 week since last intrathecal therapy was given 
prior to initiation of Cycle 2. Disease status definitions for bone marrow status are provided in 
Section 9.2.2. 
Subjects will receive the following treatment during Cycle 2. Disease status definitions for 
central nervous system (CNS) leukemia are provided in Section 9.2.3. The order of 
administration for study medications may vary and a window of ±1 day is allowed in order to 
meet local requirements. However, on daratumumab dosing days, intrathecal therapy should be 
given first, then daratumumab should be administered prior to any other study drugs. Routine 
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
Intrathecal methotrexate (CNS negative subjects; CNS 1 or 2 at study entry) on Days 2 
and 15
o
Age 1 to <2 years=8 mg
o
Age 2 to <3 years=10 mg
o
Age 3 to <9 years=12 mg
o
Age ≥9 years=15 mg

Intrathecal MTX/HC/ARA-C (CNS positive subjects; CNS 3 only at study entry) on Days 2 
and 15
o
Age 1 to <2 years=MTX 8 mg, HC 8 mg, ARA-C 16 mg
o
Age 2 to <3 years=MTX 10 mg, HC 10 mg, ARA-C 20 mg
o
Age 3 to <9 years=MTX 12 mg, HC 12 mg, ARA-C 24mg
o
Age ≥9 years=MTX 15 mg, HC 15 mg, ARA-C 30 mg

Daratumumab 16 mg/kg IV weekly for 4 doses on Days 1, 8, 15, and 22

Methotrexate 5 g/m2 IV once on Day 2 (see Attachment 5 for infusion guidelines)

Cyclophosphamide IV 1 g/m2 once on Day 15

Cytarabine 75 mg/m2 IV/subcutaneous for 8 doses on Days 16 to 19 and 23 to 26

6-mercaptopurine 60 mg/m2 orally daily for 14 doses on Days 15 to 28
For subjects in the T-cell ALL/LL arm who achieve a CR after Cycle 1, the second cycle of 
therapy will be optional as a bridge to allogeneic HSCT. 
6.1.3.
Daratumumab Continuation Phase Prior to Transplant
For those subjects in either cohort who achieve a CR and require a short interval of treatment 
prior to transplant, daratumumab may be given at a dose of 16 mg/kg IV in weekly doses for a 
total of 4 doses after completion of Cycle 1 or every 2 weeks for a total of 2 doses after 
completion of Cycles 2 to 6, or once after completion of Cycles 7+. There should be a 2-week 
interval from the last dose of daratumumab and the start of conditioning therapy for the 
transplant. 
Other standard maintenance chemotherapy may also be given after the discontinuation of study 
treatment and prior to transplant, at the discretion of the investigator.  All maintenance therapy 
must be documented in the eCRF.


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6.2.
Daratumumab Preparation and Administration
6.2.1.
Daratumumab Preparation
Infusion solution will be prepared as a dilution of daratumumab in sterile, pyrogen-free 0.9% 
NaCl. Preparation of infusion bags should be done on the day of the planned infusion. 
Daratumumab must be administered as an IV infusion given through a well-functioning IV 
catheter by using an infusion pump. The study drug must be filtered by using an inline filter 
(0.2 μM) during the infusion. Manuals with detailed descriptions for preparation and 
administration of daratumumab will be supplied to each pharmacy and site.
6.2.2.
Daratumumab Administration
Daratumumab will be administered as an IV infusion. Each subject’s dose will be calculated 
based on the subject’s weight at Cycle 1 Day 1 rounded to the nearest kilogram. The dose of 
daratumumab will remain constant throughout the study, unless the subject’s weight changes 
more than 10% from Cycle 1 Day 1. Daratumumab infusion on Cycle 1 Day 1 will be given in 
the hospital; subsequent doses may be given in an outpatient clinic. Subjects will receive 
preinfusion medications and postinfusion medications (if indicated) as detailed in the protocol 
(Sections 6.3.1 and 6.3.2, respectively).
The dilution volumes, initial infusion rates, and increments for the first, second, and subsequent 
doses are provided in Table 6. For volume requirements, please see below:

Subjects weighing <10 kg: please consult the medical monitor.

Subjects weighing ≥10 to <20 kg will have daratumumab administered in a volume of 
250 mL for the first infusion (Cycle 1 Day 1), then in a volume of 100 mL for all subsequent 
infusions.

Subjects weighing ≥20 to ≤40 kg will have daratumumab administered in a volume of 
500 mL for the first infusion (Cycle 1 Day 1), then in a volume of 250 mL for all subsequent 
infusions. 

Subjects weighing >40 kg will have daratumumab administered in a volume of 1000 mL for 
the first infusion (Cycle 1 Day 1), then in a volume of 500 mL for all subsequent infusions.


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Table 6:
Daratumumab Infusion Rates
Subject 
Weight
Dilution 
Volume
Initial Infusion 
Rate (first hour)
Increments of 
Increase of 
Infusion Ratea
Maximum 
Infusion Rate
First infusion
≥10 to 
<20 kg
250 mL
10 mL/hr
10 mL every hr 
until maximum rate
40 mL/hr
≥20-≤40 
kg
500 mL
20 mL/hr
20 mL every hr 
until maximum rate 
80 mL/hr
>40 kg
1000 mL
50 mL/hr
50 mL every hr 
until maximum rate
200 mL/hour
Second infusionb
≥10 to 
<20 kg
100 mL
10 mL/hr
10 mL every hr 
until maximum rate
40 mL/hr
≥20-≤40 
kg
250 mL
20 mL/hr
20 mL/hr every hr 
until maximum rate
80 mL/hr
>40 kg
500 mL
50 mL/hr
50 mL every hr 
until maximum rate
200 mL/hour
Subsequent 
infusionsc
≥10 to 
<20 kg
100 mL
20 mL/hr
10 mL every hr 
until maximum rate
40 mL/hr
≥20-≤40 
kg
250 mL
40 mL/hr
20 mL every hr 
until maximum rate
80 mL/hr
>40kg
500 mL
100 mL/hr
50 mL every hour 
until maximum rate
200 mL/hour
a
Consider titration of the infusion rate only in the absence of infusion reactions.
b
A decreased dilution volume should be used only if there were no Grade 1 (mild) or greater IRRs during the first 
3 hours of the first infusion. Otherwise, continue to use the first infusion dilution volume and follow instructions 
for the first infusion. 
c    Use a modified initial rate for subsequent infusions (ie, third infusion onwards) only if there were no Grade 1 
(mild) or greater IRRs during the first 3 hours of the prior infusion. Otherwise, continue to use instructions for 
the second infusion.
As noted in the Time and Events Schedule (Table 2), vital signs should be monitored extensively 
on Cycle 1 Day 1 before, during, and after the first infusion of daratumumab and subjects will be 
hospitalized overnight due to the long duration of the first infusion. For all other infusions, vital 
signs should be measured before the start of the infusion and at the end of the infusion. If a 
subject experiences a significant medical event, then the investigator should assess whether the 
subject should stay overnight for observation. If the subject has not experienced a significant 
medical event but is hospitalized overnight only for observation, then the hospitalization should
not be reported as an SAE.
6.3.
Guidelines for Prevention and Management of Infusion-related Reactions
6.3.1.
Preinfusion Medications
In an effort to prevent IRRs, all subjects will receive the following medications 1 to 3 hours prior 
to each study drug administration (1 hour prior to study drug administration is preferred):

An antipyretic: paracetamol (acetaminophen) 15 mg/kg (maximum 1000 mg) PO

An antihistamine: diphenhydramine or equivalent, 0.5 to 1 mg/kg (maximum 50 mg) IV or 
PO (see Attachment 6 for list of antihistamines that may be used)

A glucocorticoid: methylprednisolone 2 mg/kg (maximum 100 mg) IV or PO (IV preferred). 
Substitutions for methylprednisolone are allowed (refer to Attachment 2).


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Predose administration of a leukotriene inhibitor (montelukast 5 to 10 mg PO [age appropriate 
dosing]) is optional on Cycle 1 Day 1 and can be administered up to 24 hours before infusion as 
per investigator discretion.
If necessary, all PO preinfusion medications may be administered outside of the clinic on the day 
of the infusion, provided they are taken within 3 hours before the infusion.
6.3.2.
Postinfusion Medications
For subjects with a higher risk of respiratory complications (eg, subjects with mild asthma or 
subjects with underlying pulmonary conditions, the following postinfusion medications should 
be considered:

Antihistamine (diphenhydramine or equivalent) 

Leukotriene inhibitor (montelukast or equivalent)

Short-acting β2 adrenergic receptor agonist such as salbutamol aerosol 

Control medications for lung disease (eg, inhaled; use nebulizer, if necessary) 
glucocorticoid ± long-acting β2 adrenergic receptor agonists for subjects with asthma; 
long-acting bronchodilators such as tiotropium or salmeterol ± inhaled glucocorticoid for 
subjects with pulmonary conditions)
In addition, these at-risk subjects may be hospitalized for monitoring for up to 2 nights after 
daratumumab administration. If subjects are hospitalized, then an improvement in either oxygen 
saturation as measured by pulse oximetry or forced expiratory volume in 1 second (FEV1), if the 
test is feasible, should be documented prior to discharge. If these subjects are not hospitalized, 
then a follow-up telephone call should be made to monitor their condition within 48 hours after 
all infusions. If the subject has not experienced a significant medical event but is hospitalized 
overnight only for observation, then the hospitalization should not be reported as an SAE. 
Investigators may prescribe bronchodilators, H1-antihistamines, and glucocorticoid that are 
deemed necessary to provide adequate supportive care in the event a bronchospasm occurs after 
subjects are released from the hospital/clinic. If an at-risk subject experiences no major IRRs, 
then these postinfusion medications may be waived after 4 doses at the investigator’s discretion. 
6.3.3.
Management of Infusion-related Reactions
Subjects should be observed carefully during daratumumab infusions. Trained study staff at the 
clinic should be prepared to intervene in case of any IRRs, and resources necessary for 
resuscitation (eg, agents such as epinephrine and aerosolized bronchodilator, also medical 
equipment such as oxygen tanks, tracheostomy equipment, and a defibrillator) must be available 
at the bedside. Attention to staffing should be considered when multiple subjects will be dosed at 
the same time. 
If an IRR develops, then daratumumab administration should be temporarily interrupted. Please 
see the IPPI for further details. Subjects who experience adverse events during daratumumab 
administration must be treated for their symptoms. Subjects should be treated with 
acetaminophen, antihistamine, or corticosteroids, as needed. Intravenous saline may be indicated. 


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For bronchospasm, urticaria, or dyspnea, subjects may require antihistamines, oxygen, 
corticosteroids, or bronchodilators. For hypotension, subjects may require vasopressors. In the 
event of a life-threatening IRR (which may include pulmonary or cardiac events) or anaphylactic 
reaction, daratumumab should be discontinued and no additional daratumumab should be 
administered to the subject.

Grade 1-2 (mild to moderate) IRRs: If the investigator assesses a Grade 1-2 IRR adverse 
event to be related to administration of study drug, then the daratumumab administration 
should be paused. When the subject's condition is stable, daratumumab administration may 
be restarted at half of the rate at the investigator's discretion.
If the subject experiences a Grade 2 or higher event of laryngeal edema, or a Grade 2 or 
higher event of bronchospasm that does not respond to systemic therapy and does not 
resolve within 6 hours from onset, then the subject must be permanently discontinued from 
daratumumab treatment.

Grade 3 or higher IRRs: For IRR adverse events (other than laryngeal edema or 
bronchospasm) that are Grade 3, the daratumumab administration must be stopped and the 
subject must be observed carefully until resolution of the adverse event or until the intensity 
of the event decreases to Grade 1, at which point the daratumumab administration may be 
restarted at half of the rate at the investigator’s discretion. If the intensity of the adverse 
event returns to Grade 3 after restart of the daratumumab administration, then the subject 
must be withdrawn from daratumumab treatment. For IRR adverse events that are Grade 4, 
the daratumumab administration must be stopped and the subject withdrawn from 
daratumumab treatment.

Recurrent IRRs: If a Grade 3 IRR (or ≥Grade 2 event of laryngeal edema or 
bronchospasm) recurs during or within 24 hours after a subsequent daratumumab 
administration, the daratumumab treatment must be discontinued.
6.4.
Delay and Modifications
Subjects who need to discontinue treatment with any one component of study treatment may 
continue to receive treatment with the other components of study treatment.
6.4.1.
Daratumumab
Dose modification of daratumumab is not permitted. Dose delay is the primary method for 
managing daratumumab-related toxicities.
On the first day of each new treatment cycle and before each daratumumab dose, the subject will 
be evaluated by the treating physician for possible toxicities that may have occurred after the 
previous dose(s). Toxicities are to be assessed according to NCI-CTCAE, Version 4.03. Dose 
modifications or delays will be made based on the toxicity experienced during the previous cycle 
of therapy or newly encountered on Day 1 of a cycle.
Only if any of the following criteria are met and the event cannot be ascribed to components of 
the chemotherapy regimen or if the causality is unclear, then the daratumumab infusion must be 
held to allow for recovery from toxicity. If there are any questions regarding dose delay, contact 
the medical monitor. 


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The criteria for dose delay are:

Grade 4 thrombocytopenia with bleeding

Grade 4 febrile neutropenia

Grade 4 infection

Grade 3 or higher non-hematologic toxicities with the following exceptions: 
o
Grade 3 nausea that responds to antiemetic treatment within 7 days
o
Grade 3 vomiting that responds to antiemetic treatment within 7 days
o
Grade 3 diarrhea that responds to antidiarrheal treatment within 7 days
o
Grade 3 fatigue that was present at baseline or that lasts for <7 days after the last 
administration of daratumumab
o
Grade 3 asthenia that was present at baseline or that lasts for <7 days after the last 
administration of daratumumab
Administration of daratumumab may be restarted upon recovery from toxicity to Grade 2 or 
baseline, with the exception that Grade 2 laryngeal edema or Grade 2 bronchospasm must be 
fully recovered.
If daratumumab administration does not commence within the prespecified window (Table 7) of 
the scheduled administration date, then the dose will be considered a missed dose. 
Administration may resume at the next planned dosing date. A missed dose will not be made up.
Table 7:
Daratumumab-Related Toxicity Management
Cycles
Frequency
Dose Missed
Dosing Resumption
1-2
Weekly
>3 days
next planned weekly dosing date
3-6
Every 2 weeks
>7 days
next planned every-2-weeks dosing date
7+
Every 4 weeks
>14 days
next planned every-4-weeks dosing date
If Day 1 of a cycle is delayed, then Day 1 of subsequent cycles should be adjusted accordingly to 
maintain the cycle duration. However, if a within-cycle dose is delayed, then the dates of the 
subsequent within-cycle doses should not be adjusted. If a dose delay occurs, then PK 
assessments should be performed on the actual administration day of daratumumab, not on the 
original scheduled administration day. 
Any adverse event deemed to be related to daratumumab that requires a dose hold of more than 
4 weeks will result in permanent discontinuation of daratumumab, unless, upon consultation with 
the sponsor and the review of safety and efficacy, continuation is agreed upon.


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6.4.2.
Intrathecal Methotrexate/Triple Intrathecal Therapy 
The criteria for dose delay or modifications are as follows:

Systemic toxicity: the dosage for intrathecal methotrexate will not be reduced for systemic 
toxicity (myelosuppression, mucositis, etc.). Leucovorin may be used if a subject experiences 
myelosuppression with ANC <0.5x109/L or mucositis. Start leucovorin at a dose of 
5 mg/m2/dose every 12 hours x 2 doses, beginning 48 hours after the intrathecal therapy. 

Acute neurotoxicity: discuss with medical monitor before administration of intrathecal 
therapy.

Hydrocephalus, microcephaly or known abnormality of CSF flow precluding intrathecal 
chemotherapy through LP: intraventricular chemotherapy through Ommaya catheter may be 
used in place of intrathecal therapy delivered by LP. Intraventricular chemotherapy should be 
given according to the same schedule, but at 50% of the corresponding age-based doses that 
would be given by LP. NOTE: Obstruction to CSF flow may be a contraindication to 
intrathecal or intraventricular therapy. 

Viral, bacterial, or fungal meningitis: hold intrathecal therapy until infection is resolved.
6.4.3.
Vincristine 
The criteria for dose delay or modifications are as follows:

Severe neuropathic pain (Grade 3 or greater): hold dose. When symptoms resolve to Grade 1 
or baseline, resume at 50% dose reduction (maximum dose: 1 mg), then escalate to full dose 
as tolerated. 

Vocal cord paralysis: hold dose. When symptoms subside, resume at 50% previous 
calculated dose (maximum dose: 1 mg), then escalate to full dose as tolerated. 

Foot drop, paresis (Grade 3 or higher): consider holding or decreasing dose. 

Jaw pain: treat with analgesics; do not modify vincristine dose. 

Hyperbilirubinemia.
Direct Bilirubin %
Dose Reduction
<3.1 mg/dL
Full dose (maximum dose: 2 mg)
3.1 – 5.0 mg/dL
50% 
of 
calculated 
dose 
(maximum dose: 1 mg)
5.1 – 6.0 mg/dL
75% 
of 
calculated 
dose 
(maximum dose: 0.5 mg)
>6.0 mg/dL
Hold dose and administer next 
scheduled dose if toxicity has 
resolved. *
*Do not make up missed doses. 


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
Constipation or ileus (≥Grade 3) or typhlitis: hold dose; initiate treatment. When symptoms 
resolve, resume at 50% of dose (maximum dose: 1 mg) and escalate to full dose as tolerated.

Extravasation: in the event of an extravasation, discontinue the IV administration of the drug 
and institute appropriate measures to prevent further extravasation and damage according to 
institutional guidelines.
6.4.4.
Glucocorticoid (Prednisone) 
Toxicities related to glucocorticoids should be managed clinically without dose modifications. If 
there is any consideration of discontinuation, then the investigator must consult with the medical 
monitor.
If there is an inability to use oral doses, substitute IV methylprednisolone at 80% of the oral 
prednisone dose. Note that if substituting oral prednisolone for prednisone, the doses are the 
same.
6.4.5.
Doxorubicin (Anthracycline) 
The criteria for dose delay or modifications are as follows:

Hyperbilirubinemia:
Direct Bilirubin %
Dose Reduction
<1.2 mg/dL
Full dose
1.2 – 3.0 mg/dL
50%

Extravasation: in the event of an extravasation, discontinue the IV administration of the drug 
and institute appropriate measures to prevent further extravasation and damage according to 
institutional guidelines. 
6.4.6.
Asparaginase (Pegaspargase [PEG-Asparaginase] or Erwinia) 
The criteria for dose delay or modifications are as follows:

Allergy 
o
Local allergic reactions (inflammation at injection site, swelling): continue pegaspargase 
administration in the presence of Grade 1 allergy as defined by CTCAE Version 4.03 
(transient flushing or rash; drug fever <38ºC). 
o
Systemic allergic reactions: discontinuation may be considered for severe Grade 2 or 
higher allergic reactions as defined by CTCAE Version 4.03. 
Note: Premedication with antihistamines to decrease the risk of overt allergy symptoms is 
strongly discouraged because antihistamine use may mask the appearance of systemic 
allergy. In the event of severe systemic or recurrent local allergic reaction, Erwinia 
asparaginase should be substituted as noted in the table below. 


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o
Anaphylaxis: discontinue pegaspargase if the subject develops Grade 3 anaphylaxis as 
defined by CTCAE Version 4.03 (symptomatic bronchospasm, with or without urticaria, 
parenteral intervention indicated; allergy-related edema/angioedema; hypotension). If this 
occurs, then Erwinia asparaginase should be substituted as noted in the table below. 
Substitute Erwinia asparaginase for pegaspargase utilizing the following schedule.
Phase(s) of Treatment
Drug(s)
Replacement Schedule for Erwinia 
asparaginase*
Cycle 1 T-cell ALL cohort
Pegaspargase  
(2,500 IU/m2)
25,000 IU/m2/dose IM 
Give 6 doses of Erwinia on M/W/F schedule 
for each dose of pegaspargase except the last 
dose of pegaspargase
*If a subject develops a Grade 3 or higher anaphylaxis to Erwinia, discontinue future asparaginase therapy. 
Consider discontinuation for severe Grade 2 or higher allergic reactions.

Coagulopathy: if symptomatic, hold asparaginase until symptoms resolve, then resume with 
the next scheduled dose. Consider prophylaxis for coagulopathy. No dose modification for 
abnormal laboratory findings without clinical symptoms. 

Hyperglycemia: 
o
Grade 1 or 2: no dose modification required. Treat hyperglycemia as medically indicated. 
o
Grade 3 or 4 including ketoacidosis: hold asparaginase until blood glucose can be 
regulated with insulin, then asparaginase can be resumed. 

Pancreatitis (Grade 3 or 4): permanently discontinue asparaginase in the presence of 
hemorrhagic pancreatitis or severe pancreatitis. In the case of mild pancreatitis, asparaginase 
should be held until symptoms and signs subside, and amylase levels return to normal and 
then resumed. 

Thrombosis: withhold asparaginase until resolved, and treat with appropriate antithrombotic 
therapy, as indicated. Upon resolution of symptoms consider resuming asparaginase, while 
continuing low molecular weight heparin or antithrombotic therapy. Do not withhold dose 
for abnormal laboratory findings without clinical correlate. 


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6.4.7.
Cyclophosphamide
The criteria for dose delay or modifications are as follows:

Hematuria: hold dose if there is macroscopic hematuria. If there is a history of previous 
significant hematuria, hydrate before cyclophosphamide until specific gravity is < 1.010 and 
hydrate at 125 mL/m2/hr for 24 hours after dose. Monitor for adequate urine output according 
to institution guidelines. Give IV mesna at a total dose that is 60% of the cyclophosphamide 
dose divided into 3 doses (eg, if the cyclophosphamide dose is 1000 mg/m2, the total mesna 
dose is 600 mg/m2 or 200 mg/m2/dose x 3). Give the first mesna dose 15 minutes before or at 
the same time as the cyclophosphamide dose and repeat 4 and 8 hours after the start of 
cyclophosphamide. This total daily dose of mesna may also be administered as an IV 
continuous infusion. The continuous infusion should be started 15 to 30 minutes before or at 
the same time as cyclophosphamide and finished no sooner than 8 hours after the end of 
cyclophosphamide infusion. 

Renal dysfunction: if creatinine clearance or radioisotope GFR is < 10 mL/min/1.73 m2, 
reduce dose of cyclophosphamide by 50%. Prior to dose adjustment of cyclophosphamide, 
the creatinine clearance should be repeated with good hydration. 
6.4.8.
Cytarabine (ARA-C) 
Withhold ARA-C for Grade 3 or 4 rash until resolved. Do not withhold ARA-C for fever if it is 
likely to have been caused by the ARA-C. Obtain blood cultures if a central line is present. 
6.4.9.
Mercaptopurine
No dose adjustments should be made to mercaptopurine dosing.
6.4.10.
High-dose Methotrexate (HD MTX) 
The criteria for dose delay or modifications are as follows:

Nephrotoxicity: hold MTX if serum creatinine is >1.5 x baseline or GFR creatinine clearance 
<65 mL/min/1.73 m2. For subjects who have markedly delayed MTX clearance secondary to 
renal dysfunction, consider using glucarpidase (carboxypeptidase G2)  

Liver toxicity: ALT >20 x ULN or hyperbilirubinemia (direct bilirubin >2.0 mg/dL.): delay 
IV MTX until resolved.

Mucositis: for Grade 3 or 4 mucositis from a previous course of chemotherapy, delay IV 
MTX until resolved. 

Myelosuppression: hold IV methotrexate until ANC >0.75x109/L and platelets >75x109/L.


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7.
TREATMENT COMPLIANCE
Study drug (daratumumab) and all backbone therapies except for prednisone and 
6-mercaptopurine, will be administered by qualified study-site personnel as specified in Table 2.
The details of each administration will be recorded in the electronic case report form (eCRF), 
including date, start and stop times of infusions, and the volume infused. Prednisone and 
6-mercaptopurine will be dispensed for self-administration. Subjects/caregivers will be provided 
with a diary card to record intake at home. Site personnel are to instruct the subject/caregiver to 
bring the diary card and any unused prednisone to the site at the beginning of each treatment 
cycle to check dosing compliance.
The Interactive Web Response System will be used to assign centrally open-label supplied study 
treatment (daratumumab) kits for each subject. The investigator or the site pharmacist will 
maintain a log of all daratumumab dispensed and returned. Drug supplies for each subject will be 
inventoried and accounted for throughout the study.
8.
PRESTUDY AND CONCOMITANT THERAPY
All therapies (prescription or over-the-counter medications, including vaccines, vitamins, herbal 
supplements; non-pharmacologic therapies such as electrical stimulation, acupuncture, special 
diets, exercise regimens) different from the study drug must be recorded in the eCRF. Recorded 
information will include a description of the type of the drug, treatment period, dosing regimen, 
route of administration, and its indication.
8.1.
Prestudy Therapy
All prior oncologic therapies, including those administered since diagnosis of ALL or LL, must
be recorded at screening. Transfusions administered up to 2 weeks prior to screening must also 
be recorded at screening. All other prestudy therapies administered up to 30 days before first 
dose of study drug must be recorded at screening.
8.2.
Concomitant Therapy
Throughout the study, investigators may prescribe any concomitant medications or treatments 
deemed necessary to provide adequate supportive care except for those listed in Section 8.2.3. 
The sponsor must be notified in advance (or as soon as possible thereafter) of any instances in 
which prohibited therapies are administered.
Routine systemic use of concomitant medications will be collected in the eCRF and recorded in 
the source documents beginning with signing of the ICF/assent form until 30 days after the last 
dose of the last study treatment or until the start of subsequent anticancer treatment, if earlier.
8.2.1.
Recommended Concomitant Therapies
8.2.1.1.
Prophylaxis for Tumor Lysis Syndrome
Subjects should be monitored for symptoms of tumor lysis syndrome. Subjects should be treated 
prophylactically in accordance with local standards (including vigorous hydration, alkalinization, 
diuretics, and allopurinol or rasburicase prior to initiation of therapy).


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8.2.1.2.
Prophylaxis for Infection
Prophylaxis 
for 
infection 
(including 
bacterial, 
fungal, 
and 
Pneumocystis 
pneumonia/Pneumocystis carinii/ jirovecii pneumonia) should be performed according to local 
institutional practice. 
8.2.1.3.
Prophylaxis for Nausea
Subjects should be given antiemetics during each chemotherapy course individualized to the 
subject’s best response. However, glucocorticoids and aprepitant/fosaprepitant should not be 
used as antiemetics.
8.2.1.4.
Prophylaxis for Herpes Zoster Reactivation
Prophylaxis for herpes zoster reactivation is recommended during the Treatment Period, as per 
institutional guidelines, and for 3 months following treatment.
8.2.1.5.
Prophylaxis for Glucocorticoid-Induced Gastritis
Glucocorticoids may induce gastritis. Medications to prevent gastritis may be given according to 
institutional guidelines (eg, proton pump inhibitors [omeprazole or equivalent], sucralfate, or H2 
blockers [ranitidine or equivalent]).
8.2.1.6.
Management of Hepatitis B Virus Reactivation
Primary antiviral prophylaxis is permitted as per local standard of care. Per protocol, HBV DNA 
testing by PCR is mandatory for subjects at risk for HBV reactivation; see Section 9.5.
For subjects who are diagnosed with HBV reactivation while on treatment, study treatment 
should be interrupted until the infection is adequately controlled. If the benefits outweigh the 
risks, study treatment may be resumed with concomitant antiviral prophylaxis as per local 
standard of care. Consult a liver disease specialist as clinically indicated.
8.2.2.
Permitted Concomitant Therapies
Subjects are to receive full supportive care during the study. The following medications and 
supportive therapies are examples of support therapies that may be used during the study:

Antivirals

Prevention of constipation (eg, adequate hydration, high-fiber diet, and stool softeners if 
needed)

Prophylactic antiemetics, with the exception of glucocorticoids and aprepitant/fosaprepitant

Colony stimulating factors, erythropoietin, and transfusion of platelets and red blood cells; 
routine transfusions should not be given on daratumumab dosing days

Loperamide is recommended for the treatment of diarrhea, starting at the time of the first 
watery stool. The loperamide dose and regimen is according to institutional guidelines. 
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Other symptoms may be managed according to institutional guidelines provided prohibited 
therapies are not administered (see Section 8.2.3).
8.2.3.
Prohibited Concomitant Therapies
Concomitant administration of the following therapies is prohibited during the study:

Any antineoplastic therapy for the intention of treating ALL or LL is prohibited, including 
conventional chemotherapy agents, investigational agents, and approved or investigational 
medications that target CD38 

Aprepitant/fosaprepitant

Strong CYP3A4 and P glycoprotein inhibitors, such as ketoconazole or itraconazole, is 
prohibited. 
For 
an 
ongoing 
list 
of 
CYP3A 
inhibitors 
and 
inducers, 
see 
http://medicine.iupui.edu/flockhart/  

Live vaccines during the study and for 3 months after the last dose of vincristine 
The sponsor must be notified in advance (or as soon as possible thereafter) of any instances in 
which prohibited therapies are administered.
9.
STUDY EVALUATIONS
9.1.
Study Procedures
9.1.1.
Overview
The study is divided into 3 periods: a Screening Period, a Treatment Period, and a Posttreatment 
Period. The Time and Events Schedule summarizes the frequency and timing of efficacy, PK, 
immunogenicity, biomarker, and safety measurements applicable to this study. Study 
assessments will be performed only after written informed consent is obtained.
The total blood volume to be withdrawn during the study will vary depending on the number of 
cycles of treatment that each subject receives. It is not expected to exceed approximately 17 mL 
during screening, 38 mL per cycle, and 18 mL for End of Treatment and follow-up assessments 
(Attachment 7). Repeat or unscheduled samples may be taken for safety reasons or for technical 
issues with the samples but should not exceed allowable daily blood volume limits according to 
local standards. 
9.1.2.
Screening Period
All subjects, or their legally acceptable representatives, must sign an ICF prior to the conduct of 
any study-related procedures. Where applicable, subjects below the age of legal consent should 
sign an assent form prior to the conduct of any study-related procedures. 
The Screening Period begins when the first screening procedure is conducted. During the 
Screening Period, eligibility criteria will be reviewed and a complete clinical evaluation will be 
performed as specified in the Time and Events Schedule (Table 1). Screening procedures will be 
performed within 21 days before first dose, except for pregnancy tests, which are to be 
performed within 14 days before Cycle 1 Day 1 for female subjects of childbearing potential 


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only. Results from standard of care procedures obtained within 21 days before Cycle 1 Day 1 
may be used without these tests being repeated.
9.1.3.
Treatment Period
Details of the procedures performed during the Treatment Period are outlined in the Time and 
Events Schedule (Table 1). Subjects will be closely monitored for adverse events (AEs), 
laboratory abnormalities, and clinical response. Subjects with B-cell ALL/LL will receive 
treatment until disease progression, unacceptable toxicity, or achievement of CR followed by 
HSCT. Subjects with T-cell ALL/LL will receive treatment for up to 2 cycles. There is an 
optional maintenance phase in all subjects who achieve CR to bridge therapy to allogeneic 
HSCT. If disease progression is confirmed, then the subject will discontinue study treatment, 
complete the End-of-Treatment Visit, and enter the Posttreatment Period.
End-of-Treatment Visit
Unless a subject/caregiver withdraws consent for study participation or the subject is lost to 
follow-up, an End-of-Treatment Visit is to occur 30 days (+7 days) after the last dose of study 
treatment. If a subject is unable to return to the site for the End-of-Treatment Visit, then the 
subject should be contacted to collect information on AEs that occur up to 30 days after the last 
dose of study treatment. Additional information on reporting of AEs is presented in Section 12.
9.1.4.
Posttreatment Period (Follow-Up)
For all subjects who discontinue study drug prior to CR or PD, disease evaluations will continue 
every 8 weeks until CR, PD, subsequent anticancer therapy is initiated, or study completion 
(see Section 17.9.1). After CR or PD, follow-up will occur every 12 weeks to record information 
on subsequent anticancer therapy, second primary malignancies, documentation of progressive 
disease or relapsed disease, and survival status. 
For all subjects proceeding to transplant, the following information will be collected and 
documented in the eCRF: date of transplant, type of transplant, time to engraftment, and any 
graft failures. In addition, any maintenance chemotherapy given after discontinuation of study 
treatment and prior to transplant must be documented in the eCRF. If the information is obtained 
by telephone contact, then written documentation of the communication must be available for 
review in the source documents. If the subject has died, then the date and cause of death will be 
collected and documented on the eCRF. Serious adverse events that are considered related to 
daratumumab within the Follow-up Period must be reported using the Serious Adverse Event 
Form (see Section 12.3.1).
The study will end 1 year after the last subject has initiated treatment or when the Sponsor 
decides to stop the study.


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9.2.
Efficacy Evaluations 
Bone marrow evaluations will be performed as specified in the Time and Events Schedule
(Table 1). CSF will be evaluated at the time of each IT therapy per the Time and Events 
Schedule (Table 1); status at the closest evaluation to Day 28 of a cycle will define response of 
CNS. Blood samples will be collected for Ph+ subjects only for assessment of BCR-ABL 
locally. 
A chest X-ray will be performed at screening and as clinically indicated thereafter to evaluate for 
mediastinal masses. Computed tomography (CT) or MRI scans of the chest will be performed for 
subjects with ALL and mediastinal mass at screening and on treatment until resolution of the 
mass.  CT or MRI scan of the chest and abdomen/pelvis with contrast is required for all subjects 
with LL at screening and during treatment if positive at screening as specified in the Time and 
Events Schedule (Table 1) for subjects with ALL with mediastinal mass and subjects with LL. 
IV contrast is required for chest CT scan; IV and oral contrast is required for abdomen/pelvis CT 
scan, and IV contrast is required for the MRI. CT or MRI scans can be deferred until the subject 
is medically stable if unable to perform due to subject’s medical condition (ie, large mediastinal 
mass with cardiorespiratory compromise).
9.2.1.
Response Categories
Disease evaluations will be performed as specified in Table 1 on the scheduled assessment day 
(window of +7 days). If treatment has been delayed for any reason, then the disease evaluations 
must continue to be performed as scheduled, regardless of any changes to the dosing regimen 
schedule. Disease evaluations scheduled for treatment days should be collected before study drug 
is administered. Disease response should reflect response in all areas of disease (ie, bone marrow 
and mediastinal mass, or bone marrow and extramedullary disease). If a subject does not have a 
CR in an extramedullary compartment, response will be considered “refractory disease” as per 
Section 9.2.1.1.
9.2.1.1.
Acute Lymphoblastic Leukemia
Assessments of disease response and progression for subjects with ALL will be based on the 
modified National Comprehensive Cancer Network (NCCN) criteria29:

CR:
o
Less than 5% blasts in the bone marrow
o
No evidence of circulating blasts or extramedullary disease
o
Full recovery of peripheral blood counts:

Platelets >100x109/L

ANC >1.0x109/L

CRi:
o
Less than 5% blasts in the bone marrow
o
No evidence of circulating blasts or extramedullary disease


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o
Partial recovery of peripheral blood counts not meeting criteria for CR noted above

ORR=CR+CRi

Relapse from CR
o
Reappearance of leukemia blasts in the peripheral blood or >5% blasts in the bone 
marrow
o
Reappearance of extramedullary disease or new extramedullary disease

Refractory disease: failure to achieve CR at end of induction therapy and does not meet 
criteria for progressive disease

Progressive disease: increase of at least 25% in the absolute number of circulating peripheral 
or bone marrow blasts, or development of new extramedullary disease
MRD negative is defined as <0.01% abnormal population counts to nucleated mononuclear cells 
when measured by flow.
9.2.1.2.
Central Nervous System Disease
Response criteria for CNS disease (M2 or M3 subjects only) are as follows:

Remission: achievement of M1 CNS status

Relapse: development of new M3 CNS status or development of new symptoms of CNS 
leukemia
Subjects with M2 or M3 CNS status who do not improve to M1 CNS status after 1 cycle of 
treatment should permanently discontinue all study treatment.
9.2.1.3.
Mediastinal Mass
Response criteria for mediastinal mass (subjects with ALL only) are as follows:

CR: complete resolution of the mediastinal mass by CT or MRI

PR: a decrease of ≥50% in the sum of the products of the diameter (SPD) of the lesions 
with no new lesions 

Progressive disease: an increase of ≥25% in the size of any lesions or appearance of new 
lesions

Stable disease: not meeting criteria for CR or PR noted above

Relapse: recurrence of mass or new lesions 


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9.2.1.4.
Lymphoblastic Lymphoma
Measurable disease is defined as any nodal mass with longest transverse diameter > 2 cm, or any 
measurable, focal mass lesion of a visceral organ (such as liver, spleen, kidney). Measurable 
lesions in a visceral organ are lesions that can be accurately measured in 2 axial dimensions by 
CT.
Response criteria for subjects with LL are as follows (based on response criteria in adult NHL8): 

CR: disappearance of all evidence of disease from all sites. This will be determined by 
physical examination and appropriate imaging studies. Bone marrow aspirate/biopsy must 
be normal and any macroscopic nodules in any organs detectable on imaging techniques 
should no longer be present. 

CR unconfirmed (CRu): a residual lymph node mass >1.5 cm in greatest transverse diameter 
that has regressed by >75% in sum of the products of the greatest perpendicular diameters. 

PR: a decrease of ≥50% in the SPD of the lesions of up to 6 of the largest dominant nodes or 
nodal masses with no new lesions. 

Stable disease: failure to qualify for a CR, CRu, PR, or progressive disease. No new lesions. 

Progressive disease: an increase of ≥25% in the size of any lesions or appearance of new 
lesions.
9.2.2.
Bone Marrow Evaluation
Fresh bone marrow aspirate will be collected according to the Time and Events Schedule 
(Table 1 and Table 2). Local and central bone marrow evaluations will be performed as 
described in Table 8. Bone marrow aspirate is required for central bone marrow evaluations; 
bone marrow biopsy is not acceptable for central testing.  If the aspirate procedure is deemed 
inadequate, biopsy is required for local testing.


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Table 8:
Local and Central Bone Marrow Evaluations
Timepoint
Local Testing
Central Testing
Screening
Disease characterization

Morphology (evaluate percentage of 
tumorous leukemia/lymphoma cells and 
cellularity)

Immunohistochemistry, 
immunofluorescence, or flow cytometry
(evaluate presence of tumorous 
leukemia/lymphoma cells present by 
immunophenotyping and indicate probes 
used for immunophenotyping)
Cytogenetics

Either by FISH or conventional karyotype
MRD: a portion of fresh bone marrow 
aspirate collected at screening will be 
sent to a central laboratory for 
assessment of MRD by flow cytometry 
and PCR
Biomarkers: baseline assessment of 
biomarkers predictive of clinical 
response or resistance to therapy
Disease evaluations 
prior to PD or CR, 
and prior to start of 
subsequent 
anticancer therapya
Disease characterization

Morphology (evaluate percentage of tumorous 
leukemia/lymphoma cells and cellularity)
MRD: a portion of fresh bone marrow 
aspirate collected at each disease 
evaluation time point will be sent to a 
central laboratory
Biomarkers: assessment of biomarkers 
predictive of clinical response or 
resistance to therapy
End of Treatment 
(if feasible)
Disease characterization

Morphology (evaluate percentage of 
tumorous leukemia/lymphoma cells and 
cellularity)
MRD: a portion of fresh bone marrow 
aspirate collected will be sent to a 
central laboratory
Biomarkers: assessment of biomarkers 
predictive of clinical response or 
resistance to therapy
Abbreviations: CR=complete response; FISH=fluorescence in situ hybridization; LL=lymphoblastic lymphoma; 
MRD=minimal residual disease; PCR=polymerase chain reaction; PD=progressive disease. 
a.
For subjects with LL, on-treatment bone marrow evaluations are only required if bone marrow disease is 
present at Screening.
If there is no hematologic recovery at the end of Cycle 1, bone marrow evaluations will be 
repeated when count recovery occurs (ANC >1.0x109/L, platelets >100x109/L) within 7 days of 
Cycle 1 Day 28 unless there is evidence of blasts, then continue to Cycle 2.
For subjects with LL, on-study bone marrow evaluation is only required if bone marrow disease 
is present at study entry.
If subject receives continuation therapy with daratumumab prior to transplant, a repeat bone 
marrow evaluation must be performed within 2 weeks of transplant.
The definitions for bone marrow status are as follows:

M1 <5% lymphoblasts 

M2 5 to 25% lymphoblasts 

M3 >25% lymphoblasts 


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9.2.3.
Lumbar Puncture
Cerebrospinal fluid will be collected to evaluate for CNS leukemia as described in the Time and 
Events Schedule (Table 1) for assessment of disease status. The definitions for CNS leukemia 
are as follows:

CNS 1: in CSF, absence of blasts in pathology evaluation (ie, cytospin or flow cytometry) 
regardless of the number of white blood cells (WBCs). 

CNS 2: in CSF, presence <5/μL WBCs and pathology evaluation (ie, cytospin or flow 
cytometry) positive for blasts, or ≥5/μL WBCs but negative by Steinherz/Bleyer algorithm 
(see below): 
o
CNS 2a: <10/μL RBCs; <5/μL WBCs and pathology evaluation (ie, cytospin or flow 
cytometry) positive for blasts; 
o
CNS 2b: ≥10/μL RBCs; <5/μL WBCs and pathology evaluation (ie, cytospin or flow 
cytometry) positive for blasts; and 
o
CNS 2c: ≥10/μL RBCs; ≥5/μL WBCs and pathology evaluation (ie, cytospin or flow 
cytometry) positive for blasts but negative by Steinherz/Bleyer algorithm (see below); 

CNS 3: in CSF, presence of ≥5/μL WBCs and pathology evaluation (ie, cytospin or flow 
cytometry) positive for blasts or clinical signs of CNS leukemia: 
o
CNS 3a: <10/μL RBCs; ≥5/μL WBCs and pathology evaluation (ie, cytospin or flow 
cytometry) positive for blasts; 
o
CNS 3b: ≥10/μL RBCs, ≥5/μL WBCs and positive by Steinherz/Bleyer algorithm (see 
below); 
o
CNS 3c: clinical signs of CNS leukemia (such as facial nerve palsy, brain/eye 
involvement or hypothalamic syndrome). 
Method of Evaluating Initial Traumatic Lumbar Punctures 
If the subject has leukemic cells in the peripheral blood and the LP is traumatic and contains 
≥5 WBC/μL and blasts, then the following Steinherz/Bleyer algorithm should be used to 
distinguish between CNS2 and CNS3 disease: 
(CSF WBC/CSF RBC) >2X (Blood WBC/Blood RBC)
A subject with CSF WBC ≥5/μL blasts, whose CSF WBC/RBC ratio is 2x greater than the blood 
WBC/RBC ratio, has CNS disease at diagnosis. Example: CSF WBC=60/μL; CSF 
RBC=1,500/μL; blood WBC=46,000/μL; blood RBC=3.0X106/μL: (60/1500)=0.04 >2X 
(46,000/3.0X106) = 0.015 


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9.3.
Pharmacokinetics and Immunogenicity 
9.3.1.
Evaluations
Serum samples to assess both the serum concentration (PK) of daratumumab and the generation 
of anti-daratumumab antibodies (immunogenicity) will be obtained from all subjects according 
to the Time and Events Schedule (Table 3). At specified time points, venous blood samples 
(1.1 to 5 mL per sample according to the Laboratory Manual) will be collected and the serum 
will be divided into 2 or 3 aliquots according to the Laboratory Manual (PK analysis, 
immunogenicity assessment [when appropriate], and back-up). Up to 1 mL of CSF will also be 
collected for assessment of daratumumab concentrations as specified in the Time and Events 
Schedule 
(Table 2).
The exact dates and times of blood and CSF sampling must be recorded. Refer to the Laboratory 
Manual or equivalent document for sample collection requirements. Collected samples must be 
stored under the specified and controlled conditions for the temperatures indicated in the 
Laboratory Manual. 
Samples collected for determining serum concentrations of daratumumab in this study may be 
retained to address questions about drug characteristics that may arise at a later time point. 
Genetic analyses will not be performed on these samples, and subject confidentiality will be 
maintained.
9.3.2.
Analytical Procedures
Serum samples will be analyzed to determine concentrations of daratumumab or generation of 
anti-daratumumab antibodies using validated immunoassay methods by or under the supervision 
of the sponsor’s bioanalytical facility. Cerebrospinal fluid samples will be analyzed to determine 
concentrations of daratumumab using a validated assay method by or under the supervision of 
the sponsor’s bioanalytical facility. For the immunogenicity assessments, serum samples will be 
screened for antibodies binding to daratumumab and serum titer will also be determined from 
confirmed positive samples. Other immunogenicity analyses (eg, assessment of neutralizing 
capabilities) may be performed to further characterize the immune responses that are generated.
9.3.3.
Pharmacokinetic Assessments
The PK parameters are defined as: 
Cmax: Maximum observed concentration 
Cmin: Minimum observed concentration 
For daratumumab, the PK evaluations include Cmin and Cmax. If sufficient data are available, then 
other PK parameters may be calculated. The Cmin and Cmax will be determined based on the 
assigned collection timepoints. Population PK analysis of serum concentration-time data of 
daratumumab will be performed and include data from other clinical studies; details will be 
provided in a population PK analysis plan and results would be presented in a separate report.


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9.3.4.
Immunogenicity Assessments 
Serum from venous blood samples will be assessed for the generation of anti-daratumumab 
antibodies (immunogenicity) according to the Time and Events Schedule (Table 3). 
Daratumumab concentration is also evaluated at all immunogenicity time points to ensure 
appropriate interpretation of immunogenicity data. When both serum concentration and 
immunogenicity analyses are specified, they are performed on aliquots from the same blood 
draw and no additional sampling is required. Procedures for sample collection, preparation, 
identification, storage, and shipment will be provided in the Laboratory Manual or equivalent 
document. 
A blood sample should be drawn, if possible, for determination of anti-daratumumab antibodies 
any time an infusion reaction is observed or reported for the second or later infusion. 
Daratumumab serum concentration will also be determined from the same infusion reaction 
sample for the purpose of interpreting immunogenicity data. These samples will be stored and 
evaluated if deemed necessary. If the infusion reaction results in treatment discontinuation, then 
subjects should undergo all scheduled safety and efficacy evaluations. Samples collected for the 
analysis of daratumumab immunogenicity/serum concentration may additionally be used to 
evaluate safety or efficacy aspects that address concerns arising during or after the study period 
or for the evaluation of relevant biomarkers by the sponsor or sponsor’s designee.
9.3.5.
Pharmacokinetic/Pharmacodynamic Evaluations
If sufficient data are available, then other PK/pharmacodynamic modeling may be performed, 
including exploring the relationship between serum concentrations of daratumumab and 
endpoints of clinical efficacy and safety. If these analyses are performed, then the details and 
results will be presented in a separate report.
9.4.
Biomarkers
Biomarker assessments will focus on 3 main objectives: to evaluate the ability of daratumumab 
to induce MRD, to confirm pharmacodynamic biomarkers, and to evaluate CD38 expression on 
blast cells. All biomarker assessments will be performed centrally. 
Bone marrow aspirate will be collected as specified in the Time and Events Schedule (Table 1). 
MRD assessments will be done by flow cytometry with baseline bone marrow aspirate to define 
tumor burden, posttreatment samples to determine MRD negativity (end of both Cycle 1 and 
Cycle 2 for T-cell cohort), and End of Treatment, if feasible, to monitor CD38 expression 
kinetics and depth of response. Residual bone marrow aspirate cells collected for MRD flow 
analysis will be stored as frozen pellets. Exploratory MRD analysis may be performed using 
PCR on DNA isolated from these pellets. Any genomic research on samples will only include 
specific changes related to the disease (somatic). Comparison of MRD assessment by flow and 
PCR could inform future trial designs as PCR is a preferred method for MRD assessment in the 
EU. If these methodologies are unavailable, or determined to be scientifically inferior, then 
alternative methods for MRD assessment may be utilized. A portion of aspirate may be evaluated 
by flow cytometry to determine CD38 expression in both B-cell and T-cell ALL/LL subtypes 


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and will be sent to the central laboratory. Characterization of CD38 levels could clarify the in 
vivo pharmacology and identify potential response trends.
Previous observations from daratumumab monotherapy studies in multiple myeloma have 
included immune changes (ie, reduction of NK cells and CD38 positive regulatory T cells) post 
drug administration. This reduction did not lead to any decrease in response or emergence of 
AEs. However, due to this observation, immune cell pharmacodynamics may be evaluated in 
whole blood samples by flow cytometry collected at times as indicated in the Time and Events 
Schedule (Table 1).
Biomarker analyses are dependent upon the availability of appropriate biomarker assays and may 
be deferred or not performed, if during or at the end of the study it becomes clear that the 
analysis will have no scientific value, or if there are not enough samples or not enough 
responders to allow for adequate biomarker evaluation. In the event the study is terminated early 
or shows poor clinical efficacy, completion of biomarker assessments is based on justification 
and intended utility of the data.
9.5.
Safety Evaluations
Any clinically relevant changes occurring during the study must be recorded on the adverse 
event section of the eCRF. Any clinically significant abnormalities persisting at the end of the 
study/early withdrawal will be followed by the investigator until resolution or until a clinically 
stable endpoint is reached. The study will include the following evaluations of safety and 
tolerability per the time points provided in the Time and Events Schedule (Table 1).
Adverse Events
Adverse events will be reported by the subject (or, when appropriate, by a caregiver, surrogate, 
or the subject's legally acceptable representative) for the duration of the study. Adverse events 
will be followed by the investigator as specified in Section 12, Adverse Event Reporting.
Clinical Laboratory Tests 
Blood samples for serum chemistry and hematology will be collected. The investigator must 
review the laboratory results, document this review, and record any clinically relevant changes 
occurring during the study in the adverse event section of the eCRF. 
The following tests will be performed by the local laboratory:

Hematology panel 
-hemoglobin
-platelet count
-white blood cell count, absolute lymphocyte 
count, ANC, and peripheral blast count (if 
WBC is too low for automated assessment, a 
manual differential should be performed to 
document absolute lymphocyte count, ANC, 
and peripheral blast count)


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
Serum chemistry panel 
-sodium
-alkaline phosphatase
-potassium
-lactic acid dehydrogenase 
-creatinine
-uric acid
-aspartate aminotransferase 
-calcium
-alanine aminotransferase 
-phosphate
-total bilirubin (direct bilirubin if total bilirubin is 
abnormal)
-albumin
-total protein
-amylase or lipase

Cerebrospinal fluid
o
RBC count
o
WBC count
o
Pathologic evaluation for lymphoblast count (ie, cytospin or flow cytometry)

Serum or urine pregnancy testing for female subjects of childbearing potential only
HBV Serology
All subjects will be tested locally for HBsAg, Anti-HBs, and Anti-HBc at Screening. 
Additionally, subjects ongoing in the Treatment Phase who are within 6 months of starting study
treatment when Protocol Amendment 3 is implemented will be required to have HBV serology 
performed locally once upon signing the updated ICF.
HBV serology is not required at Screening or for subjects ongoing in the Treatment Phase who 
are within 6 months of starting study treatment if this was performed as part of standard of care
within 3 months prior to first dose.
HBV DNA Tests 
Subjects who are positive for Anti-HBc or Anti-HBs will undergo testing for HBV DNA by 
PCR. Subjects with serologic findings suggestive of HBV vaccination (Anti-HBs positivity as 
the only serologic marker) and a known history of prior HBV vaccination do not need to be 
tested for HBV DNA by PCR. During and following study treatment, subjects who have history 
of HBV infection will be closely monitored for clinical and laboratory signs of reactivation of 
HBV as specified in the Time and Events Schedule (Table 1). Where required by local law, the 
results of HBV testing may be reported to the local health authorities.
Indirect Antiglobulin Test 
Blood type, Rh, and indirect antiglobulin test (IAT) should be done locally within 3 days prior to 
Cycle 1 Day 1. Subject RBC phenotyping or genotyping (standard or extended) is an alternative 
option to the IAT test, if locally required. Either method must be completed prior to first 
daratumumab infusion.
Daratumumab interferes with the IAT, which is a routine pre-transfusion test performed to 
identify a subject’s antibodies to minor antigens so that suitable donor blood can be given for 
transfusion. Daratumumab does not interfere with ABO/RhD typing. CD38 is expressed at very 


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low levels on erythrocytes. Daratumumab binds to the CD38 on erythrocytes, which results in a 
positive IAT (Indirect Coombs Test). This positive result masks the detection of antibodies to 
minor antigens and may prevent or delay blood banks from issuing donor blood for transfusion. 
This effect occurs during daratumumab treatment and for up to 6 months after treatment ends. 
Subjects will receive a subject identification wallet card for the study that includes the blood 
profile (ABO, Rh, and IAT or phenotyping) determined before the first infusion of daratumumab 
along with information on the IAT interference for healthcare providers/blood banks. Subjects 
are to carry this card throughout the treatment period and for at least 6 months after treatment 
ends. Blood banks can eliminate the daratumumab interference with IAT by treating reagent 
RBCs with dithiothreitol (DTT).6,7
Possible methods for blood banks to provide safe RBCs for transfusion to subjects receiving 
daratumumab include:
a.
Providing ABO/RhD compatible, phenotypically (standard or extended phenotyping) or 
genotypically matched units
b. Providing ABO/RhD compatible, K-negative units after ruling out or identifying 
alloantibodies using DTT-treated reagent RBCs
Uncrossmatched, ABO/RhD compatible RBC units should be administered if transfusion is 
needed emergently in accordance with local blood bank practice.
Despite daratumumab binding to CD38 on erythrocytes, no indication of clinically significant 
hemolysis has been observed in daratumumab studies. For additional details, refer to the 
daratumumab Investigator’s Brochure.
Electrocardiogram 
Electrocardiograms will be performed locally at screening. During the collection of ECGs, 
subjects should be in a quiet setting without distractions (eg, television, cell phones). Subjects 
should rest in a supine position for at least 5 minutes before ECG collection and should refrain 
from talking or moving arms or legs. If blood sampling or vital sign measurement is scheduled 
for the same time point as ECG recording, the procedures should be performed in the following 
order: ECG(s), vital signs, blood draw.
Vital Signs 
Vital signs will include heart rate, blood pressure, oxygen saturation, temperature, and 
respiration rate. Blood pressure should be preceded by at least 5 minutes of rest in a quiet setting 
without distractions (eg, television, cell phones).
Physical Examination 
Physical examinations will be performed as specified in the Time and Events Schedule (Table 1). 
At screening, the physical examination includes neurological examination. Any change from 
baseline must be recorded as an adverse event.


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Karnofsky and Lansky Performance Status
The Karnofsky and Lansky performance status scales provided in Attachment 1 will be used to 
determine the functional status of each subject. The frequency of performance status assessment 
is provided in the Time and Events Schedule (Table 1).
9.6.
Sample Collection and Handling
The actual dates and times of sample collection must be recorded in the eCRF or laboratory 
requisition form. Refer to the Time and Events Schedule (Table 1) for the timing and frequency 
of all sample collections.
Instructions for the collection, handling, storage, and shipment of samples are found in the 
Laboratory Manual that will be provided. Collection, handling, storage, and shipment of samples 
must be under the specified, and where applicable, controlled temperature conditions as indicated 
in the Laboratory Manual.
10.
SUBJECT COMPLETION/DISCONTINUATION OF STUDY TREATMENT/ 
WITHDRAWAL FROM THE STUDY
10.1.
Completion
A subject will be considered to have completed the study if he or she has finished all 
protocol-specified procedures before the end of the study, has died before the end of the study, 
has not been lost to follow-up, or has not withdrawn consent for study participation before the 
end of the study. 
10.2.
Discontinuation of Study Treatment/Withdrawal from the Study 
Discontinuation of Study Treatment
A subject's study treatment must be discontinued for any of the following reasons:

The investigator believes that for safety reasons or tolerability reasons (eg, adverse event) it 
is in the best interest of the subject to discontinue study treatment

The subject becomes pregnant, unless the subject (or the subject's legally acceptable 
representative), investigator, and sponsor agree the benefits outweigh the risks to the fetus 
and continuation of study treatment is in the best interest of the subject

Progression of disease or relapse as defined in Section 9.2.1

Subjects with CNS M2 or CNS M3 status at baseline who do not achieve CNS M1 status 
(ie, 2 successive negative CSF evaluations) after completion of Cycle 1

Withdrawal of consent

Subject initiates treatment with any prohibited medication

Subject experiences unacceptable toxicity, including IRRs, as described in Section 6.3.3

Subject’s daratumumab dose is held for more than 4 weeks due to a daratumumab-related 
toxicity as described in Section 6.4.1 (unless sponsor approves continuation)


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
Subject experiences a second primary malignancy that cannot be treated by surgery or 
radiotherapy alone

Subjects who achieve CR and proceed to allogeneic HSCT
If a subject discontinues study treatment for any reason before the end of the treatment period, 
end-of-treatment and posttreatment assessments should be obtained.
Withdrawal From the Study
A subject will be withdrawn from the study for any of the following reasons:

Lost to follow-up

Withdrawal of consent

Death

Sponsor discontinues the study
If a subject discontinues study drug and withdraws from the study before the end of the treatment 
period, end-of-treatment and posttreatment assessments should be obtained. If a subject is lost to 
follow-up, every reasonable effort must be made by the study-site personnel to contact the 
subject and determine the reason for discontinuation/withdrawal. The measures taken to follow 
up must be documented.
When a subject withdraws before completing the study, the reason for withdrawal is to be 
documented in the eCRF and in the source document. Study drug assigned to the withdrawn 
subject may not be assigned to another subject. Subjects who withdraw will not be replaced. If a 
subject withdraws from the study before the end of the treatment phase, then end-of-treatment 
and posttreatment assessments should be obtained.
10.3.
Withdrawal From the Use of Research Samples
The subject may withdraw consent for use of samples for research (refer to Section 16.2.5, 
Long-Term Retention of Samples for Additional Future Research). In such a case, samples will 
be destroyed after they are no longer needed for the clinical study. Details of the sample 
retention for research are presented in the main ICF.
11.
STATISTICAL METHODS
Statistical analysis will be done by the sponsor or under the authority of the sponsor. A general 
description of the statistical methods to be used to analyze the efficacy and safety data is outlined 
below. Specific details will be provided in the Statistical Analysis Plan. All statistical testing will 
be performed using a 1-sided test at the 5% level of significance, unless otherwise noted. 
Confidence intervals will be presented as two-sided 90% CIs. Summary statistics for continuous 
variables include mean, SD, median, minimum, and maximum unless otherwise specified. 
Categorical data will be presented as frequencies and percentages.


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11.1.
Subject Information
The study analysis populations are defined as follows:

All treated population:  all enrolled subjects who receive any study treatment. This 
population will be used for efficacy and safety analyses. All subjects in the all treated 
analysis population will be analyzed according to the treatment that they actually received.

Response evaluable population: all treated subjects who have at least 1 adequate postbaseline 
disease assessment. Sensitivity analyses of CR rate and ORR will be based on the response 
evaluable population.

PK evaluable population: all treated subjects who provide at least one postinfusion sample. 
All PK parameters will be analyzed based on the PK evaluable population.
11.2.
Sample Size Determination
The study utilizes a Simon’s 2-stage design and will require 49 subjects age 1 year up to 
18 years. 
For the B-cell ALL cohort, the following hypotheses will be tested: 

H0: CR rate ≤15% vs.

Ha: CR rate ≥40%
These hypotheses are based on recent response rates with novel therapies indicating that a CR 
rate of 15% or less is considered of no clinical interest, while a CR of 40% is deemed clinically 
meaningful for this population of subjects with pediatric B-cell ALL, consistent with the recent 
results from a Phase 1/2 single-agent study of blinatumomab.47
The B-cell ALL cohort will enroll 25 subjects age 1 year to <18 years, which provides 80% 
power to show that the true CR rate is >15% at a one-sided alpha of 5%. Stage 1 of the cohort 
will accrue 7 subjects (including the first 3 subjects in a safety run-in). After the seventh subject 
has received 2 cycles of treatment at the dose and regimen determined to be safe in the safety 
run-in, a futility analysis will be conducted. If the futility criterion is met (1 or 0 responders), no 
expansion will be planned. Otherwise, an additional 18 subjects will be enrolled into Stage 2. If 6 
or fewer subjects in the B-cell ALL arm respond, then the drug will be considered ineffective 
and further development in this disease will be stopped. 
A similar design applies to the T-cell ALL cohort, which tests the following hypotheses:

H0: CR rate ≤30% vs.

Ha: CR rate ≥60%
These hypotheses are based on response rates observed in recent studies indicating that a CR rate 
of 30% is considered of no clinical interest, while a CR of 60% is deemed clinically meaningful 
for this population of pediatric subjects with T-cell ALL. This is consistent with study 
COGALL07P1 utilizing this backbone in combination with bortezomib which achieved a CR of 
about 68% (COG data on file). The T-cell ALL cohort will enroll 24 subjects aged 1 to <18 


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years, 8 in Stage 1 (including 3 subjects in a safety run-in) and 16 in Stage 2, which provides 
80% power to show that the true CR rate is >30% at a one-sided alpha of 5%. After the eighth 
subject has received 1 cycles of treatment at the dose and regimen determined to be safe in the 
safety run-in, a futility analysis will be conducted. This cohort will be terminated for futility if 3 
or fewer responders are observed in Stage 1, and for ineffectiveness if 10 or fewer subjects 
respond at the end of Stage 2. 
A maximum of 10 young adult subjects (aged 18 to 30 years) and a maximum of 10 subjects 
with LL (aged 1 to 30 years) will be included in addition to the pediatric subjects included for the 
Simon’s 2-stage study design to evaluate the safety and efficacy in this patient population and 
the data will be summarized descriptively. 
11.3.
Efficacy Analyses 
11.3.1.
Primary Endpoint
For subjects 1 to <18 years of age, the number and percentage of subjects who achieve a CR 
including 90% exact CI will be calculated for each cohort. The exact p-value to test the 
hypothesis, H0: CR rate ≤15% in the B-cell ALL cohort and H0: CR rate ≤30% in the T-cell ALL 
cohort, will also be calculated. 
11.3.2.
Secondary Endpoints

ORR: The proportion of ALL subjects who have an OR (CR + CRi) and the 90% exact CI 
will be calculated for each cohort. 

EFS: The median EFS and 90% CI will be estimated using the Kaplan-Meier method for 
each cohort. 

RFS: The median RFS and 90% CI will be estimated using the Kaplan-Meier method for 
each cohort. 

OS: The median OS and 90% CI will be estimated using the Kaplan-Meier method for each 
cohort. 

MRD negative rate: The proportion of subjects who are MRD negative and the exact 
90% CI will be calculated for each cohort.

Allogeneic HSCT rate: The proportion of subjects who received an allogeneic HSCT after 
treatment with daratumumab will be calculated. An exact 90% CI will also be calculated.
11.4.
Pharmacokinetic Analyses 
The PK evaluable population includes all enrolled subjects who receive daratumumab and 
provide at least one postinfusion sample. All serum concentrations below the lowest quantifiable 
concentration in a sample or missing data will be labeled as such in the concentration data 
listings. Concentrations below the lowest quantifiable concentration in a sample will be treated 
as zero in the summary statistics. 
Descriptive statistics will be used to summarize daratumumab serum concentrations at each 
sampling timepoint and PK parameters of daratumumab: Cmin and Cmax. Other PK parameters, if 


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available, will also be summarized. Descriptive statistics will be used to summarize 
daratumumab CSF concentrations at each sampling timepoint.
Population PK analysis of serum concentration-time data of daratumumab will be performed and 
the analysis may include data from other studies. The population PK details will be specified in 
an analysis plan and the results will be presented in a separate report. If an exposure-response 
analysis is performed, it will also be detailed in a separate analysis plan and report.
11.5.
Immunogenicity Analyses 
The incidence of anti-daratumumab antibodies will be summarized for all subjects who receive 
at least 1 dose of daratumumab and have appropriate samples for detection of antibodies to 
daratumumab. A listing of subjects who are positive for anti-daratumumab antibodies will be 
provided. 
11.6.
Biomarker Analyses
Biomarker studies are designed to identify markers predictive of response (or resistance) to 
daratumumab. Analyses will be stratified by clinical covariates or molecular subgroups using the 
appropriate statistical methods (eg, parametric or non-parametric, univariate or multivariate, 
analysis of variance, or survival analysis, depending on the endpoint). Correlation of baseline 
expression levels or changes in expression levels with response to time-to-event endpoints will 
identify responsive (or resistant) subgroups in addition to genes and pathways attenuated 
following treatment with daratumumab.
Any pharmacodynamic measures will be listed, tabulated, and where appropriate, plotted. 
Subjects may be grouped by dose schedule or clinical response. As this is an open-label study 
without a control treatment, statistical analyses will be done to aid in the understanding of the 
results.
Results of biomarker and pharmacodynamic analyses may be presented in a separate report. 
Planned analyses are based on the availability of clinically valid assays and may be deferred if 
emerging study data show no likelihood of providing useful scientific information.
11.7.
Safety Analyses
Adverse Events
The verbatim terms used in the eCRF by investigators to identify AEs will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA). All reported AEs will be included in 
the analysis.
Treatment-emergent AEs are AEs with onset during the treatment phase or that are a 
consequence of a pre-existing condition that has worsened since baseline, and occur during 
treatment or within 30 days following the last dose of study treatment, or any adverse event that 
is considered study treatment-related regardless of the start date of the event. The number and 
percent of subjects with TEAEs will be summarized according to intensity using the NCI-
CTCAE (Version 4.03), drug relationship, and outcome. For each adverse event, the percentage 


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of subjects who experience at least 1 occurrence of the given event will be summarized by 
treatment group. In addition, comparisons between treatment groups will be provided if 
appropriate. Summaries, listings, datasets, or subject narratives may be provided, as appropriate, 
for those subjects who die, who discontinue treatment due to an adverse event, or who 
experience a severe or a serious adverse event.
Clinical Laboratory Tests
Laboratory data will be summarized by type of laboratory test. Reference ranges and markedly 
abnormal results (specified in the Statistical Analysis Plan) will be used in the summary of 
laboratory data. Descriptive statistics will be calculated for each laboratory analyte at baseline 
and for observed values and changes from baseline at each scheduled time point. 
Parameters with predefined National Cancer Institute CTCAE toxicity grades will be 
summarized. Change from baseline to the worst adverse event grade experienced by the subject 
during the study will be provided as shift tables. 
Vital Signs
Descriptive statistics of post baseline changes in temperature, heart rate, oxygen saturation, 
blood pressure (systolic and diastolic), and respiration rate will be summarized.
Karnofsky and Lansky Performance Status
Descriptive statistics of changes from baseline will be summarized at each scheduled time point.
11.8.
Safety Evaluation Team
Subject safety will be monitored in each cohort separately during the safety run-in of the first 
3 subjects in each cohort by the SET established by the sponsor. This committee will monitor all 
available treatment-emergent data on an ongoing basis during the safety run-in and as needed 
during the conduct of the study for the purpose of ensuring the continued safety of subjects 
enrolled in this study. 
The SET will consist of the participating principal investigators, the sponsor’s responsible 
medical officer, sponsor’s statistician, sponsor’s clinical pharmacologist and sponsor’s safety 
management team chair. Other sponsor’s medical representatives may participate in the SET, if 
deemed necessary. The team will meet after the first 3 subjects have completed 1 cycle of 
daratumumab therapy during the safety run-in and throughout the study conduct as deemed 
necessary; documentation of meeting outcomes will be maintained by the sponsor. Decisions 
with the potential to effect subject safety (eg, unfavorable change in risk/benefit assessment) will 
be documented and promptly communicated to investigators and regulatory authorities as 
appropriate.


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12.
ADVERSE EVENT REPORTING
Timely, accurate, and complete reporting and analysis of safety information from clinical studies 
are crucial for the protection of subjects, investigators, and the sponsor, and are mandated by 
regulatory agencies worldwide. The sponsor has established Standard Operating Procedures in 
conformity with regulatory requirements worldwide to ensure appropriate reporting of safety 
information; all clinical studies conducted by the sponsor or its affiliates will be conducted in 
accordance with those procedures.
12.1.
Definitions
12.1.1.
Adverse Event Definitions and Classifications
Adverse Event
An adverse event is any untoward medical occurrence in a clinical study subject administered a 
medicinal (investigational or non-investigational) product. An adverse event does not necessarily 
have a causal relationship with the treatment. An adverse event can therefore be any unfavorable 
and unintended sign (including an abnormal finding), symptom, or disease temporally associated 
with the use of a medicinal (investigational or non-investigational) product, whether or not 
related to that medicinal (investigational or non-investigational) product. (Definition per 
International Council for Harmonisation [ICH])
This includes any occurrence that is new in onset or aggravated in severity or frequency from the 
baseline condition, or abnormal results of diagnostic procedures, including laboratory test 
abnormalities.
Note: The sponsor collects AEs starting with the signing of the ICF (refer to Section 12.3.1, All 
Adverse Events, for time of last adverse event recording).
Serious Adverse Event
A serious adverse event based on ICH and EU Guidelines on Pharmacovigilance for Medicinal 
Products for Human Use is any untoward medical occurrence that at any dose:

Results in death

Is life-threatening
(The subject was at risk of death at the time of the event. It does not refer to an event that 
hypothetically might have caused death if it were more severe.)

Requires inpatient hospitalization or prolongation of existing hospitalization

Results in persistent or significant disability/incapacity

Is a congenital anomaly/birth defect

Is a suspected transmission of any infectious agent via a medicinal product

Is Medically Important*


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*Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
also appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the subject 
or may require intervention to prevent one of the other outcomes listed in the definition above. 
These should usually be considered serious.
If a serious and unexpected adverse event occurs for which there is evidence suggesting a causal 
relationship between the study drug and the event (eg, death from anaphylaxis), the event must 
be reported as a serious and unexpected suspected adverse reaction even if it is a component of 
the study endpoint (eg, all-cause mortality), other than progressive disease of ALL/LL. 
Progressive disease of ALL/LL should not be reported as a serious and unexpected adverse 
event.
Unlisted (Unexpected) Adverse Event/Reference Safety Information
An adverse event is considered unlisted if the nature or severity is not consistent with the 
applicable product reference safety information. For daratumumab, the expectedness of an 
adverse event will be determined by whether or not it is listed in the Reference Safety 
Information of the Investigator's Brochure. 
Adverse Event Associated With the Use of the Drug
An adverse event is considered associated with the use of the drug if the attribution is possible, 
probable, or very likely by the definitions listed in Section 12.1.2, Attribution Definitions.
12.1.2.
Attribution Definitions
Not Related
An adverse event that is not related to the use of the drug.
Doubtful
An adverse event for which an alternative explanation is more likely, eg, concomitant drug(s), 
concomitant disease(s), or the relationship in time suggests that a causal relationship is unlikely.
Possible
An adverse event that might be due to the use of the drug. An alternative explanation, 
eg, concomitant drug(s), concomitant disease(s), is inconclusive. The relationship in time is 
reasonable; therefore, the causal relationship cannot be excluded.
Probable
An adverse event that might be due to the use of the drug. The relationship in time is suggestive 
(eg, confirmed by dechallenge). An alternative explanation is less likely, eg, concomitant 
drug(s), concomitant disease(s).


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Very Likely
An adverse event that is listed as a possible adverse reaction and cannot be reasonably explained 
by an alternative explanation, eg, concomitant drug(s), concomitant disease(s). The relationship 
in time is very suggestive (eg, it is confirmed by dechallenge and rechallenge).
12.1.3.
Severity Criteria 
An assessment of severity grade will be made using the NCI-CTCAE, Version 4.03. The 
investigator should use clinical judgment in assessing the severity of events not directly 
experienced by the subject (eg, laboratory abnormalities).
12.2.
Special Reporting Situations
Safety events of interest on a sponsor study drug that may require expedited reporting or safety 
evaluation include, but are not limited to:

Overdose of a sponsor study drug

Suspected abuse/misuse of a sponsor study drug

Accidental or occupational exposure to a sponsor study drug

Medication error involving a sponsor product (with or without subject/patient exposure to 
the sponsor study drug, eg, name confusion)

Exposure to a sponsor study drug from breastfeeding
Special reporting situations should be recorded in the eCRF. Any special reporting situation that 
meets the criteria of a serious adverse event should be recorded on the serious adverse event page 
of the eCRF.
12.3.
Procedures
12.3.1.
All Adverse Events
All AEs and special reporting situations, whether serious or non-serious, will be reported from 
the time a signed and dated ICF is obtained until 30 days after the last dose of study drug, unless 
the subject withdraws consent for study participation, or starts subsequent anticancer therapy. 
For subjects who have received additional treatment with therapeutic intent for ALL/LL during 
the adverse event reporting period, only AEs that are considered to be possibly, probably, or 
definitely related to study drug must be reported (unless the subject has been withdrawn from the 
study). Serious adverse events, including those spontaneously reported to the investigator within 
30 days after the last dose of study drug, and those that are considered related to daratumumab 
within the follow-up phase, must be reported using the Serious Adverse Event Form. The 
sponsor will evaluate any safety information that is spontaneously reported by an investigator 
beyond the time frame specified in the protocol.


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Progressive disease should not be reported as an adverse event, but instead symptoms/clinical 
signs of disease progression may be reported, which then should be attributed to progressive 
disease. 
All AEs, regardless of seriousness, severity, or presumed relationship to study drug, must be 
recorded using medical terminology in the source document and the eCRF. Whenever possible, 
diagnoses should be given when signs and symptoms are due to a common etiology (eg, cough, 
runny nose, sneezing, sore throat, and head congestion should be reported as "upper respiratory 
infection"). Investigators must record in the eCRF their opinion concerning the relationship of 
the adverse event to study therapy. All measures required for adverse event management must be 
recorded in the source document and reported according to sponsor instructions.
The sponsor assumes responsibility for appropriate reporting of AEs to the regulatory authorities. 
The sponsor will also report to the investigator (and the head of the investigational institute 
where required) all suspected unexpected serious adverse reactions (SUSARs). No anticipated 
events are required to be monitored as all the anticipated events identified in the study 
population, such as anemia, neutropenia, thrombocytopenia, infection, and fatigue, are known 
adverse drug reactions for daratumumab. The investigator (or sponsor where required) must 
report SUSARs to the appropriate Independent Ethics Committee/Institutional Review Board 
(IEC/IRB) that approved the protocol unless otherwise required and documented by the 
IEC/IRB. 
For all studies with an outpatient phase, including open-label studies, the subject must be 
provided with a "wallet (study) card" and instructed to carry this card with them for the duration 
of the study indicating the following: 

Study number

Statement, in the local language(s), that the subject is participating in a clinical study

Investigator's name and 24-hour contact telephone number

Local sponsor's name and 24-hour contact telephone number (for medical staff only)

Site number

Subject number

Blood profile (ABO, Rh, and IAT results; see Section 9.5)
12.3.2.
Serious Adverse Events
All SAEs occurring during the study must be reported to the appropriate sponsor contact person 
by study-site personnel within 24 hours of their knowledge of the event. Information regarding 
SAEs will be transmitted to the sponsor using the Serious Adverse Event Form, which must be 
completed and signed by a physician from the study site, and transmitted to the sponsor within 
24 hours. The initial and follow-up reports of a serious adverse event should be made by 
facsimile (fax). 


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All SAEs that have not resolved by the end of the study, or that have not resolved upon 
discontinuation of the subject's participation in the study, must be followed until any of the 
following occurs:

The event resolves

The event stabilizes

The event returns to baseline, if a baseline value/status is available

The event can be attributed to agents other than the study drug or to factors unrelated to 
study conduct

It becomes unlikely that any additional information can be obtained (subject or health care 
practitioner refusal to provide additional information, lost to follow-up after demonstration 
of due diligence with follow-up efforts)
Suspected transmission of an infectious agent by a medicinal product will be reported as a 
serious adverse event. Any event requiring hospitalization (or prolongation of hospitalization) 
that occurs during the course of a subject's participation in a study must be reported as a serious 
adverse event, except hospitalizations for the following:

Hospitalizations not intended to treat an acute illness or adverse event (eg, social reasons 
such as pending placement in long-term care facility).

Surgery or procedure planned before entry into the study (must be documented in the 
eCRF). Note: Hospitalizations that were planned before the signing of the ICF, and where 
the underlying condition for which the hospitalization was planned has not worsened, will 
not be considered SAEs. Any adverse event that results in a prolongation of the originally 
planned hospitalization is to be reported as a new serious adverse event.

If the subject is hospitalized overnight due to slow daratumumab infusion or for observation 
after daratumumab infusion and in the absence of a significant medical event.
Disease progression should not be recorded as an adverse event or serious adverse event term; 
instead, signs and symptoms of clinical sequelae resulting from disease progression/lack of 
efficacy will be reported if they fulfill the serious adverse event definition (refer to 
Section 12.1.1, Adverse Event Definitions and Classifications).
12.3.3.
Pregnancy 
All initial reports of pregnancy in female subjects or partners of male subjects must be reported 
to the sponsor by the study-site personnel within 24 hours of their knowledge of the event using 
the appropriate pregnancy notification form. Abnormal pregnancy outcomes (eg, spontaneous 
abortion, fetal death, stillbirth, congenital anomalies, ectopic pregnancy) are considered SAEs 
and must be reported using the Serious Adverse Event Form. Follow-up information regarding 
the outcome of the pregnancy and any postnatal sequelae in the infant will be required.


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12.4.
Contacting Sponsor Regarding Safety
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding safety issues or questions regarding the study are listed in the Contact Information 
page(s), which will be provided as a separate document.
13.
PRODUCT QUALITY COMPLAINT HANDLING
A product quality complaint (PQC) is defined as any suspicion of a product defect related to 
manufacturing, labeling, or packaging, ie, any dissatisfaction relative to the identity, quality, 
durability, or reliability of a product, including its labeling or package integrity. A PQC may 
have an impact on the safety and efficacy of the product. Timely, accurate, and complete 
reporting and analysis of PQC information from studies are crucial for the protection of subjects, 
investigators, and the sponsor, and are mandated by regulatory agencies worldwide. The sponsor 
has established procedures in conformity with regulatory requirements worldwide to ensure 
appropriate reporting of PQC information; all studies conducted by the sponsor or its affiliates 
will be conducted in accordance with those procedures.
13.1.
Procedures
All initial PQCs must be reported to the sponsor by the study-site personnel within 24 hours after 
being made aware of the event. If the defect is combined with a serious adverse event, the 
study-site personnel must report the PQC to the sponsor according to the serious adverse event 
reporting timelines (refer to Section 12.3.2, Serious Adverse Events). A sample of the suspected 
product should be maintained for further investigation if requested by the sponsor.
13.2.
Contacting Sponsor Regarding Product Quality
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding product quality issues are listed in the Contact Information page(s), which will be 
provided as a separate document.
14.
STUDY DRUG INFORMATION
For the purposes of this study, “study drug” refers to daratumumab and daratumumab will be 
provided by the sponsor. The backbone treatment will be purchased from commercial sources by 
each study site, unless local legal requirements state differently. For backbone therapies, refer to 
local prescribing information for instructions on preparation, handling, and storage.
14.1.
Physical Description of Study Drugs
The daratumumab supplied for IV infusion is a colorless to yellow liquid and sterile concentrate 
of 20 mg/mL as a liquid vial. The study agent should be essentially free of visible particulate 
matter at the time of dosage preparation and drug product administration. It will be manufactured 
and provided under the responsibility of the sponsor. 
14.2.
Packaging
Daratumumab for IV infusion is supplied in glass vials containing daratumumab at a 
concentration of 20 mg/mL. It will be supplied to the site/pharmacy as open-label supply. 


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14.3.
Labeling
Study drug labels will contain information to meet the applicable regulatory requirements. Each 
vial will contain a study-specific label with a unique identification number.
14.4.
Preparation, Handling, and Storage 
Daratumumab for IV infusion must be stored in the original carton in a refrigerator at controlled 
temperatures ranging from 2°C to 8°C until it is removed for dose preparation. Study drug must 
not be utilized after the expiry date printed on the label. The daratumumab product must be 
protected from light and must not be frozen. Daratumumab does not contain preservatives; 
therefore, any unused portion remaining in the vial must be discarded. Refer to the 
investigational product and procedures instruction manual and study site investigational product 
and procedures manual for additional guidance on study drug preparation, handling, and storage.
14.5.
Drug Accountability
The investigator is responsible for ensuring that all study drug received at the site is inventoried 
and accounted for throughout the study. The study drug administered to the subject must be 
documented on the drug accountability form. All study drug will be stored and disposed of 
according to the sponsor's instructions. Study-site personnel must not combine contents of the 
study drug containers. All study treatment will be stored and disposed of according to the 
sponsor's instructions. Study-site personnel must not combine contents of the study drug 
containers.
Study drug must be handled in strict accordance with the protocol and the container label, and 
must be stored at the study site in a limited-access area or in a locked cabinet under appropriate 
environmental conditions. Unused study drug must be available for verification by the sponsor's 
study site monitor during on-site monitoring visits. The return to the sponsor of unused study 
drug will be documented on the drug return form. When the study site is an authorized 
destruction unit and study drug supplies are destroyed on-site, this must also be documented on 
the drug return form.
Potentially hazardous materials such as used ampules, needles, syringes and vials containing 
hazardous liquids, should be disposed of immediately in a safe manner and therefore will not be 
retained for drug accountability purposes. 
Study drug should be dispensed under the supervision of the investigator or a qualified member 
of the study-site personnel, or by a hospital/clinic pharmacist. Study drug will be supplied only 
to subjects participating in the study. Returned study drug must not be dispensed again, even to 
the same subject. Study drug may not be relabeled or reassigned for use by other subjects. The 
investigator agrees neither to dispense the study drug from, nor store it at, any site other than the 
study sites agreed upon with the sponsor.


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15.
STUDY-SPECIFIC MATERIALS
The investigator will be provided with the following supplies:

Investigator's Brochure for daratumumab

Pharmacy manual/study site investigational product and procedures manual

Laboratory Manual

NCI-CTCAE Version 4.03

Study drug diary

Electronic data capture (eDC) Manual

Sample ICF and assent form

Subject wallet card indicating blood type
16.
ETHICAL ASPECTS
16.1.
Study-Specific Design Considerations
This study has been designed to evaluate daratumumab in subjects with relapsed or refractory 
ALL or LL. B-cell ALL/LL is being studied in second or greater relapse or subjects with 
refractory disease. It is expected that subjects will have exhausted available standard therapeutic 
options prior to enrolling in this study. Due to the accumulation of toxicity with each subsequent 
therapy after multiple relapses, it is anticipated that the combination of daratumumab with 
vincristine and prednisone will provide disease control with minimal added toxicity. T-cell 
ALL/LL is being studied in first relapse or subjects with refractory disease as there are fewer 
therapeutic options for this disease, and outcomes are dismal, even in first relapse. Thus, subjects 
will receive daratumumab in combination with a 4-drug re-induction therapy followed by further 
intensive therapy for those subjects who achieve a response to this therapy.
The primary safety profile of daratumumab is predominantly characterized by IRRs; see 
Section 6.3 for guidelines for prevention and management of IRRs. Based on the mechanism of 
action of daratumumab, a potential risk could be infection; therefore, the protocol requires the 
review of hematological laboratory results prior to daratumumab administration. CD38 is 
distributed in erythrocytes and platelets. A significant reduction of platelets was reported in an 
animal study. In a human clinical study of subjects with relapsed or refractory multiple myeloma 
(Study GEN501), thrombocytopenia was also reported. However, safety laboratory monitoring 
did not show a clinically meaningful reduction of platelets, and no bleeding events were 
observed. Safety data from a Phase 3 clinical study (MMY3004) in subjects with relapsed or 
refractory multiple myeloma comparing daratumumab, bortezomib and dexamethasone (DVd) vs 
bortezomib and dexamethasone (Vd), showed daratumumab may increase thrombocytopenia 
associated with bortezomib-based regimens. However, the incidence of bleeding events was low 
and the majority of events were mild (less than 1% of subjects experienced Grade 3 or 4 bleeding 
events). Anemia was also reported in Study GEN501. Free hemoglobin was mildly elevated, but 
other parameters did not support hemolysis. Anemia, all grades and Grade 3 or 4 in the 


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MMY3004 study, were similar among the 2 treatment groups. Routine safety laboratory 
measurement of hemoglobin and platelets will be closely monitored in this study.
Potential subjects will be fully informed of the risks and requirements of the study and, during 
the study, subjects will be given any new information that may affect their decision to continue 
participation. They will be told that their consent to participate in the study is voluntary and may 
be withdrawn at any time with no reason given and without penalty or loss of benefits to which 
they would otherwise be entitled. Only subjects who are fully able to understand the risks, 
benefits, and potential AEs of the study, and provide their consent voluntarily will be enrolled.
When referring to the signing of the ICF, the terms legal guardian and legally acceptable 
representative refer to the legally appointed guardian of the child with authority to authorize 
participation in research. For each subject, his or her parent(s) (preferably both parents, if 
available) or legally acceptable representative(s), as required by local regulations, must give 
written consent (permission) according to local requirements after the nature of the study has 
been fully explained and before the performance of any study-related assessments. Assent must 
be obtained from children (minors) capable of understanding the nature of the study; refer to 
local regulations. For the purposes of this study, all references to subjects who have provided 
consent (and assent as applicable) refers to the subjects and his or her parent(s) or the subject's 
legal guardian(s) or legally acceptable representative(s) who have provided consent according to 
this process. Minors who assent to a study and later withdraw that assent should not be 
maintained in the study against their will, even if their parents still want them to participate.
The volume of blood collected will be consistent with the recommendations of the EMA for 
study-related blood loss (see Attachment 7).12 Sample volumes will be adjusted according to 
standards for pediatric subjects.
16.2.
Regulatory Ethics Compliance
16.2.1.
Investigator Responsibilities
The investigator is responsible for ensuring that the study is performed in accordance with the 
protocol, current ICH guidelines on Good Clinical Practice (GCP), and applicable regulatory and 
country-specific requirements.
Good Clinical Practice is an international ethical and scientific quality standard for designing, 
conducting, recording, and reporting studies that involve the participation of human subjects. 
Compliance with this standard provides public assurance that the rights, safety, and well-being of 
study subjects are protected, consistent with the principles that originated in the Declaration of 
Helsinki, and that the study data are credible.


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16.2.2.
Independent Ethics Committee or Institutional Review Board
Before the start of the study, the investigator (or sponsor where required) will provide the 
IEC/IRB with current and complete copies of the following documents (as required by local 
regulations):

Final protocol and, if applicable, amendments

Sponsor-approved ICF and assent form (and any other written materials to be provided to 
the subjects)

Investigator's Brochure (or equivalent information) and amendments/addenda

Sponsor-approved subject recruiting materials

Information on compensation for study-related injuries

Investigator's curriculum vitae or equivalent information (unless not required, as 
documented by the IEC/IRB)

Information regarding funding, name of the sponsor, institutional affiliations, other potential 
conflicts of interest, and incentives for subjects

Any other documents that the IEC/IRB requests to fulfill its obligation
This study will be undertaken only after the IEC/IRB has given full approval of the final 
protocol, amendments (if any, excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct, unless required locally), the ICF, applicable 
recruiting materials, and subject compensation programs, and the sponsor has received a copy of 
this approval. This approval letter must be dated and must clearly identify the IEC/IRB and the 
documents being approved. 
During the study the investigator (or sponsor where required) will send the following documents 
and updates to the IEC/IRB for their review and approval, where appropriate:

Protocol amendments (excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct)

Revision(s) to ICF/assent form and any other written materials to be provided to subjects

If applicable, new or revised subject recruiting materials approved by the sponsor

Revisions to compensation for study-related injuries

New edition(s) of the Investigator's Brochure and amendments/addenda

Summaries of the status of the study at intervals stipulated in guidelines of the IEC/IRB (at 
least annually)

Reports of AEs that are serious, unlisted/unexpected, and associated with the study drug

New information that may adversely affect the safety of the subjects or the conduct of the 
study

Deviations from or changes to the protocol to eliminate immediate hazards to the subjects

Report of deaths of subjects under the investigator's care


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
Notification if a new investigator is responsible for the study at the site

Development Safety Update Report and Line Listings, where applicable

Any other requirements of the IEC/IRB
For all protocol amendments (excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct), the amendment and applicable ICF/assent 
revisions must be submitted promptly to the IEC/IRB for review and approval before 
implementation of the change(s). At least once a year, the IEC/IRB will be asked to review and 
reapprove this study, where required. At the end of the study, the investigator (or sponsor where 
required) will notify the IEC/IRB about the study completion (if applicable, the notification will 
be submitted through the head of investigational institution). 
16.2.3.
Informed Consent and Assent Form
Each subject (or a legally acceptable representative) must give written consent according to local 
requirements after the nature of the study has been fully explained. The ICF(s) must be signed 
before performance of any study-related activity. The ICF(s) and assent form that is/are used 
must be approved by both the sponsor and by the reviewing IEC/IRB and be in a language that 
the subject can read and understand. The informed consent should be in accordance with 
principles that originated in the Declaration of Helsinki, current ICH and GCP guidelines, 
applicable regulatory requirements, and sponsor policy.
Before enrollment in the study, the investigator or an authorized member of the study-site 
personnel must explain to potential subjects or their legally acceptable representatives the aims, 
methods, reasonably anticipated benefits, and potential hazards of the study, and any discomfort 
participation in the study may entail. Subjects will be informed that their participation is 
voluntary and that they may withdraw consent to participate at any time. They will be informed 
that choosing not to participate will not affect the care the subject will receive for the treatment 
of his or her disease. Subjects will be told that alternative treatments are available if they refuse 
to take part and that such refusal will not prejudice future treatment. Finally, they will be told 
that the investigator will maintain a subject identification register for the purposes of long-term 
follow-up if needed and that their records may be accessed by health authorities and authorized 
sponsor personnel without violating the confidentiality of the subject, to the extent permitted by 
the applicable law(s) or regulations. By signing the ICF the subject or legally acceptable 
representative is authorizing such access, which includes permission to obtain information about 
his or her survival status. 
The subject or legally acceptable representative will be given sufficient time to read the ICF and 
the opportunity to ask questions. After this explanation and before entry into the study, consent 
should be appropriately recorded by means of the subject's or his or her legally acceptable 
representative's personally dated signature. After having obtained the consent, a copy of the ICF 
must be given to the subject.
If the subject or legally acceptable representative is unable to read or write, an impartial witness 
should be present for the entire informed consent process (which includes reading and explaining 


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all written information) and should personally date and sign the ICF after the oral consent of the 
subject or legally acceptable representative is obtained.
Children (minors) or subjects who are unable to comprehend the information provided can be 
enrolled only after obtaining consent of a legally acceptable representative. Assent must be 
obtained from children (minors) capable of understanding the nature of the study; please refer to 
local regulations. Written assent should be obtained from subjects who are able to write. A 
separate assent form written in language the subject can understand should be developed for 
adolescents. After having obtained the assent, a copy of the assent form must be given to the 
subject, and to the subject's parent or if applicable legally acceptable representative.
16.2.4.
Privacy of Personal Data
The collection and processing of personal data from subjects enrolled in this study will be 
limited to those data that are necessary to fulfill the objectives of the study. These data must be 
collected and processed with adequate precautions to ensure confidentiality and compliance with 
applicable data privacy protection laws and regulations. Appropriate technical and organizational 
measures to protect the personal data against unauthorized disclosures or access, accidental or 
unlawful destruction, or accidental loss or alteration must be put in place. Sponsor personnel 
whose responsibilities require access to personal data agree to keep the identity of subjects 
confidential.
The informed consent obtained from the subject (or his or her legally acceptable representative) 
includes explicit consent for the processing of personal data and for the investigator/institution to 
allow direct access to his or her original medical records (source data/documents) for 
study-related monitoring, audit, IEC/IRB review, and regulatory inspection. This consent also 
addresses the transfer of the data to other entities and to other countries.
The subject has the right to request through the investigator access to his or her personal data and 
the right to request rectification of any data that are not correct or complete. Reasonable steps 
will be taken to respond to such a request, taking into consideration the nature of the request, the 
conditions of the study, and the applicable laws and regulations.
16.2.5.
Long-Term Retention of Samples for Additional Future Research 
Samples collected in this study may be stored for up to 15 years (or according to local 
regulations) for additional research. Samples will only be used to understand daratumumab, to 
understand ALL/LL, to understand differential drug responders, and to develop tests/assays 
related to daratumumab and ALL/LL. The research may begin at any time during the study or the 
post-study storage period. 
Stored samples will be coded throughout the sample storage and analysis process and will not be 
labeled with personal identifiers. Subjects may withdraw their consent for their samples to be 
stored for research (refer to Section 10.3, Withdrawal From the Use of Samples in Future 
Research.


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16.2.6.
Country Selection
This study will only be conducted in those countries where the intent is to launch or otherwise 
help ensure access to the developed product if the need for the product persists, unless explicitly 
addressed as a specific ethical consideration in Section 16.1, Study-Specific Design 
Considerations.
17.
ADMINISTRATIVE REQUIREMENTS
17.1.
Protocol Amendments
Neither the investigator nor the sponsor will modify this protocol without a formal amendment 
by the sponsor. All protocol amendments must be issued by the sponsor, and signed and dated by 
the investigator. Protocol amendments must not be implemented without prior IEC/IRB 
approval, or when the relevant competent authority has raised any grounds for non-acceptance, 
except when necessary to eliminate immediate hazards to the subjects, in which case the 
amendment must be promptly submitted to the IEC/IRB and relevant competent authority. 
Documentation of amendment approval by the investigator and IEC/IRB must be provided to the 
sponsor. When the change(s) involves only logistic or administrative aspects of the study, the 
IEC/IRB (where required) only needs to be notified.
During the course of the study, in situations where a departure from the protocol is unavoidable, 
the investigator or other physician in attendance will contact the appropriate sponsor 
representative listed in the Contact Information page(s), which will be provided as a separate 
document. Except in emergency situations, this contact should be made before implementing any 
departure from the protocol. In all cases, contact with the sponsor must be made as soon as 
possible to discuss the situation and agree on an appropriate course of action. The data recorded 
in the eCRF and source documents will reflect any departure from the protocol, and the source 
documents will describe this departure and the circumstances requiring it.
17.2.
Regulatory Documentation
17.2.1.
Regulatory Approval/Notification
This protocol and any amendment(s) must be submitted to the appropriate regulatory authorities 
in each respective country, if applicable. A study may not be initiated until all local regulatory 
requirements are met.
17.2.2.
Required Prestudy Documentation
The following documents must be provided to the sponsor before shipment of study drug to the 
study site:

Protocol and amendment(s), if any, signed and dated by the principal investigator.

A copy of the dated and signed (or sealed, where appropriate per local regulations), written 
IEC/IRB approval of the protocol, amendments, ICF/assent, any recruiting materials, and if 
applicable, subject compensation programs. This approval must clearly identify the specific 


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protocol by title and number and must be signed (or sealed, where appropriate per local
regulations) by the chairman or authorized designee.

Name and address of the IEC/IRB, including a current list of the IEC/IRB members and 
their function, with a statement that it is organized and operates according to GCP and the 
applicable laws and regulations. If accompanied by a letter of explanation, or equivalent, 
from the IEC/IRB, a general statement may be substituted for this list. If an investigator or a 
member of the study-site personnel is a member of the IEC/IRB, documentation must be 
obtained to state that this person did not participate in the deliberations or in the 
vote/opinion of the study.

Regulatory authority approval or notification, if applicable.

Signed and dated statement of investigator (eg, Form FDA 1572), if applicable.

Documentation of investigator qualifications (eg, curriculum vitae).

Completed investigator financial disclosure form from the principal investigator, where 
required.

Signed and dated Clinical Trial Agreement, which includes the financial agreement.

Any other documentation required by local regulations.
The following documents must be provided to the sponsor before enrollment of the first subject:

Completed investigator financial disclosure forms from all subinvestigators

Documentation of subinvestigator qualifications (eg, curriculum vitae)

Name and address of any local laboratory conducting tests for the study, and a dated copy of 
current laboratory normal ranges for these tests, if applicable

Local 
laboratory 
documentation 
demonstrating 
competence 
and 
test 
reliability 
(eg, accreditation/license), if applicable
17.3.
Subject Identification, Enrollment, and Screening Logs
The investigator agrees to complete a subject identification and enrollment log to permit easy 
identification of each subject during and after the study. This document will be reviewed by the 
sponsor study-site contact for completeness. The subject identification and enrollment log will be 
treated as confidential and will be filed by the investigator in the study file. To ensure subject 
confidentiality, no copy will be made. All reports and communications relating to the study will 
identify subjects by subject identification and date of birth (as allowed by local regulations). In 
cases where the subject is not enrolled into the study, the date seen and date of birth (as allowed 
by local regulations) will be used. The investigator must also complete a subject screening log, 
which reports on all subjects who were seen to determine eligibility for inclusion in the study.


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17.4.
Source Documentation
At a minimum, source documents consistent in the type and level of detail with that commonly 
recorded at the study site as a basis for standard medical care must be available for the following: 
subject identification, eligibility, and study identification; study discussion and date of signed 
informed consent; dates of visits; results of safety and efficacy parameters as required by the 
protocol; record of all AEs and follow-up of AEs; concomitant medication; drug 
receipt/dispensing/return records; study drug administration information; and date of study 
completion and reason for early discontinuation of study drug or withdrawal from the study, if 
applicable. The author of an entry in the source documents should be identifiable.
Specific details required as source data for the study and source data collection methods will be 
reviewed with the investigator before the study and will be described in the monitoring 
guidelines (or other equivalent document). The minimum source documentation requirements for 
Section 4.1, Inclusion Criteria and Section 4.2, Exclusion Criteria that specify a need for 
documented medical history are as follows:

Referral letter from treating physician

Complete history of medical notes at the site

Discharge summaries
Inclusion and exclusion criteria not requiring documented medical history must be verified at a 
minimum by subject interview or other protocol required assessment (eg, physical examination, 
laboratory assessment) and documented in the source documents.
An electronic source system may be utilized, which contains data traditionally maintained in a 
hospital or clinic record to document medical care (eg, electronic source documents) as well as 
the clinical study-specific data fields as determined by the protocol. This data is electronically 
extracted for use by the sponsor. If the electronic source system is utilized, references made to 
the eCRF in the protocol include the electronic source system but information collected through 
the electronic source system may not be limited to that found in the eCRF. Data in this system 
may be considered source documentation.
17.5.
Case Report Form Completion
Case report forms are prepared and provided by the sponsor for each subject in electronic format. 
All eCRF entries, corrections, and alterations must be made by the investigator or authorized 
study-site personnel. Electronic data capture (eDC) will be used for this study. Study site 
personnel must log into eDC in a secure manner (ie, using a personal password). The individual 
password must be kept confidential for personal use). The investigator must verify that all data 
entries in the eCRF are accurate and correct. The study data will be transcribed by study-site 
personnel from the source documents onto an eCRF, if applicable. Study-specific data will be 
transmitted in a secure manner to the sponsor.


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The study data will be transcribed by study-site personnel from the source documents onto an 
electronic eCRF, if applicable. Study-specific data will be transmitted in a secure manner to the 
sponsor.
If necessary, queries will be generated in the eDC tool. If corrections to a eCRF are needed after 
the initial entry into the eCRF, this can be done in either of the following ways:

Investigator and study-site personnel can make corrections in the eDC tool at their own 
initiative or as a response to an auto query (generated by the eDC tool).

Sponsor or sponsor delegate can generate a query for resolution by the investigator and 
study-site personnel.
17.6.
Data Quality Assurance/Quality Control
Steps to be taken to ensure the accuracy and reliability of data include the selection of qualified 
investigators and appropriate study sites, review of protocol procedures with the investigator and 
study-site personnel before the study, and periodic monitoring visits by the sponsor into the 
sponsor's data base. Written instructions will be provided for collection, handling, storage, and 
shipment of samples. 
Guidelines for eCRF completion will be provided and reviewed with study-site personnel before 
the start of the study. The sponsor will review eCRF for accuracy and completeness during on-
site monitoring visits and after transmission to the sponsor; any discrepancies will be resolved 
with the investigator or designee, as appropriate. After upload of the data into the study database 
they will be verified for accuracy and consistency with the data sources.
17.7.
Record Retention
In compliance with the ICH/GCP guidelines, the investigator/institution will maintain all eCRF 
and all source documents that support the data collected from each subject, as well as all study 
documents as specified in ICH/GCP Section 8, Essential Documents for the Conduct of a 
Clinical Trial, and all study documents as specified by the applicable regulatory requirement(s). 
The investigator/institution will take measures to prevent accidental or premature destruction of 
these documents.
Essential documents must be retained until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or until at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product. These documents will be 
retained for a longer period if required by the applicable regulatory requirements or by an 
agreement with the sponsor. It is the responsibility of the sponsor to inform the 
investigator/institution as to when these documents no longer need to be retained.
If the responsible investigator retires, relocates, or for other reasons withdraws from the 
responsibility of keeping the study records, custody must be transferred to a person who will 
accept the responsibility. The sponsor must be notified in writing of the name and address of the 
new custodian. Under no circumstance shall the investigator relocate or dispose of any study 


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documents before having obtained written approval from the sponsor. If it becomes necessary for 
the sponsor or the appropriate regulatory authority to review any documentation relating to this 
study, the investigator/institution must permit access to such reports.
17.8.
Monitoring
The sponsor will use a combination of monitoring techniques (central, remote, or on-site 
monitoring) to monitor this study. The sponsor will perform on-site monitoring visits as 
frequently as necessary. The monitor will record dates of the visits in a study site visit log that 
will be kept at the study site. The first post-initiation visit will be made as soon as possible after 
enrollment has begun. At these visits, the monitor will compare the data entered into the eCRF 
with the source documents (eg, hospital/clinic/physician’s office medical records). The nature 
and location of all source documents will be identified to ensure that all sources of original data 
required to complete the eCRF are known to the sponsor and study-site personnel and are 
accessible for verification by the sponsor study-site contact. If electronic records are maintained 
at the study site, the method of verification must be discussed with the study-site personnel. 
Direct access to source documents (medical records) must be allowed for the purpose of 
verifying that the recorded data are consistent with the original source data. Findings from this 
review will be discussed with the study-site personnel. The sponsor expects that, during 
monitoring visits, the relevant study-site personnel will be available, the source documents will 
be accessible, and a suitable environment will be provided for review of study-related 
documents. The monitor will meet with the investigator on a regular basis during the study to 
provide feedback on the study conduct.
In addition to on-site monitoring visits, remote contacts can occur. It is expected that during 
these remote contacts, study-site personnel will be available to provide an update on the progress 
of the study at the site.
Central monitoring will take place for data identified by the sponsor as requiring central review.
17.9.
Study Completion/Termination
17.9.1.
Study Completion/End of Study
The study will end 1 year after the last subject has initiated treatment or when the Sponsor 
decides to stop the study. The final data from the study site will be sent to the sponsor (or 
designee) after completion of the final subject visit, in the time frame specified in the Clinical 
Trial Agreement.
17.9.2.
Study Termination
The sponsor reserves the right to close the study site or terminate the study at any time for any 
reason at the sole discretion of the sponsor. Study sites will be closed upon study completion. A 
study site is considered closed when all required documents and study supplies have been 
collected and a study-site closure visit has been performed.


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The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. Reasons for the early 
closure of a study site by the sponsor or investigator may include but are not limited to:

Failure of the investigator to comply with the protocol, the requirements of the IEC/IRB or 
local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate recruitment of subjects by the investigator

Discontinuation of further study drug development
17.10. On-Site Audits
Representatives of the sponsor's clinical quality assurance department may visit the study site at 
any time during or after completion of the study to conduct an audit of the study in compliance 
with regulatory guidelines and company policy. These audits will require access to all study 
records, including source documents, for inspection. Subject privacy must, however, be 
respected. The investigator and study-site personnel are responsible for being present and 
available for consultation during routinely scheduled study-site audit visits conducted by the 
sponsor or its designees. 
Similar auditing procedures may also be conducted by agents of any regulatory body, either as 
part of a national GCP compliance program or to review the results of this study in support of a 
regulatory submission. The investigator should immediately notify the sponsor if he or she has 
been contacted by a regulatory agency concerning an upcoming inspection.
17.11. Use of Information and Publication
All information, including but not limited to information regarding daratumumab or the sponsor's 
operations (eg, patent application, formulas, manufacturing processes, basic scientific data, prior 
clinical data, formulation information) supplied by the sponsor to the investigator and not 
previously published, and any data, including pharmacogenomic or exploratory biomarker 
research data, generated as a result of this study, are considered confidential and remain the sole 
property of the sponsor. The investigator agrees to maintain this information in confidence and 
use this information only to accomplish this study, and will not use it for other purposes without 
the sponsor's prior written consent.
The investigator understands that the information developed in the study will be used by the 
sponsor in connection with the continued development of daratumumab, and thus may be 
disclosed as required to other clinical investigators or regulatory agencies. To permit the 
information derived from the clinical studies to be used, the investigator is obligated to provide 
the sponsor with all data obtained in the study.
The results of the study will be reported in a Clinical Study Report generated by the sponsor and 
will contain data from all study sites that participated in the study as per protocol. Recruitment 
performance or specific expertise related to the nature and the key assessment parameters of the 
study will be used to determine a coordinating investigator for the study. Results of 
pharmacogenomic exploratory biomarker analyses performed after the Clinical Study Report has 


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been issued will be reported in a separate report and will not require a revision of the Clinical 
Study Report. Study subject identifiers will not be used in publication of results. Any work 
created in connection with performance of the study and contained in the data that can benefit 
from copyright protection (except any publication by the investigator as provided for below) 
shall be the property of the sponsor as author and owner of copyright in such work.
Consistent with Good Publication Practices and International Committee of Medical Journal 
Editors guidelines, the sponsor shall have the right to publish such primary (multicenter) data 
and information without approval from the investigator. The investigator has the right to publish 
study site-specific data after the primary data are published. If an investigator wishes to publish 
information from the study, a copy of the manuscript must be provided to the sponsor for review 
at least 60 days before submission for publication or presentation. Expedited reviews will be 
arranged for abstracts, poster presentations, or other materials. If requested by the sponsor in 
writing, the investigator will withhold such publication for up to an additional 60 days to allow 
for filing of a patent application. In the event that issues arise regarding scientific integrity or 
regulatory compliance, the sponsor will review these issues with the investigator. The sponsor 
will not mandate modifications to scientific content and does not have the right to suppress 
information. For multicenter study designs and substudy approaches, secondary results generally 
should not be published before the primary endpoints of a study have been published. Similarly, 
investigators will recognize the integrity of a multicenter study by not submitting for publication 
data derived from the individual study site until the combined results from the completed study 
have been submitted for publication, within 18 months of the availability of the final data (tables, 
listings, graphs), or the sponsor confirms there will be no multicenter study publication. 
Authorship of publications resulting from this study will be based on the guidelines on 
authorship, such as those described in the ICMJE Recommendations for the Conduct, Reporting, 
Editing and Publication of Scholarly Work in Medical Journals, which state that the named 
authors must have made a significant contribution to the conception or design of the work; or the 
acquisition, analysis, or interpretation of the data for the work; and drafted the work or revised it 
critically for important intellectual content; and given final approval of the version to be 
published; and agreed to be accountable for all aspects of the work in ensuring that questions 
related to the accuracy or integrity of any part of the work are appropriately investigated and 
resolved.
Registration of Clinical Studies and Disclosure of Results
The sponsor will register and disclose the existence of and the results of clinical studies as 
required by law.


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Attachment 1: Karnofsky and Lansky Performance Status Scales
Karnofsky Scalea (recipient age ≥16 years)
Lansky Scaleb (recipient age <16 years)
100: Normal, no complaints, no evidence of 
disease
100: Fully active, normal
90: Able to carry on normal activity. Minor 
signs or symptoms of disease.
90: Minor restriction with strenuous physical 
activity
80: Normal activity with effort. Some signs or 
symptoms of disease.
80: Active, but gets tired more quickly
70: Cares for self, unable to carry on normal 
activity or to do active work
70: Both greater restrictions of, and less time 
spent in, active play
60: Requires occasional assistance but is able 
to care for most of personal needs
60: Up and around, but minimal active play; 
keeps busy with quieter activities
50: Requires considerable assistance and 
frequent medical care
50: Lying around much of the day, but gets 
dressed; no active play; participates in all quiet 
play and activities
40: Disabled, requires special care and
assistance
40: Mostly in bed; participates in quiet 
activities
30: Severely disabled, hospitalization 
indicated, although death not imminent
30: Stuck in bed; needs help even for quiet 
play
20: Hospitalization necessary. Very sick, 
active supportive treatment necessary.
20: Often sleeping; play is entirely limited to 
very passive activities
10: Moribund, fatal process progressing 
rapidly
10: Does not play or get out of bed to play
0: Dead
0: Unresponsive
a
Karnofsky DA, Burchenal JH. The clinical evaluation of chemotherapeutic agents in cancer. In Evaluation of 
chemotherapeutic agents. Edited by MacLeod CM. New York: Columbia University Press; 1949:191-205.21
b
Lansky SB, List MA, Lansky LL, Ritter-Sterr C, Miller DR. The measurement of performance in childhood 
cancer patients. Cancer. 1987;60(7):1651-1656.24


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Attachment 2: Conversion Table for Glucocorticoid Dose
Glucocorticoid
Approximate Equivalent 
Dose (mg)
Half-life (Biologic) hours
Intermediate-Acting
Methylprednisolone
4
18-36
Prednisolone
5
18-36
Prednisone
5
18-36
Triamcinolone
4
18-36
Long-Acting
Betamethasone
0.6 – 0.75
36-54
Dexamethasone
0.75
36-54


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Attachment 3: Serum Creatinine Guidelines
Age
Maximum Serum Creatinine (mg/dL)
Male
Female
1 to < 2 years 
0.6 
0.6 
2 to < 6 years 
0.8 
0.8 
6 to < 10 years 
1 
1 
10 to < 13 years 
1.2 
1.2 
13 to < 16 years 
1.5 
1.4 
≥ 16 years 
1.7 
1.4 
Note: The threshold creatinine values in this table were derived from the Schwartz formula for estimating glomerular filtration 
rate41 utilizing child length and stature data published by the CDC.
Cockcroft-Gault formula:
To calculate the subject’s creatinine clearance (CrCl), use the following Cockcroft-Gault formula:
CrCl =
(140 - age [in years]) x weight (kg)
(x 0.85 for females)
(72 x serum creatinine [mg/dL])
If the serum creatinine is obtained using the International System of Units (SI) (ie, micromol/L), use the following 
formula to convert SI units to conventional (mg/dL) units (Manual of Laboratory & Diagnostic Tests, 2004):
serum creatinine (micromol/L) divided by 88.4 = serum creatinine (mg/dL).


JNJ-54767414  (daratumumab)
Clinical Protocol 54767414ALL2005 Amendment 3
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Approved, Date: 22 January 2019
Attachment 4: Asthma Guidelines
Components of
Severity
Classification of Asthma Severity
Intermittent
Persistent
Mild
Moderate
Severe
0-4
yrs
5-11 yrs
12 + yrs
0-4 yrs
5-11 yrs 12 + yrs
0-4 yrs
5-11 yrs
12 + yrs
0-4 yrs
5-11 yrs
12 + yrs
Impairment
Normal 
FEV1/FVC :
8-19 yr 85%
20-39 yr 80%
40-59 yr 75%
60-80 yr 70%
Symptoms
≤2 days/week
≥2 days/week but not daily
Daily
Throughout the day
Nighttime 
awakenings
0
≤2x/month
1-2x/
month
3-4x/month
3-4x/
month
> 1x/week but not 
nightly
> 1x/
month
Often 7x/week
SABA use for 
symptom control (not 
prevention
of EIB)
≤2 days/week
≤2 days/week but not daily
>2 days/ 
week but
not daily,
and
not more 
than 1x
Daily
Several times per day
Interference with 
normal activity
None
Minor limitation
Some limitation
Extremely limited
Lung function
FEV1
FEV1/FVC
N/A
Normal FEV1 
between 
exacerbations
> 80%
> 85%
Normal FEV1 
between 
exacerbations
> 80%
Normal
N/A
> 80%
> 80%
> 80% 
Normal
N/A
60-80%
75-80%
60-80% 
Reduced 5%
N/A
< 60%
< 75%
< 60% 
Reduced
Risk
Exacerbations 
requiring oral 
systemic 
corticosteroids
0-1/year
≥2 exacerbations in 6
months requiring oral 
steroids or >4 wheezing 
episodes/1 year lasting
>1 day and risk factors
for persistent asthma
≥ 2/year
Relative 
annual risk 
may be 
related to 
FEV1.
≥ 2/year
Relative 
annual risk 
may be 
related to 
FEV1.
≥ 2 exacerbations in 6
months requiring oral 
steroids or >4 wheezing 
episodes/1 year lasting 
>1 day and risk factors
for persistent asthma
≥ 2/year
Relative 
annual risk 
may be 
related to 
FEV1.
≥ 2/year
Relative 
annual risk 
may be 
related to 
FEV1.
≥ 2 exacerbations in
6 months requiring oral 
steroids or >4 wheezing 
episodes/1 year lasting 
>1 day and risk factors 
for persistent asthma
≥ 2/year
Relative 
annual risk 
may be 
related to 
FEV1.
≥ 2/year
Relative 
annual risk
may be
related
to FEV1.
Consider severity and interval since last exacerbation. Frequency and severity may fluctuate over time for patients in any severity category.
Recommended
Step for
Initiating Treatment
Step 1
Step 2
Step 3 and consider 
short course of oral 
steroids
Step 3: 
medium
dose ICS
and 
consider
short 
course of
Step 3 and 
consider 
short course 
of oral 
steroids
Step 3 and consider 
short course of oral 
steroids
Step 3: 
medium dose 
ICS OR Step 4 
and consider 
short course of 
oral steroids
Step 4 or 5 
and
consider 
short 
course
of oral
steroids
In 2-6 weeks, evaluate level of asthma control that is achieved.
0-4 years: If no clear benefit is observed in 4-6 weeks, stop treatment and consider alternate diagnosis or adjusting therapy.  5-11 and 12+ years: adjust herapy accordingly.


JNJ-54767414  (daratumumab)
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Components of 
Control
Classification of Asthma Control
Well Controlled
Not Well Controlled
Very Poorly Controlled
0-4 yrs 5-11 yrs
12 + yrs
0-4 yrs
5-11 
12 + yrs
0-4 yrs
5-11 yrs 12 + yrs
Symptoms
≤ 2 days/week but not 
more than once on
each day
≤ 2 days/
week
> 2 days/week or 
multiple times on 
≤2 days/week
> 2 days/
week
Throughout the day
Impairment
Nighttime 
awakenings
≤ 1x/month
≤ 2x/month
> 1x/month
≥ 2x/month 1-3x/week
> 1x/week
≥ 2x/week
≥ 4x/week
Interference with 
normal activity
None
Some limitation
Extremely limited
SABA use for symptom 
control (not prevention of
EIB)
≤2 days/week
> 2 days/week
Several times per day
Lung function
FEV1 or peak flow
FEV1/FVC
N/A
> 80%
> 80%
> 80%
N/A
60-80%
75-80%
60-80%
N/A
< 60%
< 75%
< 60%
Validated questionnaires
ATAQ
ACQ
ACT
0
≤ 0.75
≥ 20
1-2
≥ 1.5
16-19
3-4
N/A
≤ 15
Risk
Exacerbations requiring oral 
systemic corticosteroids
0-1/year
≥2/year
Consider severity and interval since last exacerbation
Reduction in lung growth/ 
Progressive loss of lung 
function
Evaluation requires long-term follow-up
Recommended Action
for
Treatment
• Maintain current step
• Regular follow-up every 
1-6 months
• Consider step down if well 
controlled for at least 3 
months
Step up 1 
step
Step up at 
least 1 step
• Step up 1 
step
• Reevaluate
in 2-6 
weeks
• For side 
effects, 
consider 
alternative 
treatment 
options
• Consider short course
of oral steroids
• Step up 1-2 steps
• Consider 
short course 
of oral 
steroids
• Step up 1-2 
steps
• Reevaluate 
in 2 weeks
• For side
effects, 
consider 
alternative 
treatment 
options
• Before step up:
Review adherence to medication,
inhaler technique, and environmental 
control. If alternative treatment was 
used, discontinue it and use preferred
treatment for that step.
• Reevaluate the level of asthma
control in 2-6 weeks to achieve 
control.
0-4 years: If no clear benefit is observed 
in
4-6 weeks, consider alternative 
diagnoses or adjusting therapy.
5-11 years: Adjust therapy accordingly.
• For side effects, consider
alternative treatment options.
• Before step up:
Review adherence to medication,
inhaler technique, and environmental 
control. If alternative treatment was 
used, discontinue it and use preferred
treatment for that step.
• Reevaluate the level of asthma
control in 2-6 weeks to achieve 
control.
0-4 years: If no clear benefit is observed 
in
4-6 weeks, consider alternative 
diagnoses or adjusting therapy.
5-11 years: Adjust therapy accordingly.
• For side effects, consider
alternative treatment options.


JNJ-54767414  (daratumumab)
Clinical Protocol 54767414ALL2005 Amendment 3
116
Approved, Date: 22 January 2019
Attachment 5: High-Dose Methotrexate (HD MTX) Infusion Guidelines
When intrathecal therapy and HD MTX are scheduled for the same day, deliver the intrathecal 
therapy within 6 hours of the beginning of the IV MTX infusion (hour -6 to +6, with 0 being the 
start of the MTX bolus) or as per local standards. 
Hold TMP-SMX on the days of HD MTX infusion and for at least 72 hours after the start of the 
HD MTX infusion and until the MTX level is less than 0.4 μM. In the presence of delayed 
clearance continue to hold these medications until MTX level is less than 0.1 μM or as per local 
standards. 
Hold any nonsteroidal anti-inflammatory medications, penicillins, proton pump inhibitors or 
aspirin-containing medications on the day of HD MTX infusion and for at least 72 hours after the 
start of the HD MTX infusion and until the MTX level is less than 0.4 μM. In the presence of 
delayed clearance continue to hold these medications until MTX level is less than 0.1 μM or as 
per local standards. 
Prehydrate with D5 ¼ NS with 30 mEq NaHCO3/L at 125 mL/m2/hour until urine specific 
gravity is ≤ 1.010 and pH is ≥ 7.0 and ≤ 8.0. Ringers Lactate may be used as the initial fluid if a 
bicarbonate containing solution is unavailable. Adjust fluid volume and sodium bicarbonate to 
maintain urine specific gravity and pH at above parameters. A bicarbonate bolus (25 mEq/m2
over 15 min) may be given to raise the urine pH relatively quickly, a normal saline bolus may 
also be helpful in facilitating hydration. Continue hydration and alkalinization throughout HD 
MTX infusion, and for a minimum of 48 hours after its completion. In patients with delayed 
MTX clearance, continue hydration until the plasma MTX concentration is below 0.1 μM or as 
per local standards. 
Hour 0: MTX 500 mg/m2 IV mixed in a final volume of 65 mL/m2 D5 ¼ NS with 30 mEq 
NaHCO3/L and infused over 30 minutes. This is followed, immediately, by MTX 4500 mg/m2 
mixed in a final volume of 2935 mL/m2 D5 ¼ NS with 30 mEq NaHCO3/L given by continuous 
IV infusion over 23.5 hours at 125 mL/m2/hr. Be certain that the HD MTX infusion is completed 
in the 24-hour period. Unintentional prolongation to as long as 26 hours though not encouraged 
is acceptable. Alternatively, follow local standards.   
Hours 24, (36), 42 and 48: Draw MTX level and serum creatinine; NOTE: 36-hour level is only 
drawn if needed (see below) or as per local standards.
For MTX levels that exceed these expected values, follow local standard of care guidelines 
or  follow the rescue regimen as noted below and increase hydration to 200 mL/m2/hr, 
monitor urine pH to assure a value ≥ 7.0 and monitor urine output to determine if volume is ≥ 
80% of the fluid intake, measured every 4 hours. If serum creatinine rises significantly, at any 
time point, assure appropriate urine pH and urine volume as above and draw a 42-hour level. If 
urine output fails to continue at 80% of the fluid intake, consider furosemide or mannitol. 
Regardless of urine output, also consider glucarpidase (carboxypeptidase G2) (see below). For 


JNJ-54767414  (daratumumab)
Clinical Protocol 54767414ALL2005 Amendment 3
117
Approved, Date: 22 January 2019
patients with delayed clearance during a previous course, begin the following course with the 
increased hydration (200 mL/m2/hr) or as per local standards.
If the 24-hour level is < 150 μM draw the next level at hour 42 and refer to table below or as per 
local standards. 
If the 24-hour level is ≥ 150 μM and/or creatinine > 125% baseline, repeat level if MTX 
contamination is possible. If the value is “real” refer to the changes in hydration, etc. described 
above and repeat the level with a serum Cr at hour 36. Then refer to the table below or as per 
local standards. 
Start Leucovorin rescue for all subjects at 42 hr post start of methotrexate infusion.  For 
dose and timing of dosing follow table below based on subject’s methotrexate level at 
specific time points or as per local standards.
If the 42 and 48-hour levels are ≤ 1 and 0.4 μM, respectively, give leucovorin at 15 mg/m2 
IV/PO at 42, 48 and 54 hours post the start of methotrexate loading dose. No additional levels 
are needed, nor is additional leucovorin. Alternatively, follow local standards.
(36 hr MTX level)
42 hr MTX level
48 hr MTX level
Leucovorin Rescue++
Only required if 24 hr 
level is ≥ 150 μM. See 
below for guidelines**. 
1.01 to 9.9 μM
0.41 to 5.9 μM
Continue 15 mg/m2 q 6h 
until MTX level < 0.1 
μM (draw q12-24 h).
10 to 19.9 μM
6 to 9.9 μM
Increase to 15 mg/m2 q 
3h until MTX level < 0.1 
μM (draw q 6-24 h). 
Consider glucarpidase.
20 to 200 μM
10 to 100 μM
Increase to 100 mg/m2 q 
6h until MTX level < 0.1 
μM (draw q 6-24 h). 
Consider glucarpidase.
> 200 μM
> 100 μM
Increase to 1000 mg/m2 q 
6h until MTX level < 0.1 
μM (draw q 6-24 h). 
Consider glucarpidase. 
** If the 36-hour level exceeds 3 μM, increase hydration to 200 mL/m2/hr, monitor urine pH to assure a value ≥ 
7.0 and monitor urine output to determine if volume is ≥ 80% of the fluid intake, measured every 4 hours. If urine 
output fails to continue at 80% of the fluid intake, consider furosemide or mannitol. Regardless of urine output, also 
consider glucarpidase if 36-hour MTX level exceeds 10 μM (see below). 
++ If the level is high at hour 36 or 42, but then the patient “catches up” and the level falls to the expected values of 
≤ 1 and/or ≤ 0.4 μM at hours 42 and 48, respectively, resume standard leucovorin and hydration as long as urine 
output remains satisfactory.


JNJ-54767414  (daratumumab)
Clinical Protocol 54767414ALL2005 Amendment 3
118
Approved, Date: 22 January 2019
High-dose Methotrexate Flowchart Guidelines (alternatively, may follow local standards)


JNJ-54767414  (daratumumab)
Clinical Protocol 54767414ALL2005 Amendment 3
119
Approved, Date: 22 January 2019
Attachment 6: The Family of Antihistamine Medications
The following antihistamines may be used for daratumumab preinfusion medication (including, 
but not limited to):

Diphenhydramine

Cetirizine

Fexofenadine

Loratadine

Clemastine

Dexchlorpheniramine

Promethazine*
* The IV use of promethazine should be avoided. 


JNJ-54767414  (daratumumab)
Clinical Protocol 54767414ALL2005 Amendment 3
120
Approved, Date: 22 January 2019
Attachment 7: Estimated Total Blood Volume Collected During the Study
Estimated Maximum Volume of Blood to be Collected From Subjects with B-cell ALL/LL
Type of Samplea,b
Volume per 
Sample (mL)
No. of Samples 
per Subject
Approximate Total 
Volume of Blood 
(mL)c
Screening
Blood group and type assessment and IAT
assessment
2.0
1
2.0
BCR-ABL (Ph+ subjects only)
2.0
1
2.0
Safety
Hematologyd
2.0
1
2.0
Serum chemistryd
2.5
1
2.5
  Pregnancye
2.0
1
2.0
Hepatitis B serology
5.0
1
5.0
Cycles 1 and 2
BCR-ABL (Ph+ subjects only)
2.0
2
4.0
Safety
Hematologyd
2.0
8
16.0
Serum chemistryd
2.5
8
20.0
  Pregnancye
2.0
2
4.0
Pharmacokinetic/immunogenicity samplesf
5.0
4
20.0
Biomarker samples
2.0
2
4.0
Cycles 3 and 4
BCR-ABL (Ph+ subjects only)
2.0
2
4.0
Safety
Hematologyd
2.0
4
8.0
Serum chemistryd
2.5
4
10.0
Pregnancye
2.0
2
4.0
Pharmacokinetic/immunogenicity samplesf
5.0
2
10.0
Cycles 5+
BCR-ABL (Ph+ subjects only)
2.0
1-3
2.0-6.0
Safety
Hematologyd
2.0
2+ (2 per cycle)
4.0+
Serum chemistryd
2.5
2+ (2 per cycle)
5.0+
Pregnancye
2.0
1+ (1 per cycle)
2.0+
Pharmacokinetic/immunogenicity samplesf
5.0
4
20.0
End-of-Treatment Visit
Safety
Hematologyd
2.0
1
2.0
Serum chemistryd
2.5
1
2.5
Biomarker samples
2.0
1
2.0
Pharmacokinetic/immunogenicity samplesf
5.0
1
5.0
Follow-up Period
Pharmacokinetic/immunogenicity samplesf
5.0
1
5.0
Approximate Total 
74.5
61-63+
169.0+
a. Repeat or unscheduled samples may be taken for safety reasons or for technical issues with the samples but 
should not exceed allowable daily blood volume limits per local standards.
b. Sample volumes will be adjusted according to standards for pediatric subjects.
c. Calculated as number of samples multiplied by amount of blood per sample. 
d.   The Monoject pediatric collection containers are a 1.1 mL SST tube for chemistry and a 1.2 mL EDTA tube 
for hematology.
e.   Female subjects of reproductive potential only.
f.   Subjects aged 1 to 4 years will have 1.1 mL collected per sample. Subjects aged 5 to 12 years will have 
2.5 mL collected per sample.


JNJ-54767414  (daratumumab)
Clinical Protocol 54767414ALL2005 Amendment 3
121
Approved, Date: 22 January 2019
Estimated Maximum Volume of Blood to be Collected From Subjects with T-cell ALL/LL
Type of Samplea,b
Volume per 
Sample (mL)
No. of Samples 
per Subject
Approximate Total 
Volume of Blood 
(mL)c
Screening
Blood group and type assessment and IAT 
assessment
2.0
1
2.0
Safety
Hematologyd
2.0
1
2.0
Serum chemistryd
2.5
1
2.5
  Pregnancye
2.0
1
2.0
Hepatitis B serology
5.0
1
5.0
Cycle 1 
Safety
Hematologyd
2.0
5
10.0
Serum chemistryd
2.5
5
12.5
  Pregnancye
2.0
1
2.0
Pharmacokinetic/immunogenicity samplesf
5.0
2
10.0
Biomarker samples
2.0
1
2.0
Cycle 2
Safety
Hematologyd
2.0
5
10.0
Serum chemistryd
2.5
5
12.5
Pregnancye
2.0
1
2.0
Pharmacokinetic/immunogenicity samplesf
5.0
4
20.0
Biomarker samples
2.0
1
2.0
End-of-Treatment Visit
Safety
Hematologyd
2.0
1
2.0
Serum chemistryd
2.5
1
2.5
Biomarker samples
2.0
1
2.0
Pharmacokinetic/immunogenicity samplesf
5.0
1
5.0
Follow-up Period
Pharmacokinetic/immunogenicity samplesf
5.0
1
5.0
Approximate Total 
57.0
40
113.0
a. Repeat or unscheduled samples may be taken for safety reasons or for technical issues with the samples but 
should not exceed allowable daily blood volume limits per local standards.
b. Sample volumes will be adjusted according to standards for pediatric subjects.
c. Calculated as number of samples multiplied by amount of blood per sample. 
d.   The Monoject pediatric collection containers are a 1.1 mL SST tube for chemistry and a 1.2 mL EDTA tube 
for hematology.
e.   Female subjects of reproductive potential only.
f.   Subjects aged 1 to 4 years will have 1.1 mL collected per sample. Subjects aged 5 to 12 years will have 
2.5 mL collected per sample.


JNJ-54767414  (daratumumab)
Clinical Protocol 54767414ALL2005 Amendment 3
122
Approved, Date: 22 January 2019
Attachment 8: Doxorubicin Equivalent Conversion

Daunorubicin: multiply total dose in m2 x 1

Mitoxantrone: multiply total dose in m2 x 4

Idarubicin: multiply total dose in m2 x 5

Epirubicin: multiply total dose in m2 x 0.67
For doses in mg/kg, first multiply dose x 30 for mg/m2 then apply conversion above.
Source: Feijen 201513



SAP_001.pdf: 
1
Approved, Date: 9 November 2022
Janssen Research & Development *
Statistical Analysis Plan
An Open-label, Multicenter, Phase 2 Study Evaluating the Efficacy and Safety of 
Daratumumab in Pediatric and Young Adult Subjects ≥1 and ≤30 Years of Age with 
Relapsed/Refractory Precursor B-cell or T-cell Acute Lymphoblastic Leukemia or 
Lymphoblastic Lymphoma
Protocol 54767414ALL2005; Phase 2 
JNJ-54767414 (daratumumab)
Status:
Approved  
Date:
9 November 2022
Prepared by:
PPD
Document No.: EDMS-ERI-165382920
Compliance: The study described in this report was performed according to the principles of Good Clinical Practice (GCP). 
Confidentiality Statement
The information in this document contains trade secrets and commercial information that are privileged or confidential and may 
not be disclosed unless such disclosure is required by applicable law or regulations. In any event, persons to whom the 
information is disclosed must be informed that the information is privileged or confidential and may not be further disclosed by 
them. These restrictions on disclosure will apply equally to all future information supplied to you that is indicated as privileged or 
confidential.


JNJ-54767414  (daratumumab)
Statistical Analysis Plan 54767414ALL2005
2
Approved, Date: 9 November 2022
TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
ABBREVIATIONS ........................................................................................................................................ 4
1.
INTRODUCTION.................................................................................................................................. 5
1.1.
Trial Objectives ................................................................................................................................ 5
1.2.
Trial Design ...................................................................................................................................... 5
1.3.
Statistical Hypotheses for Trial Objectives....................................................................................... 8
1.4.
Sample Size Justification ................................................................................................................. 8
2.
GENERAL ANALYSIS DEFINITIONS ................................................................................................ 9
2.1.
Cohorts............................................................................................................................................. 9
2.2.
Visit Windows................................................................................................................................... 9
2.3.
Pooling Algorithm for Analysis Centers............................................................................................ 9
2.4.
Study Treatment and Study Drug .................................................................................................. 10
2.5.
Study Treatment Dosing Date........................................................................................................ 10
2.6.
Treatment Cycle............................................................................................................................. 10
2.7.
Study Day....................................................................................................................................... 10
2.8.
Baseline Measurement .................................................................................................................. 11
2.9.
Unique Lab Value........................................................................................................................... 11
2.10.
Imputation of Partial Dates............................................................................................................. 11
2.10.1.
Missing/Partial AE Onset Date ................................................................................................... 11
2.10.2.
Missing/Partial AE End Date....................................................................................................... 12
2.10.3.
Missing/Partial Death Date ......................................................................................................... 12
2.10.4.
Partial Concomitant Medication Start/End Date ......................................................................... 12
2.10.5.
Partial B-Cell ALL/T-Cell ALL/LL Diagnosis Date....................................................................... 13
2.10.6.
Partial Subsequent Systemic Therapy Start Date ...................................................................... 13
2.11.
General Analysis Method............................................................................................................... 14
2.12.
Analysis Sets.................................................................................................................................. 14
2.12.1.
Response Evaluable Analysis Set.............................................................................................. 14
2.12.2.
All treated Analysis Set............................................................................................................... 14
2.12.3.
Serum Pharmacokinetics Evaluable Analysis Set...................................................................... 14
2.12.4.
CSF Pharmacokinetics Evaluable Analysis Set ......................................................................... 14
2.12.5.
Immunogenicity Evaluable Analysis Set..................................................................................... 15
2.12.6.
Dose Limiting Toxicity (DLT) Evaluable Analysis Set................................................................. 15
3.
INTERIM ANALYSIS AND DATA MONITORING COMMITTEE REVIEW....................................... 15
4.
SUBJECT INFORMATION................................................................................................................ 15
4.1.
Demographics and Baseline Characteristics ................................................................................. 15
4.2.
Medical History............................................................................................................................... 16
4.3.
Disposition Information................................................................................................................... 16
4.4.
Extent of Exposure......................................................................................................................... 17
4.5.
Protocol Deviation.......................................................................................................................... 18
4.6.
Concomitant Medications............................................................................................................... 18
4.7.
Prior and Subsequent Systemic Therapy ...................................................................................... 18
5.
EFFICACY ......................................................................................................................................... 19
5.1.
Analysis Specifications................................................................................................................... 19
5.1.1.
Level of Significance................................................................................................................... 19
5.1.2.
Data Handling Rules................................................................................................................... 19
5.2.
Primary Efficacy Endpoint(s).......................................................................................................... 19
5.2.1.
Definition..................................................................................................................................... 19
5.2.2.
Estimand..................................................................................................................................... 20
5.2.3.
Analysis Methods........................................................................................................................ 20
5.3.
Major Secondary Endpoints........................................................................................................... 20


JNJ-54767414  (daratumumab)
Statistical Analysis Plan 54767414ALL2005
3
Approved, Date: 9 November 2022
5.3.1.
Overall Response Rate (ORR) ................................................................................................... 21
5.3.1.1.
Definition.................................................................................................................................. 21
5.3.1.2.
Analysis Methods .................................................................................................................... 21
5.3.2.
Event-Free Survival (EFS).......................................................................................................... 21
5.3.2.1.
Definition.................................................................................................................................. 21
5.3.2.2.
Analysis Methods .................................................................................................................... 22
5.3.3.
Relapse-Free Survival (RFS)...................................................................................................... 22
5.3.3.1.
Definition.................................................................................................................................. 22
5.3.3.2.
Analysis Methods .................................................................................................................... 23
5.3.4.
Overall Survival (OS).................................................................................................................. 23
5.3.4.1.
Definition.................................................................................................................................. 23
5.3.4.2.
Analysis Methods .................................................................................................................... 23
5.3.5.
MRD Negative Rate.................................................................................................................... 24
5.3.5.1.
Definition.................................................................................................................................. 24
5.3.5.2.
Analysis Methods .................................................................................................................... 24
5.3.6.
Allogeneic Hematopoietic Stem Cell Transplant Rate................................................................ 24
5.3.6.1.
Definition.................................................................................................................................. 24
5.3.6.2.
Analysis Methods .................................................................................................................... 24
5.4.
Other Efficacy Endpoints................................................................................................................ 24
6.
PHARMACOKINETIC AND IMMUNOGENICITY ............................................................................. 25
6.1.
Pharmacokinetic............................................................................................................................. 25
6.2.
Immunogenicity.............................................................................................................................. 26
7.
BIOMARKER..................................................................................................................................... 26
7.1.
Minimal Residual Disease (MRD) .................................................................................................. 26
7.1.1.
Sampling Timepoints .................................................................................................................. 26
7.1.2.
Analysis Methods........................................................................................................................ 26
7.2.
CD38 Expression on Lymphoblasts............................................................................................... 26
7.3.
Other Biomarker............................................................................................................................. 26
8.
SAFETY............................................................................................................................................. 27
8.1.
Adverse Events .............................................................................................................................. 27
8.1.1.
Overview of TEAEs..................................................................................................................... 28
8.1.2.
All TEAEs.................................................................................................................................... 28
8.1.3.
Toxicity Grade 3 or 4 TEAEs ...................................................................................................... 28
8.1.4.
Any Study Treatment-Related TEAEs........................................................................................ 28
8.1.5.
Serious Adverse Events ............................................................................................................. 29
8.1.6.
TEAEs Leading to Cycle Delays or Dose Modifications............................................................. 29
8.1.7.
TEAEs Leading to Discontinuation of Daratumumab................................................................. 29
8.1.8.
TEAEs Leading to Discontinuation of All Study Treatment ........................................................ 29
8.2.
Deaths............................................................................................................................................ 29
8.2.1.
All Deaths ................................................................................................................................... 29
8.2.2.
Death Due to TEAEs .................................................................................................................. 30
8.3.
Adverse Events of Clinical Interest ................................................................................................ 30
8.3.1.
Infusion-related Reactions.......................................................................................................... 30
8.3.2.
Infections and Infestations.......................................................................................................... 30
8.3.3.
Haemorrhage Events.................................................................................................................. 30
8.3.4.
Tumor Lysis Syndrome............................................................................................................... 30
8.3.5.
New Malignancies....................................................................................................................... 30
8.4.
Clinical Laboratory Tests................................................................................................................ 31
8.5.
Vital Signs Measurements ............................................................................................................. 31
8.6.
Physical Examination Findings ...................................................................................................... 31
8.7.
Karnofsky and Lansky Performance Status................................................................................... 31
8.8.
Electrocardiogram.......................................................................................................................... 31
REFERENCES............................................................................................................................................ 32


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ABBREVIATIONS
AE
adverse event
ALL
acute lymphoblastic leukemia
ALT
alanine aminotransferase
ANC
absolute neutrophil count
ARA-C
cytarabine
AST
aspartate aminotransferase
CI
confidence interval
CCO
clinical cutoff
CNS
central nervous system
COVID-19
coronavirus disease 2019
CR
complete response
CRF
case report form
CRi
complete response with only partial hematological recovery
CSF
cerebrospinal fluid
CTCAE
Common Terminology Criteria for Adverse Events
DLT
dose-limiting toxicities
ECG
electrocardiogram
EFS
event-free survival
HC
hydrocortisone
HSCT
hematopoietic stem cell transplant
ICF
informed consent form
IRR
Infusion-related reaction
LL
lymphoblastic lymphoma
MedDRA
Medical Dictionary for Regulatory Activities
MRD
minimal residual disease
MTX
methotrexate
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
NHL
non-Hodgkin lymphoma
ORR
overall response rate
OS
overall survival
PK
pharmacokinetic(s)
RBC
red blood cell
RFS
relapse-free survival
SAE
serious adverse event
SAP
statistical analysis plan
SD
standard deviation
SET
safety evaluation team
SMQ
Standardized MedDRA Queries
SOC
system organ class
TEAE
treatment-emergent adverse event
TLS
tumor lysis syndrome
WBC
white blood cell


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1.
INTRODUCTION
This statistical analysis plan (SAP) contains definitions of analysis sets, derived variables, and 
statistical methods for planned analyses for study 54767414ALL2005.
1.1.
Trial Objectives
Primary Objective
The primary objective is to evaluate the efficacy of daratumumab in combination with standard 
chemotherapy in pediatric subjects with relapsed/refractory B-cell acute lymphoblastic leukemia 
(ALL) and T-cell ALL as measured by the complete response (CR) rate.
Secondary Objectives
The secondary objectives are:

To assess the efficacy of daratumumab in addition to standard chemometry, including overall 
response rate (ORR), relapse-free survival (RFS), event-free survival (EFS), and overall 
survival (OS) in pediatric subjects with B-cell and T-cell ALL, and minimal residual disease 
(MRD) negative rate in subjects with B-cell and T-cell ALL

To assess the safety and tolerability of daratumumab in addition to standard chemometry in 
pediatric subjects with B-cell and T-cell ALL

To assess the pharmacokinetics (PK) of daratumumab in pediatric subjects with B-cell and T-
cell ALL

To assess daratumumab immunogenicity in pediatric subjects with B-cell ALL and T-cell 
ALL

To assess daratumumab concentration in cerebrospinal fluid (CSF)
Exploratory Objectives
The exploratory objectives are:

To explore biomarkers predictive of response or resistance to therapy

To assess expression of CD38 at study entry and at relapse
1.2.
Trial Design
This open-label, multicenter, Phase 2 study will enroll approximately 49 subjects aged ≥1 to 
<18 years with relapsed/refractory ALL and a maximum of 69 total subjects ≥1 and ≤30 years of 
age with relapsed/refractory ALL/LL. Cohort 1 will evaluate the safety and efficacy of 
daratumumab in combination with vincristine and prednisone in subjects with B-cell ALL/LL in 
second relapse or greater. Cohort 2 will evaluate the safety and efficacy of daratumumab in 
combination with a standard 4-drug re-induction regimen (prednisone, vincristine, doxorubicin, 
and PEG-asparaginase) in subjects with T-cell ALL/LL in first relapse.


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Subject participation will include a Screening Period, a Treatment Period, and a Post-treatment 
Period. The Screening Period will be up to 21 days before first dose. During the Treatment Period, 
cycles are 28 days. Subjects with B-cell ALL/LL will receive treatment until disease progression 
or unacceptable toxicity. Subjects with T-cell ALL/LL will receive treatment for up to 2 cycles 
(induction and consolidation). There is an optional maintenance phase for all subjects who achieve 
CR and need to bridge therapy until an allogeneic hematopoietic stem cell transplant (HSCT). The 
Post-treatment Period begins immediately following the End-of-Treatment Visit, and will continue 
until death, loss to follow-up, or consent withdrawal for study participation, whichever occurs first.
A diagram of the study design is provided below in Figure 1. The study has 2 stages. Stage 1 will 
evaluate the initial safety and efficacy in each cohort. Only B-cell or T-cell ALL subjects aged 1 
to <18 years will be enrolled in their respective cohorts in Stage 1. Stage 1 will include a safety 
run-in which will evaluate the initial 3 subjects with B-cell ALL and initial 3 subjects with T-cell 
ALL. Enrollment will continue after safety is confirmed in each cohort separately. After 
confirming safety, Cohort 1 (B-cell ALL) will enroll an additional 4 subjects aged 1 to <18 years 
in Stage 1 and Cohort 2 (T-cell ALL) will enroll an additional 5 subjects aged 1 to <18 years in 
Stage 1. During Stage 1, the dose of daratumumab will be evaluated with ongoing PK analysis to 
confirm the therapeutic dose of daratumumab to be used in Stage 2 of the study. The study will 
have a futility analysis for each cohort after Stage 1 is completed before enrolling subjects to Stage 
2. All subjects enrolled into Stage 1, including subjects in the safety run-in at the confirmed safe 
dosing regimen will be included in the futility analysis.
In Stage 2, an additional 18 subjects with B-cell ALL and 16 subjects with T-cell ALL aged 1 to 
<18 years will be enrolled for a total of 25 subjects with B-cell ALL and 24 subjects with T-cell 
ALL aged 1 to <18 years. The sponsor plans to enroll a minimum of 3 subjects with ALL in each 
of the following age groups in both cohorts if an individual cohort proceeds to Stage 2: 1 to 6, 7 to 
12, and 13 to <18 years. In Stage 2 subjects with LL and young adults with ALL will also be 
enrolled. A maximum of 10 subjects aged 1 to 30 years with LL and a maximum of 10 subjects 
aged 18 to 30 years with ALL will be enrolled to the respective B-cell and T-cell cohorts. The data 
from these subjects with LL (pediatric and young adult) and young adult subjects aged 18 to 30 
years with ALL will be descriptively summarized.


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Figure 1:
Schematic Overview of the Study
Subjects with B-cell ALL/LL will receive treatment continuously in 28-day cycles until disease 
progression or unacceptable toxicity. Treatment will consist of daratumumab 16 mg/kg IV weekly 
for 8 doses, then every 2 weeks for 8 doses, then every 28 days thereafter; vincristine 1.5 mg/m2
(maximum 2 mg) IV weekly for 4 doses, then every 2 weeks for 2 doses, then every 28 days 
thereafter; and prednisone 40 mg/m2 orally daily for 28 days, then pulses on the first 5 days of 
each cycle thereafter.
Subjects with T-cell ALL/LL will receive up to two 28-day cycles of therapy. Subjects who 
achieve CR should proceed to allogeneic hematopoietic stem cell transplant off study. Cycle 1 
treatment consists of daratumumab 16 mg/kg IV weekly for 4 doses, vincristine 1.5 mg/m2
(maximum 2 mg) IV weekly for 4 doses, prednisone 40 mg/m2 orally daily for 28 days, 
doxorubicin 60 mg/m2 IV once, and peg-asparaginase 2500 U/m2 IM or IV twice. Cycle 2 
treatment consists of daratumumab 16 mg/kg IV weekly for 4 doses, cyclophosphamide IV 1 g/m2
once, cytarabine 75 mg/m2 IV/subcutaneous for 8 doses, 6-mercaptopurine 60 mg/m2 orally daily 
for 14 doses, and methotrexate 5 g/m2 IV once.
Subjects in both cohorts will also receive age-adjusted treatment with intrathecal methotrexate (for 
subjects without central nervous system [CNS] involvement) or intrathecal methotrexate-
hydrocortisone-cytarabine (for subjects with CNS involvement).


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During the safety run-in, 3 subjects in each cohort will be evaluated for dose-limiting toxicities 
(DLTs). A Safety Evaluation Team (SET) will review the DLT data and determine whether a 
modification to the dose or schedule of study drugs is needed for any of the treatment cohorts. The 
DLT Evaluation Period is defined as the first 28 days from the start of the first dose of 
daratumumab. DLTs will be evaluated in each cohort separately at the end of Cycle 1. Only 
toxicities that occur during the DLT evaluation period will be used for the purpose of defining 
DLT and for subsequent dose or dosing schedule modifications or safety-run in expansion. 
However, toxicities that occur in all cycles will be considered in the overall decisions of the SET. 
If a subject receives less than 75% of the planned dose of daratumumab for reasons other than 
toxicity (e.g., disease progression, subject withdrawal, etc.), that subject will be considered non-
evaluable for DLTs and may be replaced, but the safety profiles of these subjects will be included 
in the SET review. Additional safety reviews will be conducted by the SET after Stage 1 of the 
study in each cohort and as deemed necessary during the conduct of the study.
If 1 or more subjects in a cohort experience a DLT, then the safety run-in for that cohort will be 
expanded to 6 subjects. After the additional 3 subjects complete 1 cycle of therapy, safety will be 
re-evaluated. If 2/6 or more subjects experience a DLT, the dose or schedule of study drugs may 
be adjusted in the remaining treatment cycles, and an additional 3 subjects may be treated at a 
lower dose or adjusted schedule for a given combination regimen. A new safety evaluation will 
begin with 3 new subjects with the adjusted dosing regimen and will follow the guidelines noted 
below.
1.3.
Statistical Hypotheses for Trial Objectives
The primary objective is to evaluate the efficacy of daratumumab in addition to standard 
chemotherapy in relapsed/refractory B-cell ALL and T-cell ALL as measured by the CR rate. 
The primary hypothesis for each ALL subtype is as follows:
For the B-cell ALL cohort, treatment with daratumumab in combination with vincristine and 
prednisone will result in a CR rate of 40% or higher. The following hypotheses will be tested:

H0: CR rate ≤15% vs.

Ha: CR rate ≥40%
For the T-cell ALL cohort, treatment with daratumumab in combination with doxorubicin, 
prednisone, vincristine, and asparaginase will result in a CR rate of 60% or higher. The following 
hypotheses will be tested:

H0: CR rate ≤30% vs.

Ha: CR rate ≥60%
1.4.
Sample Size Justification
The study utilizes a Simon’s 2-stage design for subjects aged less than 18 years. The B-cell ALL 
cohort will enroll 7 subjects in the first stage. If there is more than 1 responder after these subjects 
have received 2 cycles of treatment, then an additional 18 subjects will be enrolled in Stage 2. If 6 


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or fewer subjects in the B-cell ALL arm respond, then the drug will be considered ineffective and 
further development in this disease will be stopped. If 25 subjects are enrolled, then there is 80% 
power to show that the true CR rate is >15% at a one-sided alpha of 5%. The T-cell ALL cohort 
will enroll 8 subjects in the first stage. If there are more than 3 responders after these subjects have 
received at least 1 cycle of treatment, then an additional 16 subjects will be enrolled in Stage 2.
This cohort will be considered ineffective if 10 or fewer subjects respond at the end of Stage 2. If 
24 pediatric subjects are enrolled, then there is 80% power to show that the true CR rate is >30% 
at a one-sided alpha of 5%.
In addition, a maximum of 10 young adult subjects (aged 18 to 30 years) with ALL and a maximum 
of 10 subjects with LL (aged 1 to 30 years) will be included to evaluate the safety and efficacy in 
this subject population and their data will be summarized descriptively.
2.
GENERAL ANALYSIS DEFINITIONS
2.1.
Cohorts
In general, outputs will be displayed by the 4 cohorts listed unless otherwise specified. B-cell 
cohort terminated after futility analysis at the end of stage 1 and thus only has 1 cohort. T-cell ALL 
total will also be presented where applicable.

B-cell ALL (1-17 Yrs)

T-cell ALL (1-17 Yrs)

T-cell ALL (18-30 Yrs)

T-cell LL (1-30 Yrs)
2.2.
Visit Windows
For analyses of data by cycle, if data are collected by date (e.g., AE onset), the corresponding study 
evaluations will be assigned to actual sequential cycles, which are derived from the study treatment 
administration data. The start date of a particular cycle is defined as the date of the first actual dose 
of any component of the study treatment, and the end date of a cycle is the start date of the next 
cycle minus 1. For the last cycle, the end date is defined as the end of treatment visit date or the 
minimum of last study treatment date plus 30 days or subsequent anticancer therapy minus 1 day, 
if the end of treatment visit date is not available.  
In general, if data (e.g., laboratory and vital sign etc.) are collected by cycle, the nominal cycle 
will be used to summarize data.
2.3.
Pooling Algorithm for Analysis Centers
All participating centers in the study will be pooled together for analyses.


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2.4.
Study Treatment and Study Drug  
In this study, study treatment refers to intrathecal MTX/ Triple Intrathecal Therapy (both T and B 
cell cohorts), vincristine (both T and B cell cohorts), prednisone (both T and B cell cohorts), 
doxorubicin (T-cell only), asparaginase (Pegaspargase [PEG-Asparaginase] or Erwinia – T-cell 
only), high dose methotrexate (T-cell only), cyclophosphamide (T-cell only), cytarabine (ARA-C) 
(T-cell only), 6-mercaptopurine (T-cell only) and daratumumab. 
Study drug refers to daratumumab.
2.5.
Study Treatment Dosing Date 
Study treatment dosing date is the date on which a subject received study treatment (partial or 
complete) and will be recorded in the study treatment administration dataset.
For subjects in the B-cell ALL cohort, the first study treatment date is defined as the earliest date 
of non-zero dose of the following administration: intrathecal MTX, intrathecal MTX/HC/ARA-C, 
vincristine, prednisone or daratumumab. The last study treatment date is defined as the latest date 
of non-zero dose of the administration mentioned above.
For subjects in the T-cell ALL/LL cohort, the first study treatment date is defined as the earliest 
date of non-zero dose of the following administration: intrathecal MTX, intrathecal 
MTX/HC/ARA-C, 
doxorubicin, 
vincristine, 
prednisone, 
peg-asparaginase, 
high 
dose 
methotrexate, cyclophosphamide, cytarabine, 6-mercaptopurine, mesna, erwinia asparaginase or 
daratumumab. The last study treatment date is defined as the latest date of non-zero dose of the 
administration mentioned above.
2.6.
Treatment Cycle 
A subject is considered as treated in a cycle if he/she receives any nonzero dose of intrathecal 
MTX, intrathecal MTX/HC/ARA-C, vincristine, prednisone, doxorubicin, peg-asparaginase, high 
dose 
methotrexate, 
cyclophosphamide, 
cytarabine, 
6-mercaptopurine, 
mesna, 
erwinia 
asparaginase or daratumumab in that cycle.
2.7.
Study Day
Day 1 refers to the start of the first study drug administration. All efficacy, PK, immunogenicity, 
and safety assessments at all visits will be assigned a day relative to this date.
Study day for a visit is defined as:

Visit date - (date of Study Day 1) +1, if visit date is ≥date of Day 1

Visit date - Date of Day 1, if visit date <date of Day 1
There is no 'Day 0'.


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2.8.
Baseline Measurement
Baseline measurement is defined as the closest non-missing measurement taken on or prior to the 
first study drug administration.
2.9.
Unique Lab Value 
In general, in instances when there are multiple records at a given visit date for lab parameters 
associated with disease assessment, the following rules will be applied to select the unique lab 
value for analysis: a) multiple records from both central and local lab, central lab value always 
takes precedence over local lab value; b) multiple records from central lab, select the latest value 
as the unique lab value; c) multiple records from local lab, select the latest lab value as the unique 
lab value.   
2.10.
Imputation of Partial Dates
Unless specified otherwise, no data imputation will be applied for missing safety and efficacy 
evaluations. For analysis and reporting purpose, missing or partial date in adverse event (AE) (AE 
onset date; AE end date), death date, concomitant therapies (start date; end date), B-cell ALL/T-
cell ALL/LL initial diagnosis (date of diagnosis), and subsequent systemic therapy (start date) data 
domain will be imputed. Date as collected (missing or partial) rather than imputed date will be 
displayed in listings where applicable.
2.10.1.
Missing/Partial AE Onset Date
If the onset date of an AE is missing completely or partially, the following imputation rules will 
be used.

When month and year are present and the day is missing,

If the onset month and year are the same as the month and year of first study treatment, 
the day of first study treatment or the day-component of the AE end date (possibly 
imputed), whichever is earlier is imputed. 

If the onset month and year are not the same as the month and year of first study treatment, 
then the first day of the month is imputed.

When only a year is present, 

If the onset year is the same as the year of first study treatment
o
If AE end date is available and is prior to first study treatment, the day and month of 
AE end date are imputed. 
o
Otherwise, the day and month of first study treatment are imputed.

If the onset year is different from the year of first study treatment, the 1st of January is 
imputed.

If the onset date is completely missing, the date of first study treatment is imputed as the onset 
date.
No imputation will be done for partial or missing AE onset time. 


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If AE onset date needs imputation, but the AE onset time is available, the AE onset time will be 
dropped in the imputed AE onset date/time variable.
2.10.2.
Missing/Partial AE End Date
If the end date of an AE is partially missing, the following imputation rules will be used.

If month and year are present and the day of the month is missing, the last day of the month 
is imputed. 

If only a year is present, the 31st of December is used. 

If the imputed date is later than the date of death (if available), the date of death will be used 
as the imputed date instead.
If the end date is completely missing the AE will be considered as ongoing at the end of study and 
no imputation will be done.
No imputation will be done for partial or missing AE end time. 
If AE end date needs imputation, but the AE end time is available, the AE end time will be dropped 
in the imputed AE end date/time variable.
2.10.3.
Missing/Partial Death Date
If the death date is completely missing or the month is missing, no imputation will be performed. 
If only the day of death date is missing, the following imputation rules will be applied:

The first day of the month is imputed.

If it has the same year and month as the date of the last known alive, then the date of the last 
known alive + 1 will be used as the imputed date instead.
2.10.4.
Partial Concomitant Medication Start/End Date
In case of partially missing concomitant medication start/end dates, the following imputation rules 
will be applied. If the date is completely missing, no imputation will be performed.

If only the day is missing, the 15th day of the month will be used

If both the day and month are missing, the 30th of June will be used
If the medication was taken prior to study start, and the imputed start date is after first treatment 
date, further adjust of the imputed start date as the day prior to first dosing date; If the medication 
was taken after study start, and the imputed start date is prior to the first dosing date, the imputed 
start date will be adjusted to be the first dosing date. The imputed medication end date will also be 
adjusted so that it is on or after first dosing date. 
After applying above adjusting method, if it results in medication start date that is after medication 
end date, the medication start date needs re-adjustment as follows:
If medication start date was imputed then adjust as follows: 


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
Impute the same month and year as medication end date if the non-imputed date parts are the 
same 

Impute the first day of the month as medication start day 
If medication end date was imputed then re-adjust medication end date to be the same as the 
medication start date if the corresponding non-imputed date parts match the medication start date. 
Also adjust the imputed medication end date so that it is on or after first dosing date. 
2.10.5.
Partial B-Cell ALL/T-Cell ALL/LL Diagnosis Date
If the B-cell ALL/T-cell ALL/LL diagnosis date is completely missing, no imputation will be 
applied. For the partial date of B-cell ALL /T-cell ALL/LL initial diagnosis, the following imputation 
rules will apply:

If only the day of the diagnosis date is missing:
o
If the month and year of the diagnosis date are the same as the month and year of the 
start date of the first line of prior B-cell ALL/T-cell ALL/LL therapy, and day of the 
start date of the first line of prior B-cell ALL/T-cell ALL/LL therapy is available, 
impute day of the diagnosis date with the day of the start date of the first line of prior 
B-cell ALL/T-cell ALL/LL therapy; 
o
Otherwise, impute day of diagnosis date with 15;

If both month and day of the diagnosis date are missing:
o
If the year of the diagnosis date is the same as the year of the start date of the first line 
of prior B-cell ALL/T-cell ALL/LL, and the month of the start date of the first line of 
prior B-cell ALL/T-cell ALL/LL therapy is available:

if both month and day of the start date of the first line of prior B-cell ALL/T-
cell ALL/LL therapy are available, impute diagnosis month and day with the 
month and day of the start date of the first line of prior B-cell ALL/T-cell 
ALL/LL therapy; 

if only the month of the start date of the first line of prior B-cell ALL/T-cell 
ALL/LL therapy is available, impute the month of diagnosis date with the 
month of the start date of the first line of prior B-cell ALL/T-cell ALL/LL
therapy and the day of the diagnosis date with 15; 
o
Otherwise, impute the month and day of the diagnosis date with June 30.  
2.10.6.
Partial Subsequent Systemic Therapy Start Date
If the year or month of subsequent anticancer therapy start date is missing or no components of 
the start date are present, no imputation will be performed.  
If only the day-component is missing, the following steps apply: 


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
If the month and year of the start date are the same as the month and the year of last dosing 
date, the day of last dosing date or the day-component of the stop date of subsequent 
anticancer therapy is imputed, whichever is earlier. 

If the start month and year are not the same as the month and year of last dosing date, the first 
day of the month is imputed.
After applying above adjusting method, if it results in that medication start date is after medication 
end date, the medication start date needs to be re-adjusted to be the same as the end date.
No imputation will be applied for missing or partial subsequent anticancer therapy end date. 
2.11.
General Analysis Method
In general, summary statistics for continuous variables include mean, standard deviation, median, 
minimum, and maximum unless otherwise specified. Categorical data will be presented as 
frequencies and percentages. The Kaplan-Meier method will be used for descriptive summaries 
for time-to-event variables. For the calculation of time-to-event and duration-of-event variables, 
the difference between the start date and the end date plus 1 day will be used.
2.12.
Analysis Sets
The following analysis sets are defined for conducting planned analyses.
2.12.1.
Response Evaluable Analysis Set
The response evaluable analysis set includes all enrolled subjects who receive at least 1 dose of 
daratumumab and have at least 1 adequate post-baseline disease assessment. Sensitivity analyses 
of CR rate and ORR will be based on response evaluable analysis set.
2.12.2.
All treated Analysis Set
The all treated analysis set includes all enrolled subjects who receive at least 1 dose of 
daratumumab. This analysis set will be used for all safety analyses, analyses of the primary 
efficacy endpoint CR rate, and major secondary endpoints, such as ORR, MRD negative rate, 
HSCT rate, time-to-event variables (e.g., EFS, RFS, and OS), and subject information summaries 
that described in Section 4.
2.12.3.
Serum Pharmacokinetics Evaluable Analysis Set
The serum PK evaluable analysis set includes all enrolled subjects who receive at least 1 dose of 
daratumumab and provide at least 1 post-infusion blood sample for serum daratumumab 
concentrations. This analysis set will be used for daratumumab serum concentrations summary.
2.12.4.
CSF Pharmacokinetics Evaluable Analysis Set
The CSF PK evaluable analysis set includes all enrolled subjects who receive at least 1 dose of 
daratumumab and provide at least 1 post-infusion CSF sample for daratumumab concentrations.
This analysis set will be used for CSF daratumumab concentrations summary.


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2.12.5.
Immunogenicity Evaluable Analysis Set
The immunogenicity evaluable analysis set includes all enrolled subjects who receive at least 1 
dose of daratumumab and have at least 1 post-infusion sample for detection of anti-daratumumab 
antibodies. This analysis set will be used for daratumumab immunogenicity analysis.
2.12.6.
Dose Limiting Toxicity (DLT) Evaluable Analysis Set
The DLT-evaluable analysis set includes any subject in the safety run-in phase who has a DLT 
regardless of dose received or who completed the first 28 days from the start of the first dose of 
Daratumumab and received at least 75% of the planned dose during the DLT evaluation period, 
which is the first 28 days starting from the day of the first dose of study drug.
3.
INTERIM ANALYSIS AND DATA MONITORING COMMITTEE REVIEW
Non-binding futility analysis (based on a Simon two-stage design) will be performed for Cohorts 
1 and 2.
A SET consisting of the participating principal investigators, the sponsor’s responsible medical 
officer, sponsor’s statistician, sponsor’s clinical pharmacologist and sponsor’s safety management 
team chair will monitor safety in the run-in of the first 3 subjects in each cohort separately. 
Additional safety reviews will be conducted by the SET after Stage 1 of the study in each cohort 
and as deemed necessary during the conduct of the study. The details will be provided in a separate 
SET charter.
4.
SUBJECT INFORMATION
4.1.
Demographics and Baseline Characteristics
Unless specified otherwise, all demographic and baseline characteristics variables will be 
summarized for the all treated analysis set. All interested baseline disease characteristics variables 
that are listed in Table 2 will also be summarized for the all treated analysis set. 
The distribution of subject’s enrollment will be presented for each cohort according to region, 
country, and site.
Table 1 presents a list of demographic and baseline characteristics variables that will be 
summarized by cohort.
Table 2 presents a list of baseline disease characteristics variables that will be summarized by 
cohort.
Table 1: 
Demographic and Baseline Characteristics Variables
Continuous Variables:
Summary Type
Age (years)
Descriptive statistics (N, mean, 
standard deviation [SD], median, 
minimum and maximum).
Weight (kg)
Height (cm)
BMI (kg/m2)
BSA (Body surface area) (m2)


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Categorical Variables
Age (1-6, 7-12, 13-17, 18-30)
Frequency distribution with the 
number and percentage of subjects 
in each category.
Sex (Male, Female)
Racea (American Indian or Alaska Native, Asian, Black or African 
American, Native Hawaiian or other Pacific Islander, White, Not reported, 
Multiple)
Ethnicity (Hispanic or Latino, Not Hispanic or Latino, Not Reported)
a
If multiple race categories are indicated, the Race is recorded as 'Multiple'
Table 2: 
Baseline Disease Characteristics Variables
Continuous Variables:
Summary Type
Time from initial diagnosis to first dose (days)
Descriptive statistics (N, mean, SD, 
median, minimum and maximum).
Lines of prior systemic therapy
Time since last progression of prior systemic therapy to first dose (days)
Baseline tumorous leukemia/lymphoma cells (%) by bone marrow 
aspirate/biopsy
Categorical Variables
Frequency distribution with the 
number and percentage of subjects 
in each category.
Lines of prior systemic therapy (=1, >1)
Evidence of extramedullary disease at study entry (Yes, No)
Presence of testicular involvement at study entry (Yes, No)
CNS disease status at study entry (CNS Negative, CNS Positive)
4.2.
Medical History
Medical history will be summarized by system-organ class (SOC) and preferred term for each 
cohort and overall. A subject is counted only once within a category. Percentages are based on the 
number of subjects in the all treated analysis set within each cohort.
4.3.
Disposition Information
The number and percentage of subjects in the following disposition categories will be summarized 
for all treated subjects throughout the study by cohort: 

subjects in each of the study analysis sets 

subjects completing the study

subjects discontinued from daratumumab

primary reason for daratumumab discontinuation

subjects discontinued from backbone therapies

primary reason for backbone therapies discontinuation

subjects discontinued from the study


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
primary reason for study discontinuation 
All percentages will be based on the number of all treated subjects within each cohort.
Listings for treatment disposition and study disposition will be provided for the DLT-evaluable 
analysis set.
4.4.
Extent of Exposure
Extent of exposure to study treatments will be summarized through the following variables: 
number of treatment cycles, duration of study treatment, total dose administered, dose intensity, 
relative dose intensity, and number of subjects with cycle delay and dose modification etc. These 
summaries will be based on the all treated analysis set and presented by cohort.
The number and percentage of subjects treated within each cycle will be summarized. The 
maximum number of treatment cycles received for each subject will be summarized by frequency 
and descriptive statistics.
Duration of study treatment, defined as the number of days from the date of the first administration 
of study treatment to the date of the last administration of study treatment, will be summarized.
Exposure occurring after the subject switched to Daratumumab continuation phase will be 
considered separately and the last cycle number will be presented for these subjects.
Descriptive statistics for the number of daratumumab administrations will be provided for each 
cohort. The total dose administered for each study treatment (i.e., daratumumab (mg/kg) for both 
T and B cell cohorts, MTX (mg) for both T and B cell cohorts, vincristine (mg/m2) for both T and 
B cell cohorts, prednisone (mg/m2) for both T and B cell cohorts, doxorubicin (mg/m2) for T-cell 
only, peg-asparaginase (IU/m2) or erwinia asparaginase (IU/m2) for T-cell only , high dose MTX 
(g/m2) for T-cell only, cyclophosphamide (g/m2) for T-cell only, cytarabine (ARA-C) (mg/m2) for 
T-cell only and 6-mercaptopurine (mg/m2) for T-cell only will be summarized overall, and by 
treatment cycle.
The dose intensity, which is defined as the sum of the total dose administered in specified cycles 
divided by the number of cycles, will be calculated for each study treatment and summarized 
accordingly. The dose intensity will be summarized based on the treatment schedule, for each 
study treatment. 
The relative dose intensity (%), defined as the ratio of total actually received dose and total planned 
dose will be calculated for each study treatment and summarized using descriptive statistics and 
categories (<80%, 80%-100%, >100%). 
Duration of Daratumumab infusion in minutes for first, second and all subsequent infusions will 
be summarized.
The number of subjects with cycle delays and the number of subjects with dose modifications 
(dose delays, dose interruption, dose skipping, or dose reduction) for each study treatment 


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including reasons (AE, awaiting count recovery or other) for cycle delays and reasons for dose 
modifications, will be reported.
Listings for study agent administration and batch lot number will also be provided.
4.5.
Protocol Deviation
Subjects with major protocol deviations will be identified prior to database lock and the subjects 
with major protocol deviations will be summarized for the all treated analysis set by the following 
categories of deviation for each cohort: 

Entered but did not satisfy criteria 

Developed withdrawal criteria but not withdrawn 

Received wrong treatment or incorrect dose 

Received a disallowed concomitant treatment 

Other (Overall and COVID-19 related)
A list of subjects with major protocol deviations including subject ID, type of deviation, and 
reasons for deviation will be provided.
A list of minor protocol deviations related to COVID-19 for T-cell Subjects will be provided.
4.6.
Concomitant Medications
Concomitant medications will be coded using the World Health Organization Drug Dictionary. 
Concomitant medications are defined as those medications taken on or after the first study 
treatment dose date through 30 days after the last study treatment dose date and will be summarized 
by therapeutic class, pharmacologic class, and preferred term for each cohort based on the all 
treated analysis set. 
A similar summary of pre-infusion medications and post-infusion medications will be provided 
based on the all treated analysis set.
4.7.
Prior and Subsequent Systemic Therapy
Subsequent systemic therapy, conditioning therapy and bridging therapy recorded during the study 
will be summarized and presented by therapeutic class, pharmacologic class and preferred term 
for each cohort based on the all treated analysis set. 
For subjects who received at least one line of prior therapy, the number of lines of prior therapy 
will be calculated for each subject and summarized by cohort through frequency and descriptive 
statistics. In addition, their overall best response to the first prior therapy, relationship with 
allogenic transplant, progress/relapse on or after the first therapy will be summarized.
Listings of subsequent systemic therapy, conditioning and bridging therapy and prior systemic 
therapy will be provided.


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5.
EFFICACY
Assessments of disease response and progression for subjects with ALL will be based on the 
modified National Comprehensive Cancer Network (NCCN) criteria1. Response criteria for 
subjects with LL will be based on response criteria in adult non-Hodgkin’s lymphomas (NHL)2. 
Efficacy endpoints will be conducted using the all treated analysis set unless otherwise specified.
5.1.
Analysis Specifications
5.1.1.
Level of Significance
All statistical testing will be performed using a 1-sided test at the 5% level of significance, unless 
otherwise noted. All interval estimation will be reported using 2-sided 90% confidence intervals 
(CIs).
5.1.2.
Data Handling Rules
There is no imputation planned for missing efficacy endpoint values.
5.2.
Primary Efficacy Endpoint(s)
The primary endpoint is the CR rate prior to the start of subsequent anti-cancer therapy or 
allogeneic HSCT within 2 cycles of therapy for B-cell ALL and at the end of Cycle 1 for T-cell 
ALL/LL.
5.2.1.
Definition
A CR is defined as:

Less than 5% blasts in the bone marrow

No evidence of circulating blasts or extramedullary disease

Full recovery of peripheral blood counts:
o
Platelets >100x109/L
o
Absolute neutrophil count (ANC) >1.0x109/L 


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5.2.2.
Estimand
The primary estimand, the main clinical quantity of interest to be estimated in the study, is defined 
by the following 4 components:

Population:
o
B-cell ALL (1-17 Yrs) cohort: subjects with B-cell ALL aged from 1 to <18 years 
old;
o
T-cell ALL (1-17 Yrs) cohort: subjects with T-cell ALL aged from 1 to <18 years 
old;

Variable: CR prior to the start of subsequent anti-cancer therapy or allogeneic HSCT within 
2 cycles of therapy for B-cell ALL cohort and at the end of Cycle 1 for T-cell ALL/LL cohorts;

Intercurrent event: Treatment discontinuation is considered as an intercurrent event for overall 
response and treatment policy strategy will be implemented, i.e., disease assessments ignoring 
the treatment discontinuation will be implemented;

Population-level summary: CR rate.
5.2.3.
Analysis Methods
The analysis of CR rate will be performed based on the all treated analysis set. The number and 
percentage of subjects who achieve a CR including a two-sided 90% Clopper-Pearson exact CI 
will be calculated. The exact p-value to test the hypothesis, H0: CR rate ≤15% in the pediatric B 
cell ALL cohort and H0: CR rate ≤30% in the pediatric T-cell ALL cohort, will also be calculated.
Besides, sensitivity analyses of CR rate based on the response-evaluable analysis set will be 
performed in a similar manner. 
In addition data gathered for ALL subjects aged 18 to 30 years of age and subjects with LL will 
be summarized descriptively; the number and percentage of subjects who achieve a CR including 
a two-sided 90% Clopper-Pearson exact CI will be calculated.
5.3.
Major Secondary Endpoints
The major secondary endpoints include ORR, EFS, RFS, OS, MRD negative rate in subjects with 
B-cell and T-cell ALL, and allogeneic HSCT rate. 


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5.3.1.
Overall Response Rate (ORR)
5.3.1.1.
Definition
The ORR is defined as the proportion of ALL subjects who have a CR or CRi according to 
modified NCCN criteria, during or after treatment administration but prior to the start of 
subsequent anti-cancer therapy or allogeneic HSCT.

CR for ALL is defined as above

CRi for ALL is defined as:
o
Less than 5% blasts in the bone marrow
o
No evidence of circulating blasts or extramedullary disease
o
Partial recovery of peripheral blood counts not meeting criteria for CR noted above
For LL subjects, the ORR is defined as the proportion of subjects who have CR or PR during or 
after treatment administration but prior to the start of subsequent anti-cancer therapy or allogeneic 
HSCT.
5.3.1.2.
Analysis Methods
The number and percentage of subjects with the corresponding best overall response categories 
will be summarized for each of B-cell and T-cell ALL cohorts. The number and percentage of 
subjects who have an overall response (CR + CRi) and a two-sided 90% Clopper-Pearson exact 
CI will be calculated for each of the three ALL cohorts. These analyses will be performed based 
on the all treated analysis set.
A sensitivity analyses of ORR will be performed in a similar manner based on the response-
evaluable analysis set only. 
Besides, the number and percentage of subjects with the corresponding best overall response 
categories will be summarized for the T-cell LL cohort.
5.3.2.
Event-Free Survival (EFS)
5.3.2.1.
Definition
EFS is defined as the time from the date of first study drug administration to the first documented 
treatment failure (i.e., disease progression) or date of relapse from CR or death due to any cause, 
whichever occurs first. Relapse from CR is defined as reappearance of leukemia blasts in the 
peripheral blood or >5% blasts in the bone marrow, or reappearance of extramedullary disease or 
new extramedullary disease. Disease progression or relapse from CR reported in disease evaluation 
CRFs or in subsequent therapy CRFs will be used to identify the first disease progression/relapse 
date.
Subjects who withdrew consent from the study or lost to follow-up before disease 
progression/relapse from CR will be censored at the last disease assessment before withdrawal of 
consent from the study or lost to follow-up.


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Subjects who died after consent withdrawal will be censored at the date of consent withdrawal.
For subjects who have not progressed and are alive, data will be censored at the last disease 
assessment before the start of any subsequent systemic therapy. Conditioning, bridging and 
allogeneic HSCT therapies should not be considered as subsequent systemic therapy. Survival 
follow-up will also be considered as disease assessment for subjects who received allogeneic 
HSCT.
Subjects without any post-baseline bone marrow or peripheral blood counts assessment will be 
censored at first study drug administration.
Determination of dates of EFS event and dates for censoring is summarized in Table 3 as follows.  
Table 3:
EFS Event and Censoring Method
Situation
Date of Event or Censoring
Outcome
Disease progression/relapse from CR 
Date of disease progression
EFS event
Death prior to disease progression  
Date of death
EFS event
No post-baseline bone marrow or 
peripheral blood counts assessment
Date of first study drug administration
Censored
No EFS events
Date of last adequate disease evaluation
(including survival follow-up for subjects who 
received allogeneic HSCT)
Censored
Other (e.g., withdrawal of consent to 
study participation, lost to follow-up 
etc.)
Date of last adequate disease evaluation. Date of 
consent withdrawal if died after consent 
withdrawal.
Censored
5.3.2.2.
Analysis Methods
Analysis of EFS will be performed based on the all treated analysis set. The Kaplan-Meier method 
will be used to estimate the distribution of overall EFS for each cohort. The median EFS with 90% 
CI will be provided. In addition, the number and percentage of subjects who had an EFS event or 
were censored will be reported. The Kaplan-Meier EFS curve will also be plotted by cohort. 
Besides, reasons for EFS and censoring will be summarized for the all treated analysis set. 
5.3.3.
Relapse-Free Survival (RFS)
5.3.3.1.
Definition
RFS is defined as the time from CR to relapse from CR or disease progression or death due to any 
cause, whichever occurs first. Relapse from CR or disease progression reported in disease 
evaluation CRFs or in subsequent therapy CRFs will be used to identify the first relapse date or 
disease progression date.
Subjects who withdrew consent from the study or lost to follow-up before relapse from CR will 
be censored at the last disease assessment before withdrawal of consent to study or lost to follow-
up.
Subjects who died after consent withdrawal will be censored at the date of consent withdrawal.


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Subjects who don’t have RFS event and are still alive will be censored at the last disease 
assessment.
Survival follow-up will also be considered as disease assessment for subjects who received 
allogeneic HSCT.
Determination of dates of RFS event and dates for censoring is summarized in Table 4 as follows.  
Table 4:
RFS Event and Censoring Method
Situation
Date of Event or Censoring
Outcome
Relapse from CR / disease progression
Date of relapse from CR / disease progression
RFS event
Death prior to relapse  
Date of death
RFS event
No RFS events
Date of last adequate disease evaluation
(including survival follow-up for subjects who 
received allogeneic HSCT)  
Censored
Other (e.g., withdrawal of consent to 
study participation, lost to follow-up 
etc.)
Date of last disease adequate evaluation. Date of 
consent withdrawal if died after consent 
withdrawal.
Censored
5.3.3.2.
Analysis Methods
Analysis of RFS will be performed based on the all treated subjects who achieve a complete 
response analysis set. The Kaplan-Meier method will be used to estimate the distribution of overall 
RFS for each cohort. The median RFS with 90% CI will be provided. In addition, the number and 
percentage of subjects who had a RFS event or were censored will be reported. The Kaplan-Meier 
RFS curve will also be plotted by cohort.  
Besides, reasons for RFS and censoring will be summarized for the all treated analysis set. 
5.3.4.
Overall Survival (OS)
5.3.4.1.
Definition
OS is measured from the date of first study drug administration to the date of death due to any 
cause. Subjects who are lost to follow-up will be censored at the time of lost to follow-up. Subjects
who died after consent withdrawal will be considered as having an OS event. If the subject is alive 
or the survival status is unknown, then the subject’s data will be censored at the last known alive 
date. The date of last known alive will be determined by the maximum collection/assessment date 
from among selected data domains within the clinical database.
5.3.4.2.
Analysis Methods
Analysis of OS will be performed based on the all treated analysis set. The Kaplan-Meier method 
will be used to estimate the distribution of OS for each cohort. Median OS with 90% CI will be 
provided. In addition, the number and percentage of subjects who had died or were censored will 
be reported. The Kaplan-Meier OS curve will also be plotted by cohort.  


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5.3.5.
MRD Negative Rate
5.3.5.1.
Definition
MRD negativity is defined as <0.01% abnormal population counts to nucleated mononuclear cell 
counts when measured by flow cytometry.
MRD negativity rate is defined as the proportion of subjects who are considered MRD negative 
after MRD testing by bone marrow aspirate at any timepoint after first study treatment 
administration and before disease progression or starting subsequent anti-cancer therapy or 
allogeneic HSCT. MRD positive subjects include subjects of which all tested samples were found 
to be MRD positive or ambiguous. Subjects with missing or unevaluable MRD status will be 
considered as MRD positive. 
5.3.5.2.
Analysis Methods
Analysis of MRD negative rate will be performed based on the all treated analysis set. The 
proportion of subjects who are MRD negative and a two-sided 90% Clopper-Pearson exact CI will 
be calculated.
5.3.6.
Allogeneic Hematopoietic Stem Cell Transplant Rate
5.3.6.1.
Definition
The allogeneic HSCT rate is defined as the proportion of subjects who receive an allogeneic HSCT 
after treatment with daratumumab.
5.3.6.2.
Analysis Methods
Analysis of the allogeneic HSCT rate will be performed based on the all treated analysis set. The 
proportion of subjects who received an allogeneic HSCT after treatment with daratumumab will 
be calculated. A two-sided 90% Clopper-Pearson exact CI will also be calculated. 
Descriptive statistics for number of CD34+ cells transplanted (106/kg), the number and percentage 
of subjects in each source of CD34+ cells transplanted (chord blood, peripheral blood, bone 
marrow), the number and percentage of subjects with hematopoietic reconstruction, descriptive 
statistics for time to engraftment (days) and the number and percentage of subjects have graft 
failure will also be summarized by cohort.
5.4.
Other Efficacy Endpoints
Not Applicable


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6.
PHARMACOKINETIC AND IMMUNOGENICITY
6.1.
Pharmacokinetic
Serum samples to assess both the serum concentration (PK) of daratumumab and the generation 
of anti-daratumumab antibodies (immunogenicity) will be obtained from all subjects; analysis will 
be performed using validated immunoassay methods by or under the supervision of the sponsor’s 
bioanalytical facility. Up to 1 mL of CSF will also be collected for assessment of daratumumab 
concentrations using a validated assay method by or under the supervision of the sponsor’s 
bioanalytical facility. 
PK analyses will be performed on the serum PK evaluable analysis set for daratumumab serum 
concentration and CSF PK evaluable analysis set for daratumumab CSF concentration. Descriptive 
statistics (N, mean, SD, median, range, CV (%), geometric mean) will be provided for serum 
daratumumab and CSF concentrations at each sampling timepoint. PK parameters of daratumumab 
are defined by the assigned timepoint: Cmin (minimum observed concentration) is the predose 
concentration and Cmax (maximum observed concentration) is the end of infusion concentration. 
Concentrations for each individual and mean concentration of each cohort will be presented in 
figures with linear. Concentrations below the lowest quantifiable concentration in a sample will 
be treated as zero in the summary statistics.
Besides, by age (1 to 6 Yrs, 7 to 12 Yrs, 13 to 17 Yrs) summaries will be provided for pediatric
subjects for serum daratumumab and CSF concentrations based on serum PK evaluable analysis 
set and CSF PK evaluable analysis set, respectively if the number of subjects in the subgroups is 
sufficient. Corresponding figures will be provided. Also, by baseline body weight quartiles 
summaries will be provided for pediatric subjects for serum daratumumab and CSF concentrations 
based on serum PK evaluable analysis set and CSF PK evaluable analysis set, respectively.
Additionally, a summary of serum daratumumab concentrations by anti-daratumumab antibodies 
(negative, positive) for each cohort will be provided based on serum PK evaluable analysis set.
Corresponding data listings will be provided. All serum concentrations below the lowest 
quantifiable concentration in a sample or missing data will be labeled as such in the concentration 
data listing. 
The population PK details will be specified in an analysis plan and the results will be presented in 
a separate report. If an exposure-response analysis is performed, it will also be detailed in a 
separate analysis plan and report.


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6.2.
Immunogenicity
For the immunogenicity assessments, serum samples will be screened for antibodies binding to 
daratumumab and serum titer will also be determined from confirmed positive samples. Other 
immunogenicity analyses (e.g., assessment of neutralizing capabilities) may be performed to 
further characterize the immune responses that are generated.
Immunogenicity analyses will be performed on the immunogenicity evaluable analysis set. The 
incidence of anti-daratumumab antibodies will be summarized by cohort and listings will be 
provided of sample anti-daratumumab antibody status and the concurrent serum daratumumab 
concentration for immunogenicity evaluable analysis set and for the subset of subjects with IRR 
within this analysis set.
7.
BIOMARKER
Biomarker studies are designed to identify markers predictive of response (or resistance)
to
daratumumab. Planned analyses are based on the availability of clinically valid assays and may
be deferred if emerging study data show no likelihood of providing useful scientific
information. Results of biomarker analyses may be presented in a separate report.
7.1.
Minimal Residual Disease (MRD)
MRD will be monitored using validated flow cytometry assay at the central lab, University of 
Washington on bone marrow aspirate.
7.1.1.
Sampling Timepoints
MRD assessments will be done by flow cytometry with baseline bone marrow aspirate to define 
tumor burden, posttreatment samples to determine MRD negativity (end of both Cycle 1 and 
Cycle 2 for T-cell cohort), and End of Treatment.
7.1.2.
Analysis Methods
Details on MRD negativity rate analyses are described in Section 0. For this study, threshold value
of 10-4 will be used for the MRD negativity analysis. In addition, the relationship between MRD 
negativity and clinical outcome (CR + CRi rate) could be evaluated. 
7.2.
CD38 Expression on Lymphoblasts
Proportion of CD38+ lymphoblasts and CD38 receptor density on lymphoblasts will be measured 
on residual bone marrow aspirate samples after MRD analysis by flow cytometry ay University of 
Washington.
A figure of CD38 expression on blasts (MESF) over time by subjects will be provided.
7.3.
Other Biomarker
Figures with median and Interquartile range of NK absolute counts (CD16CD56) in peripheral 
blood over time, CDX27NMN (for B-cell) over time and CDX27PMN (for-T-cell) over time will 
be provided.


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8.
SAFETY
Safety assessment will be evaluated through AEs, clinical laboratory tests, vital signs 
measurements, physical examination findings, Karnofsky and Lansky performance status, and 
ECG assessment. Safety analyses will be based on the all treated analysis set and presented by 
cohort.
8.1.
Adverse Events
All AEs and special reporting situations, whether serious or non-serious, will be reported from the 
time a signed and dated ICF is obtained until 30 days after the last dose of study drug, unless the 
subject withdraws consent for study participation, or starts subsequent anticancer therapy. For 
subjects who have received additional treatment with therapeutic intent for ALL/LL during the AE 
reporting period, only study treatment-related AEs must be reported (unless the subject has been 
withdrawn from the study). An AE is considered study treatment-related if the attribution is 
possible, probable, or very likely. AEs will be recorded in standard medical terminology and 
graded according to the National Cancer Institute Common Terminology Criteria for Adverse 
Events (NCI-CTCAE), Version 4.03 or later.
The verbatim terms used in the case report form (CRF) by investigators to identify AEs will be 
coded using the Medical Dictionary for Regulatory Activities (MedDRA). TEAE is defined as any 
AE with onset date and time on or after that of the first study treatment through 30 days after the 
last study treatment; or the day prior to start of subsequent therapy or HSCT, whichever is earlier; 
or the follow-up AE (linked to an existing TEAE) with onset date and time beyond 30 days after 
the last study treatment but prior to the start of subsequent therapy or HSCT whichever is earlier; 
or any AE that is considered study agent related regardless of the start date of the event. AEs with 
missing or partial onset date and time will be considered as treatment-emergent unless the onset 
date and time of an AE can be determined as earlier than that of the first study treatment, or later 
than 30 days after last study treatment. All summaries of AEs will be based on treatment-emergent 
adverse events (TEAEs). For each TEAE, the number and percentage of subjects who experience 
at least 1 occurrence of the given event will be summarized by cohort.
Unless otherwise specified, at each level (e.g., SOC and/or preferred term) of subject 
summarization in reporting the incidence of the AE, a subject is counted once if one or more events 
were recorded. For summarizing new onset events, all event records of the same preferred term 
from the same subject are to be linked by the onset date and the end date. If an event is followed 
by another event of the same preferred term with an onset date (or date/time) the same as or 1 day 
(or 1 minute if applicable) after the end date (or date/time) of the previous record and any features 
of the AE (i.e.: toxicity grades/seriousness/action taken) are different between these two records, 
these 2 records should be linked together and considered as 1 event.
The incidence of TEAEs will be summarized overall, by MedDRA SOC and preferred term, by 
maximum toxicity grade, and by relationship to any study treatment administration. No toxicity 
grade or AE relationship will be imputed when missing. Specifically, the following AE summaries 
will be presented by cohort:


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
TEAEs

TEAEs by maximum toxicity grade

TEAEs by relationship to any study treatment

Toxicity grade 3 or 4 TEAEs

TEAEs related to any study treatment

Serious AEs (SAEs)

TEAEs leading to cycle delays or dose modifications

TEAEs leading to discontinuation of daratumumab

TEAEs leading to discontinuation of all study treatments
8.1.1.
Overview of TEAEs 
An overview of TEAEs reported through the study will be provided for each cohort. The overview 
will include summaries of subjects with TEAEs, TEAEs of max toxicity grade of 1 to 5, TEAEs 
with toxicity grade 3 or 4, TEAEs related to daratumumab, TEAEs related to any backbone 
therapy, SAEs, TEAEs with fatal outcome, TEAEs leading to discontinuation of daratumumab, 
and TEAEs leading to discontinuation of all study treatments. 
8.1.2.
All TEAEs 

Incidence of TEAEs by MedDRA SOC and preferred term 

Incidence of TEAEs by MedDRA SOC, preferred term and maximum toxicity grade

Incidence of TEAEs by MedDRA SOC, preferred term, and relationship to any study 
treatment

Incidence of most Common (at least 10%) TEAEs by MedDRA SOC, preferred term

A similar summary of incidence of TEAEs by MedDRA SOC and preferred term will be 
presented by treatment cycle. 
8.1.3.
Toxicity Grade 3 or 4 TEAEs

Incidence of toxicity grade  3 or 4 TEAEs, by MedDRA SOC and preferred term 

List of subjects with toxicity grade 3 or 4 TEAEs

A similar summary of incidence of toxicity grade 3 or 4 will be presented by treatment cycle.
8.1.4.
Any Study Treatment-Related TEAEs  

Incidence of TEAEs considered by the investigator to be related to any study treatment, 
by MedDRA SOC, preferred term, and relationship

Incidence of TEAEs with toxicity grade 3 or 4 considered by the investigator to be related 
to any study treatment, by MedDRA SOC, preferred term, and relationship


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8.1.5.
Serious Adverse Events 

Incidence of treatment-emergent SAEs, by MedDRA SOC and preferred term

Incidence of treatment-emergent SAEs considered by the investigator to be related to any 
study treatment, by MedDRA SOC, preferred term and relationship to treatment

List of subjects with SAEs

A similar summary of incidence of SAEs will be presented by treatment cycle.
8.1.6.
TEAEs Leading to Cycle Delays or Dose Modifications 
The incidence of TEAEs leading to treatment cycle delays or dose modifications will be 
summarized by MedDRA SOC, preferred term and maximum toxicity grade. This table will 
include TEAEs leading to cycle delays or at least 1 of study treatments dose modifications (dose 
delays, dose interruption, dose skipping, or dose reduction). The AEs leading to cycle delay are 
based on the cycle delay due to AE in the cycle delay CRF page. The AEs leading to dose 
modifications are based on action taken of dose skip or dose delay for any study treatment due to 
an AE in the study drug administration CRF pages.
8.1.7.
TEAEs Leading to Discontinuation of Daratumumab
A summary of number of subjects who discontinued daratumumab because of 1 or more TEAEs 
by MedDRA system-organ class, preferred term and maximum toxicity grade will be provided. 
The AEs leading to discontinuation of daratumumab are based on AEs recorded in the AE CRF 
page with an action taken of drug withdrawal for daratumumab.
A list of subjects with TEAEs leading to discontinuation of any study treatment will be provided. 
8.1.8.
TEAEs Leading to Discontinuation of All Study Treatment
A summary of number of subjects who discontinued all study treatment because of 1 or more 
TEAEs by MedDRA SOC, preferred term and maximum toxicity grade will be provided. This 
table includes AEs leading to discontinuation of all study treatment for those subjects indicated as 
having discontinued all study treatment due to an AE in the treatment disposition CRF page.
8.2.
Deaths
8.2.1.
All Deaths
A summary of all deaths and cause of death will be tabulated overall and by cohort. Specifically, 
the number of subjects who died within 30 days of last dose of study treatment will be summarized 
for the all treated analysis set. The primary cause of death collected on CRF page will be reported. 
If the primary cause of death reported is a TEAE, the number of subjects who have a treatment 
related AE and unrelated AE will be further reported. 
Listings of subjects who died during the will be provided.


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8.2.2.
Death Due to TEAEs
The number of subjects who died due to TEAEs will be summarized by preferred term and 
relationship to any study treatment for each cohort. The TEAEs included in this table are AEs with 
outcome death or toxicity grade of 5 recorded in the AE CRF page. 
A listing of subjects who died due to TEAEs will be provided.  
8.3.
Adverse Events of Clinical Interest
8.3.1.
Infusion-related Reactions
The incidence of infusion-related reactions (IRRs), as recorded on eCRF, will be presented by 
SOC, preferred term and maximum toxicity grade. In addition, the total number of subjects with 
IRRs in more than 1 infusion will be presented. The timing of IRR will also be evaluated through 
a summary of IRR by event onset time. Listings will be provided for IRRs:

List of subjects with any IRRs;

List of subjects with any toxicity grade 3 or higher IRRs;

List of subjects with any IRRs resulting in discontinuation of Daratumumab.
8.3.2.
Infections and Infestations
Infections and infestations refer to the adverse events with SOC of infections and infestations. The 
grade 3 or 4 treatment-emergent infections and infestations will be summarized by preferred term 
and relationship to treatment. Treatment-emergent infections and infestations may also be 
summarized by preferred term and treatment cycles.
8.3.3.
Haemorrhage Events
Haemorrhage events refer to the adverse events defined by Standardized MedDRA Queries (SMQ) 
with the first subcategory SMQ of haemorrhage terms (exclude laboratory terms). Incidences will 
be summarized by MedDRA SOC, preferred term and maximum toxicity grade. 
8.3.4.
Tumor Lysis Syndrome
Tumor lysis syndrome (TLS) events refer to the adverse events defined by narrow SMQ of tumor 
lysis syndrome (e.g., haemorrhagic tumor necrosis, tumor lysis syndrome, or tumor necrosis). A
listing of subjects who reported any treatment-emergent TLSs during the study will be provided.
8.3.5.
New Malignancies
A listing of subject who reported second primary malignancies during the AE reporting period will 
be provided. The listing will include general information of the corresponding AEs.


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8.4.
Clinical Laboratory Tests
All clinical laboratory tests will be displayed for subjects included in the all treated analysis set. 
Descriptive statistics will be used to summarize observed laboratory values and change from 
baseline in observed value at each scheduled visit for each cohort. Line plot of mean lab result 
with standard error for selected laboratory parameters over time will be displayed by cohort. The 
laboratory parameter included in the analysis will be focus on:

Hematology panel: hemoglobin, platelet count, WBC count, absolute lymphocyte count, 
ANC, and peripheral blast count

Chemistry panel: sodium, potassium, creatinine, aspartate aminotransferase (AST), 
alanine aminotransferase (ALT), total bilirubin (direct bilirubin if total bilirubin is 
abnormal), amylase, alkaline phosphatase, lactic acid dehydrogenase, uric acid, calcium, 
phosphate, albumin, total protein, lipase

CSF: RBC count, WBC count, Lymphoblasts count, Lymphoblasts/Leukocytes
Shift tables from baseline to worst toxicity grade for hematology and chemistry analytes during 
the treatment will be provided for parameters with predefined NCI-CTCAE version 4.03 or later 
toxicity grades. These tables will summarize the number of subjects with each baseline CTCAE 
grade and changes to the worst post-baseline CTCAE grade. 
8.5.
Vital Signs Measurements
Descriptive statistics of observe values and change from baseline of heart rate (beats/min), oxygen 
saturation (%), systolic blood pressure (mmHg) and diastolic blood pressure (mmHg) values will 
be summarized at each scheduled visit by cohort based on the all treated analysis set.
8.6.
Physical Examination Findings
A by-subject listing will also be presented for physical examination findings.
8.7.
Karnofsky and Lansky Performance Status 
Descriptive statistics of baseline Karnofsky/Lansky performance status and change from baseline 
values will be summarized at each scheduled visit by cohort based on the all treated analysis set. 
8.8.
Electrocardiogram
A listing of subjects with clinically significant abnormal results will be provided.


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REFERENCES
1.
National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology: Acute Lymphoblastic 
Leukemia. Version 2.2016.
2.
Cheson BD, Horning SJ, Coiffier B, et al. Report of an international workshop to standardize response criteria 
for non-Hodgkin's lymphomas. NCI Sponsored International Working Group. J Clin Oncol. 1999;17:1244-125