A Pilot Study of Vincristine Sulfate Liposome Injection (Marqibo®) in Combination With UK ALL R3 Induction Chemotherapy for Children, Adolescents, and Young Adults With Relapse of Acute Lymphoblastic Leukemia
Phase: PHASE1
Conditions: ALL, Childhood, Lymphoblastic Leukemia, Acute, Childhood, Lymphoblastic Leukemia, Acute
Sponsor: Therapeutic Advances in Childhood Leukemia Consortium

TACL Protocol:  
T2012-002  
Original Version Date: 14-May-2016  
Activated: 
                 28-Jul-2016  
Amendment #1 Date: 16-Mar-2017 
 
 
Amendment #2 Date: 16-Jul-2018 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
T2012-002 Original Version Date: 14-May-2016   
CONFIDENTIAL 
Amendment #1 Date: 16-Mar-2017 
TACL Internal Distribution Only 
Amendment #2 Date: 16-Jul-2018  
1 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
  
 
 
 
 
T2012-002: A Pilot Study of Vincristine Sulfate Liposome Injection (Marqibo®) in 
Combination with Chemotherapy for Children, Adolescents, and Young Adults with 
Relapse of Acute Lymphoblastic Leukemia 
IND 128316 
 
Protocol Chairperson 
Nirali N. Shah, MD 
 
Protocol Biology Chair 
Brigitte Widemann, MD 
 
Protocol Vice-Chair 
Alan S. Wayne, MD 
 
TACL Member Institutions 
All Children’s Hospital  
National Cancer Institute, Pediatric Oncology Branch  
Children's Healthcare of Atlanta at Egleston  
Oregon Health & Science University  
Children’s Hospital and Clinics of Minnesota  
Primary Children’s Hospital  
Children’s Hospital Los Angeles  
Rainbow Babies & Children’s Hospital  
Children’s Hospital New York-Presbyterian  
Royal Children’s Hospital, Melbourne  
Children’s Hospital Orange County  
Seattle Children’s Hospital  
Children’s Hospital of Philadelphia  
Sidney Kimmel Cancer Center at Johns Hopkins  
Children’s National Medical Center  
St. Jude Children’s Research Hospital Memphis  
Cincinnati Children’s Hospital  
Sydney Children’s Hospital  
Cook Children’s Medical Center  
Texas Children’s Cancer Center, Baylor  
CS Mott Children’s Hospital, Ann Arbor  
The Children’s Hospital at Westmead  
Dana-Farber Cancer Institute  
The Children’s Hospital, University of Colorado   
Levine Children's Hospital   
UCSF School of Medicine  
Lurie Children’s Hospital of Chicago  
University of Miami  
Medical College of Wisconsin  
University of Texas Southwestern Medical Center  
Nationwide Children’s Hospital 
 
TACL OPERATIONS CENTER 
CHLA, 4650 Sunset Blvd, MS-54, Los Angeles, CA 90027 
Phone: (323) 361-3022 Fax: 323-261-4505 https://tacl.chla.usc.edu  
TACL protocols and their content are for research purposes only and should not be copied, redistributed or used for any 
other purpose. The procedures in this protocol are intended only for use at TACL member institutions under 
the direction of TACL physicians. The most current version of the protocol should be accessed at 
https://tacl.chla.usc.edu . 
 
TACL 
Therapeutic Advances in  
Childhood Leukemia and Lymphoma 
 

TACL Protocol:  
T2012-002  
Original Version Date: 14-May-2016  
Activated: 
                 28-Jul-2016  
Amendment #1 Date: 16-Mar-2017 
 
 
Amendment #2 Date: 16-Jul-2018 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
T2012-002 Original Version Date: 14-May-2016   
CONFIDENTIAL 
Amendment #1 Date: 16-Mar-2017 
TACL Internal Distribution Only 
Amendment #2 Date: 16-Jul-2018  
2 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
TABLE OF CONTENTS 
STUDY COMMITTEE........................................................................................................5 
EXPERIMENTAL DESIGN SCHEMAS ..............................................................................6 
1.0  
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) ...............................................8 
2.0  
BACKGROUND ................................................................................................9 
2.1  
Vincristine in pediatric ALL.................................................................................9 
2.2  
Marqibo® (vincristine sulfate liposomes injection/VSLI) ......................................9 
2.3  
Overview of UK ALL R3 Regimen: ...................................................................13 
2.4  
Study Rationale ...............................................................................................15 
3.0  
PATIENT ELIGIBILITY CRITERIA AND ENROLLMENT...................................16 
3.1  
Patient Reservation .........................................................................................16 
3.2  
Enrollment.......................................................................................................17 
3.3  
Inclusion Eligibility Criteria ...............................................................................17 
3.4  
Exclusion Eligibility Criteria ..............................................................................20 
3.5  
Regulatory.......................................................................................................21 
4.0  
TREATMENT PROGRAM ...............................................................................22 
4.1  
Treatment Course ...........................................................................................22 
4.2  
Dose Limiting Toxicity......................................................................................27 
4.3  
Dose Delays and Modifications ........................................................................28 
4.4  
Concurrent Therapy and Drug Interactions.......................................................32 
5.0  
SUPPORTIVE CARE ......................................................................................33 
5.1   
Blood Products: ...............................................................................................33 
5.2  
Infection Control and Prophylaxis.....................................................................33 
5.3   
Antiemetic Protection.......................................................................................35 
5.4   
Filgrastim ........................................................................................................35 
5.5  
Bowel Prophylaxis (Appendix 6).......................................................................35 
5.6  
Dexrazoxane ...................................................................................................35 
6.0  
DRUG INFORMATION ....................................................................................35 
6.1  
Marqibo® ........................................................................................................35 
6.2  
Dexamethasone (Decadron®, Hexadrol®, Dexone®, Dexameth®) NSC#3452141 
6.3  
Mitoxantrone (Novantrone®, CL 232315, DAD, DHAD, Mitozantrone) NSC #301739
 
43 
6.4  
Methotrexate (MTX, AMETHOPTERIN) NSC #740 (112004) ............................45 

TACL Protocol:  
T2012-002  
Original Version Date: 14-May-2016  
Activated: 
                 28-Jul-2016  
Amendment #1 Date: 16-Mar-2017 
 
 
Amendment #2 Date: 16-Jul-2018 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
T2012-002 Original Version Date: 14-May-2016   
CONFIDENTIAL 
Amendment #1 Date: 16-Mar-2017 
TACL Internal Distribution Only 
Amendment #2 Date: 16-Jul-2018  
3 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
6.5  
Pegaspargase .................................................................................................47 
6.6  
Asparaginase Erwinia Chrysanthemi................................................................50 
6.7  
Mercaptopurine ...............................................................................................53 
7.0  
REQUIRED OBSERVATIONS/MATERIAL AND DATA TO BE ACCESSIONED55 
7.1  
Clinical and Laboratory Studies........................................................................55 
7.2 
Required Supportive Care Therapies During Protocol Treatment ......................58 
7.3  
Disease Evaluations During Therapy ...............................................................59 
7.4  
Research Studies ............................................................................................59 
7.5  
Required Observations Following Completion of Protocol Therapy ...................63 
8.0  
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY, OFF STUDY CRITERIA 
AND STUDY TERMINATION ..........................................................................................64 
8.1  
Criteria for Removal from Protocol Therapy......................................................64 
8.2  
Off Study Criteria .............................................................................................64 
8.3  
Termination of the Study by TACL ...................................................................64 
9.0  
STATISTICAL CONSIDERATIONS .................................................................64 
9.1  
Endpoints ........................................................................................................65 
9.2  
Study Design...................................................................................................66 
9.3  
Patient Evaluability ..........................................................................................68 
9.4  
Statistical Analysis...........................................................................................69 
9.5  
Interim Monitoring of Toxic Death ....................................................................69 
9.6  
Inclusion of Women and Minorities...................................................................70 
10.0  
RESPONSE CRITERIA ...................................................................................70 
10.1  
Bone Marrow Status Definitions .......................................................................70 
10.2  
Bone Marrow Response Criteria ......................................................................70 
10.3  
CNS Status Definitions ....................................................................................71 
10.4  
CNS Response Criteria ...................................................................................72 
11.0  
ADVERSE EVENT REPORTING REQUIREMENTS ........................................72 
11.1  
Definitions .......................................................................................................72 
11.2  
Data Collection ................................................................................................73 
11.3  
Reporting Serious Adverse Events or Serious Suspected Adverse Reactions ...73 
11.4  
Institutional Reporting to the IRB......................................................................76 
12.0  
DATA AND SAFETY MONITORING ................................................................76 
12.1  
Data Submission .............................................................................................76 

TACL Protocol:  
T2012-002  
Original Version Date: 14-May-2016  
Activated: 
                 28-Jul-2016  
Amendment #1 Date: 16-Mar-2017 
 
 
Amendment #2 Date: 16-Jul-2018 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
T2012-002 Original Version Date: 14-May-2016   
CONFIDENTIAL 
Amendment #1 Date: 16-Mar-2017 
TACL Internal Distribution Only 
Amendment #2 Date: 16-Jul-2018  
4 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
12.2  
Weekly Safety Review .....................................................................................76 
12.3  
Data Safety and Monitory Committee ...............................................................77 
14.0  
SAMPLE INFORMED CONSENT ....................................................................81 
APPENDIX 1: PERFORMANCE STATUS SCALES/SCORES .......................................105 
APPENDIX 2: GUIDANCE FOR DETERMINING PREVIOUS CUMULATIVE ANTHRACYCLINE 
DOSE ...........................................................................................................................107 
APPENDIX 3: PARTIAL LIST OF CONCOMITANT MEDICATIONS KNOWN TO INTERACT WITH 
CYTOCHROME P450-3A4 ISOENZYMES AND/OR P-GLYCOPROTEIN (TO BE USED WITH 
CAUTION) ....................................................................................................................109 
APPENDIX 4: NEUROLOGICAL EXAM.........................................................................110 
APPENDIX 5: NEUROLOGIC TOXICITY GRADING ......................................................112 
APPENDIX 6: BOWEL PROPHYLAXIS AND MANAGEMENT GUIDELINES..................113 
APPENDIX 7: PHARMACOKINETIC WORKSHEET – T2012-002 MARQIBO® Study ....116 
Appendix 8: Mercaptopurine Dosing Guidelines (As per Children’s Oncology Group AALL1131 Trial
.....................................................................................................................................119 
 
 
 

TACL Protocol:  
T2012-002  
Original Version Date: 14-May-2016  
Activated: 
                 28-Jul-2016  
Amendment #1 Date: 16-Mar-2017 
 
 
Amendment #2 Date: 16-Jul-2018 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
T2012-002 Original Version Date: 14-May-2016   
CONFIDENTIAL 
Amendment #1 Date: 16-Mar-2017 
TACL Internal Distribution Only 
Amendment #2 Date: 16-Jul-2018  
5 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
STUDY COMMITTEE  
STUDY CHAIR  
Nirali N. Shah, MD  
National Cancer Institute – Pediatric  
Oncology Branch  
Phone: 301-451-0390  
Email: shahnn@mail.nih.gov   
STUDY VICE CHAIR  
Alan S. Wayne, MD  
Children’s Hospital Los Angeles  
Phone: 323-361-3670  
Email: awayne@chla.usc.edu   
STUDY BIOLOGY CHAIR  
Brigitte Widemann, MD  
National Cancer Institute – Pediatric  
Oncology Branch  
Phone: 301-496-7387  
Email: widemanb@mail.nih.gov  
STUDY STATISTICIAN  
Yueh-Yun Chi, PhD 
Children’s Hospital Los Angeles  
Phone: 323-361-8582 
Email: ychi@chla.usc.edu 
 
Jemily Malvar, MS 
Children’s Hospital Los Angeles  
Phone: 323-361-8720 
Email: jmalvar@chla.usc.edu 
STUDY PHARMACIST  
Teresa Rushing, Pharm D, BCPS, BCOP 
Children’s Hospital Los Angeles 
Phone: 323-361-4791 
Email: TRushing@chla.usc.edu  
PHYSICIAN STUDY COMMITTEE  
MEMBER  
Eric Schafer, MD 
Texas Children’s Hospital 
Phone: 832-824-4241 
Email: esschafe@texaschildrens.org 
 
  
PHYSICIAN STUDY COMMITTEE  
MEMBER  
Lewis Silverman, MD 
Dana-Farber Cancer Institute 
 Phone: 617-632-5710 
Email: lewis_silverman@dfci.harvard.edu  
PHYSICIAN STUDY COMMITTEE  
MEMBER  
Paul Gaynon, MD  
Children’s Hospital Los Angeles  
Phone: 323-361-5600  
Email: pgaynon@chla.usc.edu   

TACL Protocol:  
T2012-002  
Original Version Date: 14-May-2016  
Activated: 
                 28-Jul-2016  
Amendment #1 Date: 16-Mar-2017 
 
 
Amendment #2 Date: 16-Jul-2018 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
T2012-002 Original Version Date: 14-May-2016   
CONFIDENTIAL 
Amendment #1 Date: 16-Mar-2017 
TACL Internal Distribution Only 
Amendment #2 Date: 16-Jul-2018  
6 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
TACL OPERATIONS COORDINATOR   
Children’s Hospital Los Angeles 
Phone: 323-361-5429 
Email: TACL@chla.usc.edu 
 
 
PHYSICIAN STUDY COMMITTEE  
MEMBER  
Kenneth Heym, MD 
Cook Children’s Hospital 
Phone: 682-885-4020 
Email: kenneth.heym@cookchildrens.org 
 
EXPERIMENTAL DESIGN SCHEMAS 
 
Cohort A: UK ALL R3/Marqibo (Days 1-28) 
  
  
Day  
1  
Day  
2  
Day  
3  
Day  
4  
Day  
5  
Day  
8  
Day  
15  
Day  
 16  
Day  
17  
Day  
18  
Day  
19  
Day  
22  
Day  
29  
Marqibo®  
    
  
  
  
  
    
  
  
  
  
 
Dexamethasone  
  
  
  
  
  
  
  
  
  
  
  
  
Mitoxantrone  
  
    
  
  
  
  
  
  
  
  
  
Pegaspargase  
  
  
  
  
  
  
  
  
    
  
  
IT Methotrexate 
    
  
  
  
    
  
  
  
  
  
  
Cohort B: UK ALL R3/Marqibo without anthracycline (Days 1-28) 
 
 
Day  
1  
Day  
2  
Day  
3  
Day  
4  
Day  
5  
Day  
8  
Day  
15  
Day  
 16  
Day  
17  
Day  
18  
Day  
19  
Day  
22  
Day  
29  
Marqibo®  
    
  
  
  
  
    
  
  
  
  
 
Dexamethasone  
  
  
  
  
  
  
  
  
  
  
  
  
Pegaspargase  
  
  
  
  
  
  
  
  
    
  
  
IT Methotrexate  
    
  
  
  
    
  
  
  
  
  
 
 
 

TACL Protocol:  
T2012-002  
Original Version Date: 14-May-2016  
Activated: 
                 28-Jul-2016  
Amendment #1 Date: 16-Mar-2017 
 
 
Amendment #2 Date: 16-Jul-2018 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
T2012-002 Original Version Date: 14-May-2016   
CONFIDENTIAL 
Amendment #1 Date: 16-Mar-2017 
TACL Internal Distribution Only 
Amendment #2 Date: 16-Jul-2018  
7 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
Cohort C: Modified Maintenance with Marqibo® (Days 1-14) 
  
 
 
Option to repeat Cycle 1 of Cohort C for a second cycle. Cycle 2 may start on Day 15 – 22 of Cycle 
1.  
 
Marqibo Dose Levels  
Dose Level 1: 1.5 mg/m2  
Dose Level 2: 2.0 mg/m2  
  
 
As of Amendment 3, cohorts A and B will be treating at dose level 1; Cohort C will be treating at dose 
level 2. Dose level may be modified as per guidance in the statistical section and sites will be 
appropriately notified if a change will be made.  
 
Cycle 1 
Day  
1  
Day  
2  
Day  
3  
Day  
4  
Day  
5  
Day  
8  
Daily 
through 
day 13 
Day  
14 
Marqibo®  
    
  
  
  
 
 
 
Dexamethasone 
            
  
Methotrexate 
(PO) 
     
 
  
  
     
Mercaptopurine 
(PO) 
  
        
 
IT Methotrexate 
as needed no 
more than once 
weekly  







 

TACL Protocol:  
T2012-002  
Original Version Date: 14-May-2016  
Activated: 
                 28-Jul-2016  
Amendment #1 Date: 16-Mar-2017 
 
 
Amendment #2 Date: 16-Jul-2018 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
T2012-002 Original Version Date: 14-May-2016   
CONFIDENTIAL 
Amendment #1 Date: 16-Mar-2017 
TACL Internal Distribution Only 
Amendment #2 Date: 16-Jul-2018  
8 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
 1.0  
GOALS AND OBJECTIVES (SCIENTIFIC AIMS)  
  
 
1.1  
Primary Objectives  
  
1.1.1 To assess the safety and feasibility of vincristine sulfate liposome injection (VSLI, Marqibo®) 
as replacement of standard vincristine in the UK ALL R3 induction regimen (Cohort A).  
1.1.2 To assess the safety and feasibility of vincristine sulfate liposome injection (VSLI, Marqibo®) 
as replacement of standard vincristine in the UK ALL R3 induction regimen that omits 
Mitoxantrone (Cohort B). 
1.1.3 To assess the safety and feasibility of vincristine sulfate liposome injection (VSLI, Marqibo®) 
as replacement of standard vincristine in a modified maintenance chemotherapy regimen 
(Cohort C).  
  
 
1.2  
Exploratory  Objectives  
  
1.2.1  To describe the constellation of toxicities experienced by patients treatment with each of 
these three regimens. 
1.2.2  To describe the number of patients who achieve a complete remission (CR), including CR 
+ CR with incomplete blood count recovery (CRi) rate for patients with acute lymphoblastic 
leukemia (ALL) and first to third relapse who are treated in cohorts A and B.   
1.2.3  To describe the number of patients with CR at end of induction who become minimal 
residual disease (MRD) negative by flow cytometry (i.e., < 10-4 blasts in a central lab) in 
cohorts A and B. 
1.2.4  To assess the pharmacokinetics of Marqibo® when used in combination with the UK ALL 
R3 induction chemotherapy regimen, in UK ALL R3 induction chemotherapy without 
mitoxantrone, and in ALL maintenance therapy.  
  
  
 

TACL Protocol:  
T2012-002  
Original Version Date: 14-May-2016  
Activated: 
                 28-Jul-2016  
Amendment #1 Date: 16-Mar-2017 
 
 
Amendment #2 Date: 16-Jul-2018 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
T2012-002 Original Version Date: 14-May-2016   
CONFIDENTIAL 
Amendment #1 Date: 16-Mar-2017 
TACL Internal Distribution Only 
Amendment #2 Date: 16-Jul-2018  
9 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 2.0  
BACKGROUND  
  
Although the majority of children diagnosed with acute lymphoblastic leukemia (ALL) can be cured 
with current standard treatment regimens, approximately 20% will relapse. Although remission 
can often be achieved using multi-agent re-induction regimens, long-term progression free 
survival (PFS) rates after relapse remain low and most of these patients will ultimately succumb 
to their leukemia. 1  
  
 2.1  
Vincristine in pediatric ALL  
  
Vincristine is an important component of therapy for ALL, as well as many other malignancies. 
However, this agent has a narrow therapeutic index due to neurotoxicity, most commonly acute 
and chronic peripheral neuropathy. Notably, the risk of neurotoxicity is higher among adolescents 
and young adults. 2 The dose of vincristine is commonly limited to a maximum individual dose of 
2 mg to avoid severe neurotoxicity. Despite this, however, vincristine-induced neurotoxicity is still 
observed and neuropathic symptoms may appear after only a few doses even with capping. 
However, some reports suggest that lower vincristine exposure in ALL may contribute to relapse 
and that capping the vincristine dose may contribute to the poorer outcome of adolescents and 
obese children. Thus, intensification of vincristine therapy might lead to superior outcomes in ALL 
provided that neurotoxicity is not treatment limiting. This hypothesis was the basis for Children’s 
Oncology Group (COG) trial AALL0433, which was designed to assess the impact of vincristine 
intensification in pediatric patients with relapsed ALL. In this study, standard vincristine dosing at 
1.5 mg/m2 with a maximum dosage cap of 2 mg was compared to higher dose of 2 mg/m2 with a 
cap at 2.5 mg. Interim analysis, demonstrated excessive peripheral neuropathy in patients older 
than 13 years of age and the study was closed early due to toxicity, preventing the ability to assess 
the efficacy of vincristine intensification in this setting.  
  
2.2  
Marqibo® (vincristine sulfate liposomes injection/VSLI)  
  
Liposomal drug carriers are capable of increasing the therapeutic index of anticancer drugs by 
altering the drug’s pharmacological behavior. Marqibo® was designed to deliver 
a larger dose of vincristine via encapsulation within an aqueous core of 
nanoparticles comprised of sphingomyelin and cholesterol liposomes. 3(Figure)   
 
 
 
  
Mechanism of action: The active drug in Marqibo® is vincristine. Vincristine 
is a cell cycle-specific agent that binds tubulin, a protein component of 
microtubules, and arrests cell growth in  
metaphase by disrupting cell division. Marqibo® formulation optimizes 
vincristine pharmacokinetics, prolongs circulating half-life, and increases 
vincristine penetration and concentration in tissues with fenestrated 
vasculature (i.e., bone marrow, lymph nodes, spleen, and tumors). A 

TACL Protocol:  
T2012-002  
Original Version Date: 14-May-2016  
Activated: 
                 28-Jul-2016  
Amendment #1 Date: 16-Mar-2017 
 
 
Amendment #2 Date: 16-Jul-2018 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
T2012-002 Original Version Date: 14-May-2016   
CONFIDENTIAL 
Amendment #1 Date: 16-Mar-2017 
TACL Internal Distribution Only 
Amendment #2 Date: 16-Jul-2018  
10 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
pharmacokinetic (PK) study was conducted in a non-human primate model at the NCI using 
rhesus monkeys (macaca mulatta) which allowed for direct comparison of vincristine to Marqibo®. 
This study demonstrated that the clearance of vincristine sulfate exceeded that of Marqibo® by 
approximately 400-fold (Figure).4 Additionally, no penetration was noted into the CSF for either 
preparation.   
  
Preclinical studies: Marqibo® was more active than vincristine sulfate in 9 tumor models 
representing 7 cancer types. Improved activity of Marqibo® over vincristine sulfate was  
observed using a variety of dosing schedules and routes of tumor implantation. In murine and 
human tumor models (L1210 and P388 leukemia, B16/BL6 melanoma and human A431 solid 
tumor xenografts) unencapsulated vincristine had negligible antitumor activity. In contrast, 
liposomal vincristine evaluated in the same tumor models had significantly greater, dose-
dependent, antitumor activity.3 These results are consistent with complementary studies 
demonstrating significant increases in the amount of vincristine accumulating in these tumors 
as a result of liposomal encapsulation. This increase in antitumor activity compared to 
equivalent doses of vincristine has been demonstrated in a wide range of tumor models, 
including lymphoma and leukemia.  
  
Clinical studies and FDA approval: Marqibo® has been evaluated in more than a dozen clinical 
trials in over 600 subjects (primarily adults) with ALL, non-Hodgkin lymphoma, and other cancers. 
Clinical experience indicates that Marqibo® can be administered safely at individual and 
cumulative doses exceeding those typically employed for standard vincristine and may provide 
anticancer activity without increased toxicities. It has been used both as a single agent as well as 
in conjunction with combination chemotherapy. Phase I studies established safe dosing for 
monotherapy. 5 In 2012 the US Food and Drug Administration (FDA) granted accelerated approval 
of Marqibo® for adults with relapsed and refractory Philadelphia chromosome-negative ALL. 6This 
approval was based on a pivotal Phase II study (rALLy trial) in which Marqibo® was administered 
as a single agent weekly at a dose of 2.25 mg/m2 without a dose cap. There was a 20% (13/65) 
CR/CRi rate and an overall response rate (ORR) of 35% (23/65; 13 CR/CRi, 4 morphologic 
remissions without blood count recovery, and 6 partial responses). 7Eight of the 13 patients 
achieving CR/CRi achieved MRD negative status. Responses were seen in both T- and B-lineage 
ALL.   
  
Pediatric studies: A small Phase II study was conducted in children (P99-401). Marqibo® was well 
tolerated and some activity was seen, although data were quite limited. Subjects were treated 
with Marqibo at 2.0 mg/m2 IV over 1 hour every 14 days ± 2 days (1 cycle). Only 1 subgroup 
(sarcomas) fully accrued prior to termination of this study. Only one patient with ALL was treated 
on that trial. Of the 29 dosed and evaluable subjects, the responses to treatment were as follows: 
2 subjects had a PR (7%), 8 subjects had stable disease (28%) and 19 subjects had disease 
progression (66%). Seven (24%) subjects were alive at the last protocol specified survival follow-
up. The median time to progression was 52 days for all subjects. Only 1 subject experienced a 
possibly related Grade 3 or higher neurologic event (peripheral neuropathy). Results of this study 
were never published beyond abstract form.8  
  

TACL Protocol:  
T2012-002  
Original Version Date: 14-May-2016  
Activated: 
                 28-Jul-2016  
Amendment #1 Date: 16-Mar-2017 
 
 
Amendment #2 Date: 16-Jul-2018 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
T2012-002 Original Version Date: 14-May-2016   
CONFIDENTIAL 
Amendment #1 Date: 16-Mar-2017 
TACL Internal Distribution Only 
Amendment #2 Date: 16-Jul-2018  
11 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
A single-agent pediatric Phase I dose-escalation trial to evaluate the safety, toxicity and 
pharmacokinetics of Marqibo® in children with relapsed refractory leukemia or solid tumors was 
recently completed at the NCI (http://clinicaltrials.gov/ct2/show/NCT01222780). Marqibo® was 
administered weekly with a cycle consisting of four doses. A rolling-six design was employed and 
21 patients were treated on this trial: 6 at dose level #1 (1.75 mg/m2/dose); 10 at dose level #2 
(2.25 mg/m2/dose), with an additional 6 subjects treated at dose level #2 in the expansion phase 
of the protocol for subjects with ALL only. (Table) The highest dose level tested was the adult 
maximum tolerated dose (MTD) of 2.25 mg/m2. Although the MTD had not been exceeded at dose 
level 2, the decision was made to forego further dose escalation and to open the expansion cohort 
for subjects with ALL at dose level 2 in accordance with protocol allowances. This was based on 
the observed toxicity profile and clinical activity at dose level 2 (2.25 mg/m2/dose x 4 weekly 
doses), which also represented the FDA approved dose and schedule for adults, and the 
likelihood that the safety profile would be negatively impacted by further dose escalation. Notably, 
ongoing dosing of VSLI appeared to be associated with the development of peripheral neuropathy 
on this trial, consistent with results in adults with ALL where cumulative dose was correlated with 
earlier onset and higher-grade neurotoxicity. A total of 17 subjects with ALL were treated.   
  
  
  
  
Table: Summary of 21 subjects treated on the pediatric phase I trial of Marqibo® (VSLI). (Subject 12 enrolled but 
did not receive any protocol specific therapy)* cycle not complete; ^ dose de-escalation with Cycle 2 Dose #3 due 
to paresthesias,  **Grade 4 LFT elevation, ALL: Acute lymphoblastic leukemia; BL: Burkitt’s Lymphoma; CR: 

TACL Protocol:  
T2012-002  
Original Version Date: 14-May-2016  
Activated: 
                 28-Jul-2016  
Amendment #1 Date: 16-Mar-2017 
 
 
Amendment #2 Date: 16-Jul-2018 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
T2012-002 Original Version Date: 14-May-2016   
CONFIDENTIAL 
Amendment #1 Date: 16-Mar-2017 
TACL Internal Distribution Only 
Amendment #2 Date: 16-Jul-2018  
12 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
complete remission; SD: stable disease; PD: progressive disease; NE: non-evaluable for response; 
HI=hematologic improvement; DLT=dose limiting toxicity (grade 4 hepatic transaminase elevation)   
In general, Marqibo® has been well tolerated with the majority of treatment-related AEs consisting 
of reversible Grade 1/2 toxicities. Drug-related Grade 3/4 AEs included decreased neutrophil 
count, decreased lymphocyte count, decreased white blood cell count and elevated liver 
transaminases. No DLT was seen at dose level 1. One patient treated at dose level 2 developed 
dose-limiting toxicity (DLT) that consisted of Grade 4 hepatic transaminase elevation and this 
dose level was expanded. Notably, in this subject who had pre-existing transaminase elevation 
and a history of chemotherapy-associated hepatic dysfunction, the grade 4 transminase elevation 
was transient. After receiving the first dose of Marqibo® hepatomegaly improved and 
transaminase levels returned to levels improved from the baseline. Subjects enrolled on this 
protocol will have close monitoring for hepatotoxicity with laboratory assessments prior to each 
dose of Marqibo® and dosing delays for transaminase and bilirubin elevations as specified in 
section 4.3.1.  
  
Seventeen subjects with ALL were treated on this trial. One of these, a 12-year-old with 
chemotherapy refractory ALL after 2 prior allogeneic stem cell transplants achieved a CR with no 
evidence of minimal residual disease (MRD) by flow cytometry, following two cycles on therapy. 
In several patients with circulating peripheral blasts, dramatic reductions in absolute peripheral 
blast count were seen, including 1 patient who experienced a greater than 4-log10 reduction in 
circulating blasts after a single dose of Marqibo®. Another patient had a 3-log10 reduction in 
circulating blasts after a single dose of Marqibo®, however, this subject was taken off treatment 
due to DLT. Six patients were non-evaluable for response because they were taken off treatment 
prior to completion of a full cycle (one for alternative therapy and the others due to complications 
of ALL). Thus, we have observed anti-leukemia activity including a CR with single agent Marqibo® 
in children with multiply relapsed/refractory ALL treated on this trial.9  
  
Combination studies: Prior studies of Marqibo® with combination chemotherapy have been 
conducted in adults. The largest trial (CA00004) enrolled 72 previously untreated subjects with 
non-Hodgkin lymphoma and was conducted to examine the efficacy and safety of substitute 
Marqibo® for conventional vincristine in standard CHOP chemotherapy with or without rituximab. 
Subjects were treated with 750 mg/m2 cyclophosphamide, 50 mg/m2 doxorubicin, and 2 mg/m2 
Marqibo on Day 1, and prednisone 100 mg orally on Days 1 to 5 in 21-day cycles. Sixty-six 
subjects with B-cell histology received 375 mg/m2 IV of rituximab prior to administration of CHOP 
(R-CHOP). An ORR of 96% was demonstrated (69/72), with 66 achieving a CR (92%), 2 a CRu 
(3%) and 1 a PR (1%). Favorable response rates, PFS, and overall survival were observed 
regardless of age group and IPI status. No subjects died within 30 days of last dose received. 
Common related Grade 3 and higher treatment emergent adverse events (>10% of subjects) 
included febrile neutropenia (19%), neutropenia (64%), and thrombocytopenia (14%). A total of 
23 subjects (32%) experienced SAEs.  18(5%) of the SAEs were assessed as possibly related to 
study drug. The most common treatment-associated SAEs were febrile neutropenia (19%) and 
neutropenia (15%).   
  
There are currently two ongoing Phase III trials in adults patients with newly diagnosed ALL and 
NHL utilizing combination chemotherapy with Marqibo®. Preliminary results from these trials 

TACL Protocol:  
T2012-002  
Original Version Date: 14-May-2016  
Activated: 
                 28-Jul-2016  
Amendment #1 Date: 16-Mar-2017 
 
 
Amendment #2 Date: 16-Jul-2018 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
T2012-002 Original Version Date: 14-May-2016   
CONFIDENTIAL 
Amendment #1 Date: 16-Mar-2017 
TACL Internal Distribution Only 
Amendment #2 Date: 16-Jul-2018  
13 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
support safety with the use of Marqibo® with combination therapy. (Clinicaltrials.gov: 
NCT01439347 and NCT01478542)  
  
Toxicity: In its standard formulation, vincristine neurotoxicity is dose-dependent and symmetrical, 
and is manifested as both peripheral sensory and motor neuropathy. Progressive neuropathy may 
occur, leading for example to weakness with foot and wrist drop. Vincristine induced peripheral 
neuropathies are generally reversible although recovery may take months and is often incomplete.  
  
The major side effects of Marqibo® are due to the active vincristine component, Thus, the most 
common treatment-related adverse events of Marqibo® have been neurological. Adverse events 
occurring in greater than or equal to 30% of patients treated with single agent Marqibo® include 
neuropathy, constipation, nausea, neutropenic fever, pyrexia, decreased appetite, and diarrhea.  
  
Patients with ALL who receive Marqibo® will generally have received vincristine previously and 
cumulative toxicity from prior vincristine exposure is possible. On the single-agent Phase II rALLy 
trial, all patients had prior vincristine exposure and patients received a median of four doses of 
Marqibo® at nearly twice the usual dose intensity of standard vincristine. Some received up to 70 
mg total vincristine exposure. Notably, 77% had prior neuropathy at study entry. Despite that, the 
observed neurotoxicity was comparable to that seen with standard vincristine. 86% had some 
neuropathy, but Grade 3 neurotoxicity was observed in only 23% of patients. Thus, even in 
patients with prior vincristine exposure, Marqibo® was fairly well tolerated. Other significant 
adverse events observed on the rALLy trial were neutropenic fever and tumor lysis syndrome. 7 
Such patients may also have experienced prior hepatotoxicity, which in the setting of Marqibo® 
administration, risk for hepatotoxicity may be increased in combination with other hepatotoxic 
chemotherapeutic agents and thus all subjects will be monitored daily.   
  
There is the potential of toxicity to liposome carrier (sphingomyelin/cholesterol) as these are 
biological lipids that are important components of plasma membranes. However, no toxicity has 
been observed in pre-clinical toxicology studies conducted with empty liposomes in mice, rats and 
dogs.   
  
 2.3  
Overview of UK ALL R3 Regimen:  
  
The UK ALL R3 platform has been shown to be among the most successful regimens in the 
management of relapsed ALL, with superiority of the mitoxantrone (vs. idarubicin) arm. 10This trial 
investigated the combination of vincristine, dexamethasone and pegaspargase with 
randomization to mitoxantrone versus idarubicin for the initial block of re-induction. Two hundred 
thirty-nine patients were enrolled on ALL R3 with 109 idarubicin and 103 mitoxantrone patients 
evaluable. Forty-four percent of idarubicin and 40% of mitoxantrone patients were MRD positive 
at a level of 10-4 at the end of Block 1 (p=0.90). Although there were no significant differences in 
MRD levels at week 5 between the mitoxantrone and idarubicin arms, the progression-free 
survival (PFS) at 3-years for those who received idarubicin was 36% vs. 65% for those who 
received mitoxantrone (p=0.0004). This difference continued to be significant when adjusted for 
differences in risk group, country, age, gender, and cytogenetic subtype. Among the standard risk 

TACL Protocol:  
T2012-002  
Original Version Date: 14-May-2016  
Activated: 
                 28-Jul-2016  
Amendment #1 Date: 16-Mar-2017 
 
 
Amendment #2 Date: 16-Jul-2018 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
T2012-002 Original Version Date: 14-May-2016   
CONFIDENTIAL 
Amendment #1 Date: 16-Mar-2017 
TACL Internal Distribution Only 
Amendment #2 Date: 16-Jul-2018  
14 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
and intermediate-risk patients, the differences in outcome were most significant (5-yr PFS 74% in 
mitoxantrone arm vs. 37% in idarubicin arm, p=0.0001). Overall mitoxantrone was reported to be 
better tolerated and less toxic than idarubicin; however a competing effects model showed that 
the difference between the two drugs was primarily related to disease control rather than toxicity 
of treatment (p=0.09). In patients who proceeded to HSCT, 35% who received idarubicin (n=48) 
and 5% who received mitoxantrone (n=44) have relapsed posthaste. Based on an intention to 
treat analysis, intermediate-risk patients who received transplant did worse in the idarubicin arm 
but had comparable results in the mitoxantrone group to those who received chemotherapy alone 
(p=0.01). As a result of these results, further randomization between the mitoxantrone and 
idarubicin arms was discontinued. 10  
  
Following this trial, additional patients were treated on the mitoxantrone induction arm by the UK 
ALL R3 investigators (n=298). (Personal communication, V. Saha, April 2013). Complete data are 
available on 201 of 298 patients. There were 8 known deaths during induction (4% treatment 
related mortality 11). 135 of 201 (67%) patients experienced a grade 3, 4, or 5 event. No patient 
was removed after induction due to toxicity and thus 193 of 201 (96%) proceeded to the 
consolidation phase.   
  
Outcomes for patients treated with the UK ALL R3 induction regimen reported to date have been 
for patients in first relapse on ALL. On this protocol, patients with first to third relapse will be 
eligible and thus many are likely to be more heavily treated and at greater risk of toxicity than 
previously reported patients. Limited data reporting on the experience with the UK ALL R3 
induction regimen in multiply relapsed patients who had received at least two prior treatment 
attempts demonstrated that there was no appreciable difference in the grade > 3 toxicities 
between first and multiply relapsed patients. However, amongst this group of patients, grade > 3 
infection was reported in 53/59 (90%) patients and 55/59 (97%) of patients experienced at least 
one  grade > 3 non-hematologic adverse event.12 Importantly, in this recent retrospective review, 
7% (3/42) of patients treated with the UK ALL R3 induction regimen in first relapse had a delay in 
starting their next treatment course beyond day 49 (95% CI 1.5% - 19.5%), and 38% (6/16) of 
patients treated in second or greater relapse were similarly delayed (95% CI 15% - 65%).  
  
Toxicity data were reported on a completed COG trial of 4-drug reinduction chemotherapy (COG 
AALL 01P2) in patients with first or greater relapse. 13, 14 This frequency of nonhematologic Grade 
3 and 4 toxicities ranged up to 58%. The post-induction toxic death (TD) rate prior to modification 
of the regimen was 14% (n=3).13 On a Phase II trial of single agent clofarabine in children with 
ALL who were in a second relapse or beyond, inclusive of those with post-transplant relapse, 8% 
(n=5) of subjects experienced a TD that was considered at least possibly related to study drug. 15 
Similarly on a Phase II study that incorporated bortezomib with combination chemotherapy in 
patients who were in second relapse or beyond, including those with post-transplant relapse there 
was a 14% (n=3) TD rate, primarily due to infection associated complications. 16 Based on these 
data, we anticipate at least a 10% toxicity death rate on this trial. We also would consider it 
unacceptable should 45% of subjects not be able to proceed to further therapy by day 49 due to 
toxicity of any grade.   
  

TACL Protocol:  
T2012-002  
Original Version Date: 14-May-2016  
Activated: 
                 28-Jul-2016  
Amendment #1 Date: 16-Mar-2017 
 
 
Amendment #2 Date: 16-Jul-2018 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
T2012-002 Original Version Date: 14-May-2016   
CONFIDENTIAL 
Amendment #1 Date: 16-Mar-2017 
TACL Internal Distribution Only 
Amendment #2 Date: 16-Jul-2018  
15 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 2.4  
Study Rationale  
 
Based on the encouraging results from the UK ALL R3 trial, the promising results observed in 
Marqibo® studies, and the potential benefit of vincristine intensification in childhood ALL, we are 
pursuing incorporating treatment with Marqibo® as replacement for standard vincristine in 
combination with UK ALL R3 induction for children with relapsed ALL. Our hypothesis is that the 
incorporation of Marqibo® with combination chemotherapy will be safe and feasible. In the context 
of this pilot study, overall outcomes and efficacy will be a secondary objective. We hypothesize 
that data from this combination may show improved efficacy including, complete remission (CR), 
minimal residual disease (MRD) negativity, and progression free survival (PFS) rates and safety 
(i.e., neurotoxicity) in comparison to outcomes in historical regimens, including the UK ALL R3 
with standard vincristine.   
  
Dose justification: This is a limited Pilot study. As this represents the first combination 
chemotherapy study utilizing Marqibo® in pediatrics, the starting dose of Marqibo® will be 1.5 
mg/m2/dose (dose level 1), with no dose cap, matching the standard vincristine dose utilized in 
the UK ALL R3 induction regimen. If an acceptable safety profile is demonstrated at this dose 
level, escalation to 2.0 mg/m2/dose (dose level 2), with no dose cap, will be performed. This higher 
dose represents a dose that has previously been safely used in combination therapy trials with 
Marqibo® in adults (CA00004). Both doses are below the highest dose tested in the pediatric 
Phase I single agent trial and the FDA approved single-agent dose for adults (2.25 mg/m2/dose, 
weekly, no dose cap). Patients will receive a total of 4 weekly doses of Marqibo®.   
 
2.4.1 Rationale for addition of cohorts B and C 
 
As of April 25, 2018, 4 subjects had been treated on study and all have tolerated the therapy well 
without DLT. All 4 were able to achieve a morphologic remission, with one patient attaining an 
MRD negative remission, enabling the patient to proceed to a first allogeneic bone marrow 
transplant. In another patient, who had 3% disease by flow cytometry and MRD testing at day 29 
evaluations, subsequent bone marrow demonstrated disease progression and the patient 
proceeded to alternative therapy.  
 
In recognition of a growing reluctance to utilize a full intensive re-induction regimen in the era of 
targeted therapies, and other competing studies, but to allow for the ability to continue to explore 
VSLI, Marqibo®, the primary purpose of Amendment # 2 is to add two additional regimens which 
will allow for the continued exploration of VSLI, Marqibo® in the combination chemotherapy 
setting. The first regimen (B) is the same regimen (A) as initially proposed, but without the 
anthracycline-like agent (the anthracenedione, mitoxantrone).  The second regimen (C) is to 
utilize VSLI, Marqibo® in a modified ALL maintenance type regimen. As both of these regimens 
B and C are inherently less toxic than the UK ALL R3 regimen, it is anticipated that these regimens 
will be well tolerated and still allow to explore the additional role of VSLI, Marqibo® as a 
substitution for standard vincristine. With the addition of these two regimens, the trial has been 
divided into 3 separate treatment cohorts with modified statistical design and a more appropriate 

TACL Protocol:  
T2012-002  
Original Version Date: 14-May-2016  
Activated: 
                 28-Jul-2016  
Amendment #1 Date: 16-Mar-2017 
 
 
Amendment #2 Date: 16-Jul-2018 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
T2012-002 Original Version Date: 14-May-2016   
CONFIDENTIAL 
Amendment #1 Date: 16-Mar-2017 
TACL Internal Distribution Only 
Amendment #2 Date: 16-Jul-2018  
16 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
enrollment target. Both these regimens are appropriate therapeutic options for patients requiring 
lower intensity re-induction, or as bridging therapy. 
 
2.4.2 Rationale for Amendment #3 
 
As of April 24, 2020, a total of 13 subjects have been treated on study.  
 
In cohort A (4-drug induction), a total of 8 subjects were treated at 2 dose levels. All four subjects 
at dose level 1 (1.5 mg/m2/dose) tolerated the therapy well without DLT and thus cohort A 
proceeded to enrollment at dose level 2 (VSLI, Marqibo®=2.0 mg/m2/dose). At dose level 2, cohort 
A, 2 subjects experienced DLT and thus cohort A was de-escalated to dose level 1 (1.5 
mg/m2/dose). The consent has been modified to update the toxicity profile. DLTs at dose level 2, 
cohort A were as follows: One patient had grade 4 sepsis, grade 3 peripheral neuropathy and 
grade 3 cardiac failure (which occurred in the setting of sepsis). The second patient had grade 5 
encephalitis along with respiratory failure, hydrocephalus and vascular disorder.  
 
In cohort B (3-drug induction without mitoxantrone), a total of 4 subjects have been treated: 2 at 
dose level 2 and 2 at dose level 1. Amongst the two patients at dose level 2, one subject 
experienced DLT with grade 3 hepatic transaminase elevation (AST/ALT) and grade 3 
hyperbilirubinemia. The second subject did not meet DLT criteria but also had elevated hepatic 
transaminase elevation that was near DLT criteria and thus based on this experience, and in 
discussion with the study team, the decision was made to electively dose de-escalation to dose 
level 1. The IRB and DSMC were notified about this change. The first patient at dose level 1 did 
not complete the regimen due to progressive disease and was taken off study. 
 
In cohort C, one patient has been treated at Dose Level 2.  
 
 
 3.0  
PATIENT ELIGIBILITY CRITERIA AND ENROLLMENT  
  
 3.1  
Patient Reservation  
  
Investigators should consult the TACL web site (https://tacl.chla.usc.edu) to determine if the study 
is currently open for accrual before approaching patients for participation. Before enrolling a 
patient on study, a reservation must be made with the TACL Operations Center. In order to make 
a reservation you may call (323) 361-3022 or send an email to TACL@chla.usc.edu with the 
following information (if sending an email, please put “Reservation Request” in the subject line):  
  
• Study for which you want to make a reservation:   
• Name of the institution requesting reservation with contact information  
• Patient Initials (Last, First)  
• Patient month and year of birth  
  

TACL Protocol:  
T2012-002  
Original Version Date: 14-May-2016  
Activated: 
                 28-Jul-2016  
Amendment #1 Date: 16-Mar-2017 
 
 
Amendment #2 Date: 16-Jul-2018 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
T2012-002 Original Version Date: 14-May-2016   
CONFIDENTIAL 
Amendment #1 Date: 16-Mar-2017 
TACL Internal Distribution Only 
Amendment #2 Date: 16-Jul-2018  
17 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
If an enrollment slot is available, you will receive an email from the TACL Operations Center to 
confirm your reservation. All reservations are good for five full calendar days starting with the next 
full day after the day the reservation is made.  
  
 3.2  
Enrollment   
  
An enrollment guide is available on the web site (https://tacl.chla.usc.edu). Patients must be 
enrolled prior to beginning treatment on this study. Patients will be enrolled by contacting the 
TACL Operations Center at Children’s Hospital Los Angeles, Monday through Friday, 8:30 am – 
5:00 pm Pacific Time at (323) 361-3022,. (weekend and holiday enrollments can be 
accommodated with advance notice to the TACL Operations Center). You will be asked to 
complete the eligibility form on the TACL RDE System prior to making your call. In addition, the 
supporting documentation, which confirms eligibility, should be faxed or emailed to the TACL 
Operations Office representative.   
  
The “Day 1” intrathecal chemotherapy dose may be given during eligibility screening evaluation 
within two weeks prior to Day 1 chemotherapy, and does not need to be repeated on Day 1.  
  
Each patient will be assigned a unique TACL registration and study subject number. An email 
confirming eligibility and assigned dose level will be sent to the treating facility, Study Chair, and 
Study Vice-Chair. Patients should begin treatment within three calendar days of study enrollment. 
If a subject cannot start therapy in the time allotted, they must be re-screened to confirm eligibility 
at a later date.  
  
 
 
 
 
 
 
 
 
Contact:              TACL Operations Center 
 
 
 
 
 
Children’s Hospital Los Angeles  
 
  
    
  
4650 Sunset Blvd, MS #54  
 
  
    
  
Los Angeles, CA 90027  
 
  
    
  
Phone: (323) 361-3022  
 
  
    
  
FAX: (323) 361-4505 
 
  
    
  
Email: TACL@chla.usc.edu  
  
 3.3  
Inclusion Eligibility Criteria   
  
The eligibility criteria listed below are interpreted literally and cannot be waived.   
     
3.3.1 Age  
Patients must be ≥ 1 and ≤ 21 years of age at the time of enrollment.   
  
3.3.2 Diagnosis  
Cohort A: Patients must have a diagnosis of acute lymphoblastic leukemia (ALL, 
T or B cell) or mixed phenotypic acute leukemia with ≥ 5% blasts in the bone 

TACL Protocol:  
T2012-002  
Original Version Date: 14-May-2016  
Activated: 
                 28-Jul-2016  
Amendment #1 Date: 16-Mar-2017 
 
 
Amendment #2 Date: 16-Jul-2018 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
T2012-002 Original Version Date: 14-May-2016   
CONFIDENTIAL 
Amendment #1 Date: 16-Mar-2017 
TACL Internal Distribution Only 
Amendment #2 Date: 16-Jul-2018  
18 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
marrow (M2 or M3 by aspirate or flow cytometry), with or without extramedullary 
disease) or a diagnosis of lymphoblastic lymphoma.   
 
Cohorts B & C: Patients must have a diagnosis of acute lymphoblastic leukemia 
(ALL, T or B cell), lymphoblastic lymphoma, or mixed phenotypic acute leukemia 
with any level of detectable disease (minimal residual disease level acceptable) 
with or without extramedullary disease  
 
 
3.3.3  Performance Level  Karnofsky > 50% for patients > 16 years of age and Lansky 
> 50% for patients ≤ 16 years of age. (Appendix 1)  
  
3.3.4 Prior Therapy  
  
a. Patients must have recovered from the acute toxic effects (< Grade 2 or baseline) 
of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this 
study, unless otherwise specified. Subjects with disease related cytopenias will be 
eligible.   
  
b. Patients must have relapsed or refractory disease.  
 
c. Patients with Philadelphia chromosome t(9;22) positive disease must have 
received at least two prior tyrosine kinase inhibitors.  
  
  
d. Patients who have experienced their relapse after a HSCT are eligible, provided 
they have no evidence of graft-versus-host disease (GVHD) and are at least 100 
days post-transplant at the time of enrollment; and at least 30 days off any systemic 
immunosuppression.  
  
e. Prior anthracycline lifetime cumulative exposure:  
 
1. Cohort A: Patients must have less than 320 mg/m2 (or 400 mg/m2 if prior 
cardioprotection) lifetime exposure of anthracycline chemotherapy (See 
Appendix 2 for anthracycline calculation worksheet).  
2. Cohorts B & C: There is no limit on prior anthracycline exposure.  
  
f. Hematopoietic growth factors: It must have been at least seven days since the 
completion of therapy with GCSF or other growth factors at the time of enrollment. 
It must have been at least 14 days since the completion of therapy with 
pegfilgrastim (Neulasta®).  
  
g. Biologic anti-neoplastic agents: At least seven days after the last dose of a biologic 
agent. For agents that have known adverse events occurring beyond seven days 
after administration, this period must be extended beyond the time during which 

TACL Protocol:  
T2012-002  
Original Version Date: 14-May-2016  
Activated: 
                 28-Jul-2016  
Amendment #1 Date: 16-Mar-2017 
 
 
Amendment #2 Date: 16-Jul-2018 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
T2012-002 Original Version Date: 14-May-2016   
CONFIDENTIAL 
Amendment #1 Date: 16-Mar-2017 
TACL Internal Distribution Only 
Amendment #2 Date: 16-Jul-2018  
19 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
adverse events are known to occur. The duration of this interval must be discussed 
with the study chair or vice chair.  
  
h. Monoclonal antibodies: At least three half-lives (or 30 days—whichever is longer) 
of the antibody must have elapsed after the last dose of monoclonal antibody. (e.g., 
Rituximab = 66 days, Epratuzumab = 69 days)  
  
i. 
Immunotherapy: At least 30 days after the completion of any type of 
immunotherapy, e.g. tumor vaccines, chimeric antigen receptor T-cells.   
  
j. 
Recent prior chemotherapy: At least 10 days after standard vincristine and the 
completion of any type of chemotherapy induction regimen. At least 3 weeks after 
radiation therapy. At least 30 days after the completion of any investigational 
neoplastic agent is also required. An investigational agent is defined as any drug 
that is not approved and licensed for sale by the FDA for institutions in the United 
States and by The Therapeutic Goods Administration for institutions in Australia.  
 
k. Physiologic steroid replacement is allowed before enrollment and during protocol 
therapy. 
 
Exceptions:   
1. There is no time restriction in regard to prior intrathecal chemotherapy provided 
there is complete recovery from any acute toxic effects of such; it is allowable 
to enroll a patient that has received IT ARA-C, IT MTX or triple IT therapy within 
14 days of enrollment as part of their evaluation to diagnose disease relapse. 
The IT therapy given within 14 days of initiation of protocol specified 
chemotherapy, may substitute for the day 1 IT in cohorts A and B.  
2. Subjects with rapidly progressive disease may receive hydroxyurea until they 
begin study therapy;   
3. Patients who relapse while on maintenance-type ALL therapy or are receiving 
maintenance therapy for disease stabilization will not require a wash-out period 
before entry into this study. However, there must be at least 10 days after any 
dose of standard vincristine. 
4. For radiation therapy: Radiation therapy must have been completed at least 3 
weeks prior to enrollment (including CNS radiation), with the exception that 
there is no time restriction if the volume of bone marrow treated is less than 
10% and also the subject has measurable/evaluable disease outside the 
radiation port.  
  
3.3.5 Renal and Hepatic Function  
a. Renal function: Patient’s serum creatinine must be ≤ 1.5 x institutional upper limit 
of normal (ULN) according to age. If the serum creatinine is greater than 1.5 times 
normal, the patient must have a calculated creatinine clearance or radioisotope 

TACL Protocol:  
T2012-002  
Original Version Date: 14-May-2016  
Activated: 
                 28-Jul-2016  
Amendment #1 Date: 16-Mar-2017 
 
 
Amendment #2 Date: 16-Jul-2018 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
T2012-002 Original Version Date: 14-May-2016   
CONFIDENTIAL 
Amendment #1 Date: 16-Mar-2017 
TACL Internal Distribution Only 
Amendment #2 Date: 16-Jul-2018  
20 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
GFR ≥ 70mL/min/1.73m2. Alternatively, a 24-hour creatinine clearance may also 
be used.   
1. Pediatric Population (age <18): Calculated creatinine clearance ≥ 70 
ml/min/1.73m2 as calculated by the Schwartz formula for estimated glomerular 
filtration rate (GFR) where GFR (ml/min/1.73 m2) = k*Height (cm)/serum 
creatinine (mg/dl). k is a proportionality constant which varies with age and is 
a function of urinary creatinine excretion per unit of body size; 0.45 up to 12 
months of age; 0.55 children and adolescent girls; and 0.70 adolescent boys.  
2. Adult Population (age 18): If serum creatinine 1.5 X ULN, then the estimated 
glomerular filtration rate (GFR) must be 70 mL/min/1.73 m2 as calculated by 
the Modification of Diet in Renal Disease equation where Predicted GFR 
(ml/min/1.73 m2) = 186 x (Serum Creatinine)-1.154 x (age in years)-0.023 x (0.742 
if patient is female) x (1.212 if patient is black.  
  
b. Hepatic function: ALT and AST must be < 5 x institutional upper limit of norm ULN. 
Total bilirubin must be ≤ 1.5 x ULN (except in the case of subjects with documented 
Gilbert’s disease ≤ 5 × ULN).   
  
3.3.6 Cardiac Function  
Patients must have a shortening fraction ≥ 27% or an ejection fraction ≥ 55% by 
echocardiogram, cardiac MRI or MUGA.   
  
3.3.7 Reproductive Function  
  
a. Female patients must not be pregnant and those of childbearing potential must 
have a negative urine or serum pregnancy test confirmed within one week prior to 
enrollment.  
b. Female patients with infants must agree not to breastfeed their infants while on 
this study.  
c. Male and female patients of childbearing potential must agree to use an effective 
method of contraception during the study.   
  
 3.4  
Exclusion Eligibility Criteria  
  
  
3.4.1 Active CNS disease (CNS 3) is exclusionary.  Patients with CNS 1 or CNS 2 disease 
may be enrolled, which is inclusive of patients with a recent history of CNS3 disease which 
is now resolved to CNS1 or CNS2 
 
3.4.2 Patients will be excluded if they have any isolated extramedullary disease, including 
isolated testicular or isolated CNS disease.  
  
3.4.3 Patients will be excluded if they have previously received Marqibo®.  
  

TACL Protocol:  
T2012-002  
Original Version Date: 14-May-2016  
Activated: 
                 28-Jul-2016  
Amendment #1 Date: 16-Mar-2017 
 
 
Amendment #2 Date: 16-Jul-2018 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
T2012-002 Original Version Date: 14-May-2016   
CONFIDENTIAL 
Amendment #1 Date: 16-Mar-2017 
TACL Internal Distribution Only 
Amendment #2 Date: 16-Jul-2018  
21 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
3.4.4 Patients will be excluded if they have a known allergy to any of the drugs used in the 
study, with the exception that patients with an allergy to pegaspargase who can 
receive Erwinia asparaginase are eligible.  Patients unable to receive any 
formulation of asparaginase may only enroll on cohort C 
  
3.4.5 Patients will be excluded if they have active, uncontrolled systemic fungal, bacterial, 
viral or other infection despite appropriate antibiotics or other treatment.   
  
3.4.6  Patients who require azole antifungal agents will be excluded. Azoles must be 
discontinued at least one week prior to the start of Marqibo®.  
  
3.4.7 Patients will be excluded if there is a plan to administer non-protocol chemotherapy, 
radiation therapy, another investigational agent or immunotherapy during the 
study period.  
  
3.4.8 Patients with pre-existing, persistent grade 2 or greater sensory or motor neuropathy 
from any cause will be excluded. (Patients on chronic stable doses of gabapentin 
or similar agents for history of neuropathy may be included if there are no active 
neuropathic symptoms)  
  
3.4.9 Patients will be excluded if they have significant concurrent disease, illness, 
psychiatric disorder or social issue that would compromise patient safety or 
adherence with the protocol treatment or procedures or interfere with consent, 
study participation, follow up, or interpretation of study results.  
 
 
a. Patients with Down syndrome will not be eligible for enrollment on Cohort A 
  
3.4.10 Patients with a known history human immunodeficiency virus (HIV) will be excluded 
due to the increased risk of complications such as severe infection and unknown 
interaction of Marqibo® with antiretroviral drugs.  
  
3.4.11 Active hepatitis B or C infection as defined by seropositive for hepatitis B (hepatitis 
B surface antigen (HBsAg)) or hepatitis C and elevated liver transaminases 
(defined as above the ULN per the institution normal ranges).  
  
 3.5  
Regulatory  
  
3.5.1 Informed Consent  
  
All patients and/or their parents or legal guardians must sign a written informed consent. 
Age appropriate assent will be obtained per institutional guidelines. To allow non-English 
speaking patients to participate in this study, bilingual health services will be provided in 
the appropriate language when feasible.  
  
  

TACL Protocol:  
T2012-002  
Original Version Date: 14-May-2016  
Activated: 
                 28-Jul-2016  
Amendment #1 Date: 16-Mar-2017 
 
 
Amendment #2 Date: 16-Jul-2018 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
T2012-002 Original Version Date: 14-May-2016   
CONFIDENTIAL 
Amendment #1 Date: 16-Mar-2017 
TACL Internal Distribution Only 
Amendment #2 Date: 16-Jul-2018  
22 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
3.5.2 Protocol Approval  
  
All institutional, FDA, and NCI requirements for human studies must be met.  
  
  
 4.0  
TREATMENT PROGRAM  
  
The following sections detail the treatment plan for therapy. Please refer to the Drug Information 
section for additional administration guidelines. Treatment should begin within three calendar 
days of enrollment.  
 
There are 3 treatment cohorts on this protocol. Please see protocol sections 2.4.1 and 2.4.2 for 
review of the experience to date on this protocol.  
 
There will be no intrapatient dose escalation or de-escalation.   
  
 
 4.1  
Treatment Course   
  
Only 1 course of treatment will be permitted. Upon completion of treatment on this study, plans 
for additional therapy will be at the discretion of the treating team.  
 
As of Amendment 3, cohorts A and B will be treating at dose level 1; Cohort C will be treating at 
dose level 2.  
 
Marqibo Dose Levels  
Dose Level 1: 1.5 mg/m2 
Dose Level 2: 2.0 mg/m2 
 
Cohort A:   
  
Day  
1  
Day  
2  
Day  
3  
Day  
4  
Day  
5  
Day  
8  
Day  
15  
Day  
 16  
Day  
17  
Day  
18  
Day  
19  
Day  
22  
Day  
29  
Marqibo®  
    
  
  
  
  
    
  
  
  
  
 
Dexamethasone  
  
  
  
  
  
  
  
  
  
  
  
  
Mitoxantrone  
  
    
  
  
  
  
  
  
  
  
  
Pegaspargase#  
  
  
  
  
  
  
  
  
    
  
  
IT Methotrexate  
    
  
  
  
    
  
  
  
  
  

TACL Protocol:  
T2012-002  
Original Version Date: 14-May-2016  
Activated: 
                 28-Jul-2016  
Amendment #1 Date: 16-Mar-2017 
 
 
Amendment #2 Date: 16-Jul-2018 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
T2012-002 Original Version Date: 14-May-2016   
CONFIDENTIAL 
Amendment #1 Date: 16-Mar-2017 
TACL Internal Distribution Only 
Amendment #2 Date: 16-Jul-2018  
23 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
# 
asparaginase 
Erwinia 
chrysanthemi (Erwinaze®), crisantapase (Erwinase®) 
asparaginase Erwinia chrysanthemi (recombinant)-rywn (Rylaze®) may be substituted for 
allergy to Pegaspargase. See below.  
  
Drug Administration Order  
Marqibo will be administered first. Mitoxantrone will follow Marqibo administration on day 1 with 
dexrazoxane to be given immediately before mitoxantrone (when dexrazoxane is utilized 
[optional]). Timing of IT methotrexate is flexible in regards to the timing of Marqibo, but should not 
be given simultaneously in order to reduce the risk of administration route error.  
  
Marqibo® (Dose level 1 only as of Amendment 3) 
• 
Dose Level 1: 1.5 mg/m2/dose (no dose cap) given IV over 60 minutes (±10 minutes) on 
days 1, 8, 15 and 22.  
• 
Dose Level 2: 2 mg/m2/dose (no dose cap) given IV over 60 minutes (±10 minutes) on 
days 1, 8, 15 and 22.  
• 
Review list of concomitant medications that are prohibited (CYP3A4 inhibitors) or to be 
used with caution (Appendix 3). See section 4.5 for drug interactions.   
• 
Dose will be given over 60 minutes ± 10 minutes  
  
Dexamethasone  
• 
20 mg/m2/day divided BID given orally on days 1 through 5 and 15 through 19. The two doses 
should be separated by at least 8 hours  
• 
Any oral formulation of dexamethasone is acceptable  
• 
IV may be given if oral formulation is not tolerated (please document reason oral could not be 
given)  
  
Mitoxantrone  
• 
10 mg/m2/day given on days 1 and 2 as a short IV infusion over 5-15 minutes. Do not infuse 
over less than 3 minutes.  
• 
Dose will be given over 5-15 minutes  
• 
See section 5.6 for guidance on optional cardioprotection. 
  
Pegaspargase  
• 
2,500 international units/m2/day IM or IV on days 3 and 17. (Cap individual dose at 3,750 
IU, based on vial size)  
• 
If available and FDA approved, asparaginase Erwinia chrysanthemi (Erwinaze®), 
asparaginase Erwinia chrysanthemi (recombinant)-rywn (Rylaze®) or crisantapase 
(Erwinase®) may be substituted for pegaspargase in patients with systemic allergic reaction.   
o 
Asparaginase Erwinia chrysanthemi (Erwinaze®) or Cristantapase (Erwinase®): May be 
dosed per package insert guidelines as 25,000 IU/m2/dose IM or IV over 1-2 hours. Give 
6 doses of asparaginase Erwinia chrysanthemi (Erwinaze®) or Cristantapase (Erwinase®) 
over 2 weeks on a schedule of every other day (for example, q 48 hours, or M/W/F dosing) 
for each dose of planned pegaspargase.  

TACL Protocol:  
T2012-002  
Original Version Date: 14-May-2016  
Activated: 
                 28-Jul-2016  
Amendment #1 Date: 16-Mar-2017 
 
 
Amendment #2 Date: 16-Jul-2018 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
T2012-002 Original Version Date: 14-May-2016   
CONFIDENTIAL 
Amendment #1 Date: 16-Mar-2017 
TACL Internal Distribution Only 
Amendment #2 Date: 16-Jul-2018  
24 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
o 
Erwinia chrysanthemi (recombinant)-rywn (Rylaze®): Refer to current FDA product 
information for dosing at the time of product administration. 
o 
For any Erwinia formulation, each individual dose not to exceed pegaspargase 
equivalent dosing of 3,750 IU (i.e., cap individual dose at 37,500 IU Erwinia). Route 
of administration, dose schedule and total doses administered  should be documented, as 
this could contribute to variability in PK data for Marqibo®.   
• 
Dose may be administered by IM or IV per product information guidelines (Please document 
route of administration).  
• 
Premedications may be given per institutional standard. 
  
Intrathecal methotrexate  
• 
Given intrathecally to all patients the dose defined by age below on days 1 and 8 (+ 2 days). 
Note: The “Day 1” intrathecal chemotherapy dose may be given during eligibility screening 
evaluation within two weeks prior to Day 1 chemotherapy, and does not need to be repeated 
on Day 1. Alternatively, per standard of care, ARA-C and hydrocorticosone may be 
substituted if methotrexate is contraindicated.  
• 
IT methotrexate may also be given at day 29 (+/- 2 days) during disease assessment 
• 
Timing of IT methotrexate is flexible in regards to timing of Marqibo®. However, these agents 
should not be given simultaneously in order to reduce the risk of administration route error.  
  
Age (years)  Methotrexate (mg)  
1-1.99  
8 mg  
2-2.99  
10 mg  
3-8.99  
12 mg  
> 9  
15 mg  
  
Cohort B:  ALL R3/Marqibo without anthracycline 
 
# 
Asparaginase 
Erwinia chrysanthemi (Erwinaze®), crisantapase 
(Erwinase®) 
asparaginase Erwinia chrysanthemi (recombinant)-rywn (Rylaze®) may be substituted for 
allergy to Pegaspargase. See below.  
  
Day  
1  
Day  
2  
Day  
3  
Day  
4  
Day  
5  
Day  
8  
Day  
15  
Day  
 16  
Day  
17  
Day  
18  
Day  
19  
Day  
22  
Day  
29  
Marqibo®  
  
  
  
  
  
  
  
  
  
  
  
  
 
Dexamethasone  
  
  
  
  
  
  
  
  
  
  
  
  
Pegaspargase#  
  
  
    
  
  
  
  
    
  
  
IT Methotrexate  
  
  
  
  
  
    
  
  
  
  
  

TACL Protocol:  
T2012-002  
Original Version Date: 14-May-2016  
Activated: 
                 28-Jul-2016  
Amendment #1 Date: 16-Mar-2017 
 
 
Amendment #2 Date: 16-Jul-2018 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
T2012-002 Original Version Date: 14-May-2016   
CONFIDENTIAL 
Amendment #1 Date: 16-Mar-2017 
TACL Internal Distribution Only 
Amendment #2 Date: 16-Jul-2018  
25 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
  
Drug Administration Details:  
As per Cohort A, without mitoxantrone  
 
Marqibo® 
• 
Dose Level 1: 1.5 mg/m2/dose (no dose cap) given IV over 60 minutes (±10 minutes) on 
days 1, 8, 15 and 22.  
• 
Dose Level 2: 2 mg/m2/dose (no dose cap) given IV over 60 minutes (±10 minutes) on 
days 1, 8, 15 and 22.  
• 
Review list of concomitant medications that are prohibited (CYP3A4 inhibitors) or to be 
used with caution (Appendix 3). See section 4.5 for drug interactions.   
• 
Dose will be given over 60 minutes ± 10 minutes  
 
Other agents and instructions as detailed above in Cohort A, without mitoxantrone. 
 
Cohort C: Modified Maintenance with Marqibo® 
  
 
Day  
1  
Day  
2  
Day  
3  
Day  
4  
Day  
5  
Day  
8  
Daily 
through 
day 13 
Day  
14 
Marqibo®  
  
  
  
  
  
 
 
 
Dexamathasone 
  
          
  
Methotrexate (PO) 
   
  
 
  
  
    
Mercaptopurine 
(PO) 
  
        
 
IT Methotrexate as 
needed 
no 
more 
than once weekly 







 
 
Marqibo® 
• 
Dose Level 1: 1.5 mg/m2/dose (no dose cap) given IV over 60 minutes (±10 minutes) on day 
1. 
• 
Dose Level 2: 2 mg/m2/dose (no dose cap) given IV over 60 minutes (±10 minutes) on day 1. 
• 
Review list of concomitant medications that are prohibited (CYP3A4 inhibitors) or to be used 
with caution (Appendix 3). See section 4.5 for drug interactions. 
• 
Dose will be given over 60 minutes ± 10 minutes 
 
Dexamethasone 
• 
6 mg/m2/day divided BID given orally on days 1 through 5. The two doses should be separated 
by at least 8 hours 

TACL Protocol:  
T2012-002  
Original Version Date: 14-May-2016  
Activated: 
                 28-Jul-2016  
Amendment #1 Date: 16-Mar-2017 
 
 
Amendment #2 Date: 16-Jul-2018 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
T2012-002 Original Version Date: 14-May-2016   
CONFIDENTIAL 
Amendment #1 Date: 16-Mar-2017 
TACL Internal Distribution Only 
Amendment #2 Date: 16-Jul-2018  
26 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
• 
Any formulation of dexamethasone is acceptable 
 
Methotrexate 
• 
20 mg/m2/dose given orally on day 1 and day 8. 
 
Mercaptopurine 
• 
75 mg/m2/dose/day given orally, daily from days 1-13. 
 
Intrathecal methotrexate  
• 
Given intrathecally as needed, but no more than once weekly. Age-based dosing as below. 
Alternatively, per standard of care, ARA-C and hydrocorticosone may be substituted if 
methotrexate is contraindicated.  
• 
Timing of IT methotrexate is flexible in regard to timing of Marqibo®. However, these agents 
should not be given simultaneously in order to reduce the risk of administration route error.  
 
Age (years)  Methotrexate (mg)  
1-1.99  
8 mg  
2-2.99  
10 mg  
3-8.99  
12 mg  
> 9  
15 mg  
 
See appendix 8 for starting dose guidelines.  
 
Dose modifications: (for patients without pre-existing disease related cytopenia) 
If neutrophil count falls below 500/mcL or if platelet count falls below 50,000/mcL during cohort C, 
mercaptopurine will be held until recovery of neutrophil count above 750/mcL and platelets > 
75,000/mcL. 
For the first drop in ANC or platelets, resume MP at the same dose the patient was taking prior to 
the episode of myelosuppression. 
If neutrophil count falls below 500/mcL or if platelet count falls below 50,000/mcL for a second (or 
greater) time, discontinue doses of MP 
 
In the setting of liver dysfunction, with 6MP and oral methotrexate:  
For increase in hepatic transaminases (SGPT/ALT or SGOT/AST) to greater than 5x ULN 
(Grade 3 toxicity), obtain total and direct bilirubin. Monitor SGPT/ALT, SGOT/AST and total and 
direct bilirubin as long as transaminases remain over 5x ULN.  
 
Continue full dose therapy unless either of the following occurs:  
- 
Direct bilirubin > 2 mg/dL  

TACL Protocol:  
T2012-002  
Original Version Date: 14-May-2016  
Activated: 
                 28-Jul-2016  
Amendment #1 Date: 16-Mar-2017 
 
 
Amendment #2 Date: 16-Jul-2018 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
T2012-002 Original Version Date: 14-May-2016   
CONFIDENTIAL 
Amendment #1 Date: 16-Mar-2017 
TACL Internal Distribution Only 
Amendment #2 Date: 16-Jul-2018  
27 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
- 
SGPT/ALT or SGOT/AST > 20x ULN (Grade 4 toxicity) on 2 determinations at least 1 
week apart.  
- 
If either of these occurs, hold mercaptopurine and monitor labs as above, weekly. 
Restart at full dose therapy when the transaminase elevation is < Grade 3 (less than 5x 
ULN), as long as direct bilirubin is < 2 mg/dl.  
 
Exclude infectious hepatitis for persistent (> 1 month) Grade 3 elevations in SGPT/ALT or 
SGOT/AST above 5x ULN.  
 
Consider discontinuing trimethoprim/sulfamethoxazole (TMP/SMX) in favor of an alternative 
approach to Pneumocystis prophylaxis and holding/modifying all other potentially hepatotoxic 
medications. 
 
Cycle 2:  
Patients who tolerate cycle 1 without DLT may have the option to repeat this cycle once. Cycle 2 
may start on Day 15 – 22 of cycle 1.  
 
 
4.2  
Dose Limiting Toxicity 
 
Toxicity will be graded using the CTCAE criteria, version 4.03. The CTCAE provides descriptive 
terminology and a grading scale for each adverse event listed. A copy of the CTCAE can be 
downloaded from the CTEP home page (http://ctep.cancer.gov ). Any dose-limiting toxicity (DLT) 
should be reported immediately through the TACL Operations Center to the Study Chair or Vice 
Chair. In addition to CTCAE, grading of sensory and motor neuropathies will be augmented by 
definitions listed in Appendix 5. 
 
4.2.1 Definition of DLT: Dose limiting toxicity (DLT) will be defined as the occurrence of 
non-hematologic DLT and/or hematologic DLT as defined below. 
 
4.2.1.1 Non-hematological DLT: 
 
(Cohorts A and B) Any Grade 3 or greater non-hematological toxicity that is 
possibly, probably or definitely attributable to the protocol regimen and prevents a 
patient from receiving the required number of doses of therapy (as specified in 
Section 9.0) or from proceeding with further therapy by day 49 of the treatment 
cycle. 
 
(Cohort C) Any Grade 3 or greater non-hematological toxicity that is possibly, 
probably or definitely attributable to the protocol regimen and prevents a patient 
from receiving the required number of doses of therapy (as specified in Section 
9.0) or from proceeding with further therapy by day 21 of the treatment cycle for 
Stratum C. 
 

TACL Protocol:  
T2012-002  
Original Version Date: 14-May-2016  
Activated: 
                 28-Jul-2016  
Amendment #1 Date: 16-Mar-2017 
 
 
Amendment #2 Date: 16-Jul-2018 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
T2012-002 Original Version Date: 14-May-2016   
CONFIDENTIAL 
Amendment #1 Date: 16-Mar-2017 
TACL Internal Distribution Only 
Amendment #2 Date: 16-Jul-2018  
28 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
4.2.1.2 Hematological DLT: 
 
(Cohorts A and B) The absence of peripheral blood count recovery (ANC >500/μL 
and platelet count > 20,000/μL) 7 weeks (49 days) after the start of chemotherapy 
in the absence of persistent leukemia or documented myelosuppressive infection. 
Subjects with abnormal blood counts (Grade 1 through 4) at baseline due to 
disease will not be evaluable for hematologic DLT and will be considered not 
having had hematologic DLT for the purposes of the definition in 4.2.1. 
 
(Cohort C) The absence of peripheral blood count recovery (ANC > 500/μL and 
platelet count > 20,000/μL) 3 weeks (21 days) after the start of  chemotherapy in 
the absence of persistent leukemia or documented myelosuppressive infection. 
Subjects with abnormal blood counts (Grade 1 through 4) at baseline due to 
disease will not be evaluable for hematologic DLT and will be considered not 
having had hematologic DLT for the purposes of the definition in 4.2.1. 
 
Adverse events (AEs) that are considered disease-related (not suspected of relationship to 
protocol specified therapy) will not be considered dose-limiting toxicities. 
 
4.3  
Dose Delays and Modifications 
 
The intent of this study design is for all patients to receive and complete one course of therapy. 
Patients who exhibit signs of disease progression or experience an unacceptable toxicity will be 
discontinued from treatment. For Marqibo® dosing delays due to hepatotoxicity (see sections 
4.3.1.3 and 4.3.1.4), a maximum delay of 7 days is allowed per dose and no dosing is permitted 
beyond day 35. There will be no dose delays or dose reductions of study drugs for hematologic 
toxicity during therapy. At the time that interim analysis is performed to evaluate toxicity (see 
sections 9.2 - 9.5), if it is determined that the regimen has excessive toxicity, protocol amendment 
may be considered to modify the dose of Marqibo®. 
 
4.3.1 Marqibo® 
 
4.3.1.1 Weekly assessment of neurologic function should be performed prior to 
administration of Marqibo®. (Appendix 4).  
• 
Subjects who develop grade 3 or greater sensory or motor neuropathy will 
discontinue Marqibo® treatment. 
• 
Subjects with < grade 3 neuropathy will be closely monitored without any 
adjustment to Marqibo® dose 
 
4.3.1.2 Dosing will NOT be held for cytopenias. 
 
4.3.1.3 Transaminase elevation: Marqibo® dosing will be delayed for grade 3 or higher 
AST (aspartate aminotransferase) or ALT (alanine aminotransferase) elevation 

TACL Protocol:  
T2012-002  
Original Version Date: 14-May-2016  
Activated: 
                 28-Jul-2016  
Amendment #1 Date: 16-Mar-2017 
 
 
Amendment #2 Date: 16-Jul-2018 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
T2012-002 Original Version Date: 14-May-2016   
CONFIDENTIAL 
Amendment #1 Date: 16-Mar-2017 
TACL Internal Distribution Only 
Amendment #2 Date: 16-Jul-2018  
29 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
until resolution to grade 2 or baseline, then resume full dose. Maximum 
allowable delays are specified in section 4.3. 
 
4.3.1.4 Hyperbilirubinemia: 
 
Bilirubin Level 
Dose Delay 
Total bilirubin < 1.5 x upper 
limit of normal and direct 
bilirubin < 1.4 mg/dL 
None, administer full dose 
Total bilirubin > 1.5 x upper 
limit of normal, and/or direct 
bilirubin > 1.4 mg/dL 
Withhold dose until resolution to grade 1 
bilirubin or baseline and direct bilirubin < 1.4, 
then resume full dose. Maximum allowable 
delays are specified in section 4.3. 
 
For subjects with documented Gilbert’s disease, no modification is necessary 
unless the total bilirubin exceeds 5 x ULN or the direct bilirubin is > 1.4  mg/dL. 
 
4.3.1.5 Jaw Pain: Treat with analgesics; do not modify Marqibo® dose. 
 
4.3.1.6 Extravasation: In the event of an extravasation, discontinue the IV 
administration of the drug and institute appropriate measures according to 
institutional guidelines. 
 
4.3.1.7 Drug Interactions: See Section 4.4 
 
4.3.2 Pegaspargase 
 
4.3.2.1 Allergic Reactions 
 
Local Reactions (inflammation at injection site, swelling): Continue 
pegaspargase administration in the presence of Grade 1 allergy (transient 
flushing or rash; drug fever < 38°C).  
 
Anaphylaxis/Systemic Allergic reactions: Systemic allergy is associated with 
the presence of pegaspargase neutralizing antibodies, which render 
asparaginase therapy ineffective. Discontinue if the patient develops a 
systemic allergic reaction (urticaria, wheezing, laryngospasm, hypotension, 
etc). 
 
 
4.3.2.2 Coagulopathy: If symptomatic, hold pegaspargase until symptoms resolve, 
allowing for up to a one-week delay in scheduled dosing or resume with the 
next scheduled dose. Consider factor replacement (FFP, cryoprecipitate, factor 

TACL Protocol:  
T2012-002  
Original Version Date: 14-May-2016  
Activated: 
                 28-Jul-2016  
Amendment #1 Date: 16-Mar-2017 
 
 
Amendment #2 Date: 16-Jul-2018 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
T2012-002 Original Version Date: 14-May-2016   
CONFIDENTIAL 
Amendment #1 Date: 16-Mar-2017 
TACL Internal Distribution Only 
Amendment #2 Date: 16-Jul-2018  
30 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
VIIa). Do not withhold dose for abnormal laboratory findings without clinical 
symptoms. 
 
4.3.2.3 Hyperbilirubinemia: Pegaspargase should be held in patients with an elevated 
direct bilirubin > 1.4 mg/dL. Resume when direct bilirubin < 1.4 mg/dL, may 
give within one week of scheduled dosing. 
 
Direct Bili 
Dose modification 
≤ 3 mg/dL 
Full dose 
3.1-5 mg/dL 
Hold asparaginase and result when 
direct bilirubin ≤ 2 mg/dL 
>5 mg/dL 
HOLD 
asparaginase; 
do 
not 
substitute 
other 
asparaginase 
products; do not make up missed 
doses 
 
 
4.3.2.4 Hyperglycemia: Do not modify dose. Treat hyperglycemia as medically 
indicated. 
 
4.3.2.5 Hyperlipidemia: Do not modify dose. 
 
4.3.2.6 Ketoacidosis: Hold pegaspargase until blood glucose can be regulated with 
insulin. 
 
4.3.2.7 Pancreatitis 
Grade 2 (Enzyme elevation or radiologic findings only) Hold until 
symptoms and signs subside, and enzyme levels return to normal and then 
resume at full dose, allowing for up to a one-week delay from scheduled dosing  
 
Grade 3-4 Asparaginase should be permanently discontinued. elevation (> 
2.0x ULN). Severe pancreatitis is a contraindication to additional asparaginase 
administration. 
 
4.3.2.8 Thrombosis (excluding minor central venous catheter tip related): Withhold 
pegaspargase and treat with appropriate anticoagulant and/or antithrombotic 
therapy, as indicated. Upon resolution of symptoms consider resuming 
asparaginase, while continuing anticoagulant and/or antithrombotic therapy, 
may allow for up to a one-week delay from scheduled dosing. Do not withhold 
dose for abnormal laboratory findings without clinical sequelae. Consider 
evaluation for inherited predisposition to thrombosis. 
 
4.3.2.9 CNS Events (bleed, thrombosis or infarction): Hold pegaspargase. Treat with 
FFP, factors or anticoagulation as appropriate. Resume at full dose when all 

TACL Protocol:  
T2012-002  
Original Version Date: 14-May-2016  
Activated: 
                 28-Jul-2016  
Amendment #1 Date: 16-Mar-2017 
 
 
Amendment #2 Date: 16-Jul-2018 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
T2012-002 Original Version Date: 14-May-2016   
CONFIDENTIAL 
Amendment #1 Date: 16-Mar-2017 
TACL Internal Distribution Only 
Amendment #2 Date: 16-Jul-2018  
31 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
symptoms have resolved (and evidence of recanalization in case of thrombosis 
by CT/MRI). May allow for up to a one-week delay from scheduled dosing. 
Consider evaluation for inherited predisposition to thrombosis. 
 
4.3.3 Intrathecal Methotrexate 
 
4.3.3.1 Systemic toxicity: The dosage for IT methotrexate will not be reduced for 
systemic toxicity (myelosuppression, mucositis, etc.). Instead, leucovorin may 
be used at a dose of 5 mg/m2/dose every 12 hours x 2 doses, beginning 48 
hours after the IT therapy has been delivered. This may reduce the risk of 
worsening myelosuppression or mucositis. Leucovorin may also be used in 
subjects with hepatic transaminase elevation to reduce risk of worsening 
hepatotoxicity from IT methotrexate. 
 
4.3.3.2 Dose modifications following an episode of acute neurotoxicity: The treating 
physician must evaluate the patient and, with the family, make the best 
possible decision with respect to the relative risk and benefit of continued 
therapy. 
 
4.3.3.3 Hydrocephalus, microcephaly or known abnormality of CSF flow precluding 
intrathecal chemotherapy via lumbar puncture: Intraventricular chemotherapy 
via 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 and/or intraventricular therapy. 
 
4.3.3.4 Viral, bacterial, or fungal meningitis: Omit until resolved. 
 
4.3.4 Dexamethasone 
 
4.3.4.1 Hypertension: Dose should not be reduced. Sodium restriction and 
antihypertensives should be employed in an effort to control hypertension. 
Avoid calcium channel blockers due to their potential prohemorrhagic effect. 
 
4.3.4.2 Hyperglycemia: Do not modify dose. Treat hyperglycemia as medically 
indicated. 
 
4.3.4.3 Pancreatitis: Do not modify dose for asymptomatic elevations of amylase 
and/or lipase. Discontinue steroids, except for stress doses, in the presence of 
hemorrhagic pancreatitis or severe pancreatitis (abdominal pain > 72 hours 
and > Grade 3 amylase elevation (> 2.0x ULN). Steroids may resume with 
resolution of pancreatitis, as defined by amylase and lipase to baseline or < 
grade 1 and resolution of pain.  

TACL Protocol:  
T2012-002  
Original Version Date: 14-May-2016  
Activated: 
                 28-Jul-2016  
Amendment #1 Date: 16-Mar-2017 
 
 
Amendment #2 Date: 16-Jul-2018 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
T2012-002 Original Version Date: 14-May-2016   
CONFIDENTIAL 
Amendment #1 Date: 16-Mar-2017 
TACL Internal Distribution Only 
Amendment #2 Date: 16-Jul-2018  
32 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
4.3.4.4 Osteonecrosis: Do not modify corticosteroid therapy for osteonecrosis. 
 
4.3.4.5 Severe infection: Do not hold or discontinue steroids without contacting the 
study chair or vice chair. 
 
4.3.4.6 Severe psychosis: Steroid dose may be reduced by 50%. 
 
4.3.5 Mitoxantrone 
 
4.3.5.1 Hyperbilirubinemia 
 
Total Bilirubin 
Dose Reduction 
< 5.0 mg/dL 
Full dose 
> 5.0 mg/dL 
Withhold dose and administer next scheduled dose if 
toxicity has resolved. Do not make up missed doses. 
 
4.4  
Concurrent Therapy and Drug Interactions 
 
Anti-Cancer Therapy: Concurrent anti-cancer therapy not defined within this protocol, including 
chemotherapy, radiation therapy, immunotherapy, or biologic therapy may NOT be administered 
to patients receiving study drug. If these treatments are administered the patient will be removed 
from protocol therapy. 
 
Investigational Agents: No other investigational agents may be given while the patient is on 
protocol therapy. 
 
Complementary/Alternative Therapies: Use of complementary/alternative therapies is not 
specifically prohibited, but is discouraged. All therapies should be reviewed with the study team 
for the potential of drug interactions with Marqibo® or any of the other chemotherapeutic agents. 
 
Allopurinol: Tumor lysis syndrome prophylaxis should be employed for all patients. Allopurinol 
should ideally be started at a dose of approximately 100 mg/m2/dose PO TID (maximum dose 600 
mg/day/subject) at least 8 hours prior to the first dose of chemotherapy and continue until it is 
apparent that no tumor lysis has developed after 1 week of treatment. Alternatively, rasburicase 
may be employed as clinically indicated. 
 
Drug Interactions: No formal drug interaction studies have been conducted with Marqibo®. 
Marqibo® is expected to interact with drugs known to interact with standard formulation vincristine 
sulfate. Simultaneous oral or intravenous administration of phenytoin and antineoplastic 
chemotherapy combinations that included non-liposomal vincristine sulfate have been reported to 
reduce blood levels of phenytoin and to increase seizure activity. Close monitoring is 
recommended for subjects taking agents with narrow therapeutic indices and metabolized by the 

TACL Protocol:  
T2012-002  
Original Version Date: 14-May-2016  
Activated: 
                 28-Jul-2016  
Amendment #1 Date: 16-Mar-2017 
 
 
Amendment #2 Date: 16-Jul-2018 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
T2012-002 Original Version Date: 14-May-2016   
CONFIDENTIAL 
Amendment #1 Date: 16-Mar-2017 
TACL Internal Distribution Only 
Amendment #2 Date: 16-Jul-2018  
33 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
liver, such as warfarin, phenytoin, quinidine, carbamazepine, phenobarbital, cyclosporine and 
digoxin. 
 
Vincristine sulfate, the active agent in Marqibo®, is a substrate for cytochrome P450 3A 
isoenzymes (CYP3A); therefore the concomitant use of strong CYP3A inhibitors should be 
avoided (e.g., ketoconazole, itraconazole, voriconazole, posaconazole, clarithromycin, 
atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin). Concurrent 
administration of itraconazole with vincristine has shown to increase onset and severity of 
neuromuscular adverse effects of vincristine. If anti-fungal therapies are required during study 
treatment, alternative anti-fungals should be evaluated prior to considering any azoles. In the 
event that it is determined that an azole antifungal is required to treat a documented or 
suspected fungal infection, the decision to initiate therapy should be made after 
discussion with the Study Chair or Vice Chair. If permission is granted for the use of azole 
therapy, all azole therapy must be held for 24 hours before AND after each dose of Marqibo®. 
 
Similarly, the concomitant use of strong CYP 3A inducers should be avoided (e.g., phenytoin, 
carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, St. John’s Wort) as these may 
decrease Marqibo® levels. 
 
Vincristine sulfate is also a substrate for p-glycoprotein (p-gp). The effects of concomitant use of 
potent p-gp inhibitors or inducers has not been investigated; it is likely that these agents will alter 
the pharmacokinetics or pharmacodynamics of Marqibo®. Therefore the concomitant use of 
potent p-gp inhibitors or inducers should be avoided. 
 
 
5.0  
SUPPORTIVE CARE 
 
Best supportive care and treatment will be given as appropriate to each patient (antiemetics, 
antibiotics, transfusions, oxygen therapy, nutritional support, palliative treatment for pain or cough, 
etc.). Patients may experience profound myelosuppression and immune suppression during this 
time. Since steroids may mask fever as well as other components of the inflammatory response 
sepsis during induction may be associated with very mild and subtle symptoms. Caregivers must 
also be made aware that patients may experience very rapid clinical deterioration. This suggests 
the need for a supportive care network that can recognize and respond to sudden changes in a 
patient’s condition. Aggressive supportive care improves outcome. The following guidelines are 
intended to give general heath direction for optimal patient care and to encourage uniformity in 
the treatment of this patient population. Notify the Study Chair or Vice Chair of any unexpected or 
unusually severe complications. 
 
5.1   Blood Products: 
Investigators should follow institutional guidelines regarding administration of blood products. 
 
5.2  
Infection Control and Prophylaxis 
 

TACL Protocol:  
T2012-002  
Original Version Date: 14-May-2016  
Activated: 
                 28-Jul-2016  
Amendment #1 Date: 16-Mar-2017 
 
 
Amendment #2 Date: 16-Jul-2018 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
T2012-002 Original Version Date: 14-May-2016   
CONFIDENTIAL 
Amendment #1 Date: 16-Mar-2017 
TACL Internal Distribution Only 
Amendment #2 Date: 16-Jul-2018  
34 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
Pneumocystis prophylaxis: PJP prophylaxis is required, with agents and dosing provided 
according to institutional guidelines. 
 
Antibacterial prophylaxis: It is recommended that consideration be given to anti-bacterial 
prophylaxis during periods of neutropenia (ANC <0.75 × 10 9/L). Treating physicians may follow 
their institutional guidelines. 
 
Herpes simplex virus (HSV) prophylaxis: Patients with history of HSV or positive antibodies should 
receive prophylaxis according to institutional guidelines. 
 
Fever and Neutropenia: All patients with a fever ≥38.5°C on a single occasion, or >38°C on 2 
occasions within 12 hours, and an ANC <0.500 × 109/L are to be treated immediately with 
intravenous broad-spectrum antibiotics after obtaining appropriate cultures. It is recommended 
that such patients be hospitalized. The specific choice of antibiotics to be used in empiric 
treatment of febrile neutropenia is dependent on each institution’s experience regarding the type 
of infecting organisms, and their antibiotic sensitivity patterns. Duration of therapy should be 
determined by site of infection, culture results, and response to treatment. Antifungal treatment is 
to be considered for the persistence of fever, or emergence of a new fever in neutropenic patients. 
Surveillance radiographic imaging surveillance for sites of infection should also be performed as 
clinically indicated. When severe mucositis or a sepsis syndrome is present in patients with febrile 
neutropenia, or a patient has a history of alpha hemolytic streptococcal infection, consider 
inclusion of vancomycin in the empiric antibiotic regimen. 
 
Anti-fungal treatment and prophylaxis: Azole antifungal agents (i.e,. fluconazole, itraconazole, 
voriconazole, posaconazole) given concurrently with Marqibo® can increase risk of neurotoxicity 
and are prohibited. Anti-fungal prophylaxis is mandated in all subjects enrolled in Cohorts A and 
B from the start of therapy until day 29, and ideally until neutrophil count recovery. All subjects 
are encouraged to continue antifungal prophylaxis beyond the treatment period especially if 
neutrophil count recovery has not occurred. The echinocandin class (e.g., caspofungin, 
micafungin) or the amphotericin class should be employed following institutional guidelines. Any 
exceptions must be discussed with the Study Chair or Vice Chair. 
In the event that it is determined that an azole antifungal is required to treat a documented 
or suspected fungal infection, the decision to initiate therapy should be made after 
discussion with the Study Chair or Vice Chair. 
 
All azole therapy must be discontinued at least 1 week prior to the start of initiation of protocol 
therapy with Marqibo®. 
 
Mucositis/Perirectal Cellulitis: Mucositis should be managed with IV hydration and 
hyperalimentation if indicated, effective analgesia, broad-spectrum gram-positive and gram-
negative antibiotic therapy and empiric antiviral and antifungal therapy as indicated. Management 
of perirectal cellulitis should include broad-spectrum antibiotic therapy with dual gram-negative 
coverage as well as anaerobic coverage (i.e. ceftazidime + aminoglycoside + metronidazole; or 
piperacillin-tazobactam + aminoglycoside), Sitz baths, a strong barrier technique and effective 
analgesia. 

TACL Protocol:  
T2012-002  
Original Version Date: 14-May-2016  
Activated: 
                 28-Jul-2016  
Amendment #1 Date: 16-Mar-2017 
 
 
Amendment #2 Date: 16-Jul-2018 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
T2012-002 Original Version Date: 14-May-2016   
CONFIDENTIAL 
Amendment #1 Date: 16-Mar-2017 
TACL Internal Distribution Only 
Amendment #2 Date: 16-Jul-2018  
35 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
5.3   
Antiemetic Protection 
 
Antiemetics should be given to all patients. Dexamethasone administration can be timed 
accordingly. 
 
5.4   Filgrastim 
 
The routine use of filgrastim is not recommended, but may be used at the discretion of the 
investigator in situations of serious infection with neutropenia. 
 
5.5  
Bowel Prophylaxis (Appendix 6) 
 
All patients must receive prophylaxis against constipation starting with the first dose of 
Marqibo unless there is diarrhea. 
 
 
 
5.6  
Dexrazoxane 
 
Dexrazoxane as a cardioprotectant may be used per treating physician discretion. 
 
Since most of the patients entering this study will have been previously treated with 
anthracyclines, the use of dexrazoxane prior to mitoxantrone will be allowed in attempt to 
mitigate further cardiotoxicity that might occur from additional mitoxantrone exposure.  
While the use of dexrazoxane before mitoxantrone is not as well documented as its use 
with doxorubicin,17 several papers have reported benefit with dexrazoxane given prior to 
mitoxantrone in doses 30-60 fold times the mitoxantrone dose.18-20 The recommended 
dose of dexrazoxane for use with doxorubicin is ten-times the doxorubicin dose. Based on 
the Children’s Oncology Group recommendations and a recent paper by Feijen et al, 21 the 
equipotent dose of mitoxantrone to doxorubicin is estimated to be about 1:4. Thus, the 
dose of dexrazoxane recommended prior to mitoxantrone is 40 times the mitoxantrone 
dose (400 mg/m2 in this study).  The dexrazoxane infusion should be given rapidly over 
15 minutes just prior to starting the bolus dose of mitoxantrone. 
 
 
6.0  
DRUG INFORMATION 
 
6.1  
Marqibo® 
 
Marqibo® 
(vincristine 
sulfate 
liposome 
injection) 
is 
vincristine 
encapsulated 
in 
sphingomyelin/cholesterol liposomes for intravenous administration. 
 
6.1.1 Nomenclature and Molecular Structure 

TACL Protocol:  
T2012-002  
Original Version Date: 14-May-2016  
Activated: 
                 28-Jul-2016  
Amendment #1 Date: 16-Mar-2017 
 
 
Amendment #2 Date: 16-Jul-2018 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
T2012-002 Original Version Date: 14-May-2016   
CONFIDENTIAL 
Amendment #1 Date: 16-Mar-2017 
TACL Internal Distribution Only 
Amendment #2 Date: 16-Jul-2018  
36 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
22-oxo-vincaleukoblastine sulfate, which is the chemotherapeutic agent and active ingredient in 
Marqibo®. 
Other names: Vincristine sulfate 
Molecular Formula: C46H56N4O10H2SO4, M.W.: 923.04 
 
IND number: #59056 
 
 
 
6.1.2 Mode of Action and Pharmacology 
Vincristine is a natural product belonging to the class of compounds commonly known as vinca 
alkaloids. It is isolated from the periwinkle (Vinca rosea Linn.) and prepared as a sulfate salt. It is 
supplied as Vincristine Sulfate Injection, USP which is a component of the Vincristine Sulfate 
Liposomes Injection (0.16 mg/mL) Marqibo® kit. Marqibo® is a sphingomyelin/cholesterol 
liposome-encapsulated formulation of vincristine sulfate. Non-liposomal vincristine sulfate binds 
to tubulin, altering the tubulin polymerization equilibrium, resulting in altered microtubule structure 
and functions. Non-liposomal vincristine sulfate stabilized the spindle apparatus, preventing 
chromosome segregation, triggering metaphase arrest and inhibition of mitosis. 
 
6.1.3 Toxicity/Adverse Events 
See investigator’s brochure (IB) or package insert for a complete discussion of AEs. 
a. Neurotoxicity is the DLT of Marqibo® 
b. Constipation is common but rarely progresses to serious situations such as bowel 
obstruction or paralytic ileus. 
c. The neuropathy events caused by Marqibo® are characterized by early sensory 
impairments (numbness, tingling, and paresthesias), followed by deep tendon reflex 
abnormalities and weakness. Cranial nerve involvement may be heralded by jaw pain, 
facial numbness, or facial muscle weakness. 
d. Myelosuppression occurs frequently, but severe myelotoxicity occurs infrequently 
e. Fatigue and non-severe gastrointestinal symptoms (nausea, vomiting, and 
constipation) occur frequently. 
f. Severe infections, including pneumonia, sepsis, and bacteremia, and alopecia have 
been seen infrequently. 
g. Insomnia is common. It may persist and resolve over time. 
h. Headache is frequent. 
 

TACL Protocol:  
T2012-002  
Original Version Date: 14-May-2016  
Activated: 
                 28-Jul-2016  
Amendment #1 Date: 16-Mar-2017 
 
 
Amendment #2 Date: 16-Jul-2018 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
T2012-002 Original Version Date: 14-May-2016   
CONFIDENTIAL 
Amendment #1 Date: 16-Mar-2017 
TACL Internal Distribution Only 
Amendment #2 Date: 16-Jul-2018  
37 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
In a Phase 1 open-label, single-center, single-arm dose escalation study to evaluate the safety, 
activity and pharmacokinetics of Marqibo in children and adolescents with refractory malignant 
disease, the most commonly reported adverse events were: 
• 
Increases in liver enzyme tests 
• 
Fatigue 
• 
Anemia, white blood cell decreased, platelet count decreased, neutrophil count decreased 
• 
Decreases in blood levels of potassium, calcium, magnesium, albumin, sodium, 
phosphorus 
• 
Increases in blood levels of glucose, triglycerides, bilirubin, cholesterol, magnesium, uric 
acid 
• 
Abdominal pain 
• 
Fast heart rate 
• 
Diarrhea 
• 
Nausea, vomiting 
• 
Febrile neutropenia 
• 
Prolonged bleeding time 
• 
Bruising, epistaxis 
• 
Anorexia 
• 
Constipation 
• 
Low blood pressure 
• 
Infections 
• 
Back pain, headache, pain, myalgia 
• 
Parasthesia 
• 
Pruritus 
• 
Rash maculo-papular 
 
In general, nonclinical toxicology studies show that Marqibo and vincristine exhibit comparable 
toxicological profiles. In clinical studies, the safety profile of Marqibo has been similar to that of 
vincristine; however, infusion-related pyrexia, which is not typical with vincristine, has been 
observed at a low incidence rate with Marqibo. 
 
Possible side effects of vincristine: 
 
 
Common 
Happens to 21-100 
children 
out 
of 
every 100 
Occasional 
Happens to 5-20 
children 
out 
of 
every 100 
Rare 
Happens 
to 
<5 
children 
out 
of 
every 100 
Immediate: 
Within 1-2 days of 
receiving drug 
Insomnia 
Jaw 
pain, 
headache 
Extravasation (rare) 
but if occurs=local 
ulceration; 
shortness of breath 
and bronchospasm 

TACL Protocol:  
T2012-002  
Original Version Date: 14-May-2016  
Activated: 
                 28-Jul-2016  
Amendment #1 Date: 16-Mar-2017 
 
 
Amendment #2 Date: 16-Jul-2018 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
T2012-002 Original Version Date: 14-May-2016   
CONFIDENTIAL 
Amendment #1 Date: 16-Mar-2017 
TACL Internal Distribution Only 
Amendment #2 Date: 16-Jul-2018  
38 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
Common 
Happens to 21-100 
children 
out 
of 
every 100 
Occasional 
Happens to 5-20 
children 
out 
of 
every 100 
Rare 
Happens 
to 
<5 
children 
out 
of 
every 100 
Prompt: 
Within 2-3 weeks, prior 
to the next course 
Alopecia, 
constipation 
Weakness, 
abdominal 
pain; 
mild brief 
myelosuppression 
(leukopenia, 
thrombocytopenia, 
anemia) 
Paralytic 
ileus; 
ptosis, 
diplopia, 
night 
blindness; 
hoarseness; vocal 
cord 
paralysis; 
SIADH, seizure; 
defective sweating, 
Delayed: 
Any time later during 
therapy, excluding the 
above conditions 
Loss 
of 
deep 
tendon reflexes 
Peripheral 
paresthesias 
including 
numbness, tingling 
and 
pain; 
clumsiness; 
wrist 
drop, 
foot drop; 
abnormal gait 
Difficulty walking or 
inability 
to walk; 
sinusoidal 
obstruction 
syndrome 
(SOS, 
formerly VOD) (in 
combination); 
blindness, 
optic 
atrophy; 
urinary 
tract 
disorders 
(including bladder 
atony, 
dysuria, 
polyuria, nocturia, 
urinary retention); 
autonomic 
 
 
 
neuropathy 
with 
postural 
hypotension; 
8th 
cranial 
nerve 
damage 
with 
dizziness, 
nystagmus, vertigo 
and hearing loss 
Late: 
Any 
time 
after 
completion of treatment 
 
 
 
Unknown Frequency and Timing: Fetal and teratogenic toxicities. Fetal toxicities and 
teratogenic effect of vincristine (either alone or in combination with other antineoplastic 
agents) have been noted in humans. The toxicities have included: chromosome 
abnormalities, malformation, pancytopenia, and low birth weight. It is unknown whether 
the drug is excreted in breast milk. 
 

TACL Protocol:  
T2012-002  
Original Version Date: 14-May-2016  
Activated: 
                 28-Jul-2016  
Amendment #1 Date: 16-Mar-2017 
 
 
Amendment #2 Date: 16-Jul-2018 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
T2012-002 Original Version Date: 14-May-2016   
CONFIDENTIAL 
Amendment #1 Date: 16-Mar-2017 
TACL Internal Distribution Only 
Amendment #2 Date: 16-Jul-2018  
39 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
Pregnancy and Breast Feeding 
Risks to a fetus and newborn are unknown. Individuals who are pregnant or lactating will not be 
candidates for this protocol. 
 
6.1.4 Formulation and Stability 
Marqibo® is supplied as a single-use, 3-vial kit designed to enable entrapment of vincristine in 
sphingomyelin/cholesterol liposomes at the time of use. The active agent consists of vincristine 
sulfate as an aqueous solution and the vehicle consists of sphingomyelin/cholesterol liposomes 
with a sodium phosphate buffer as described in the 3-vial kit component table below. 
 
Component 
(Abbreviation) 
No. 
of 
Vials/Kit 
Description 
Active (VSI) 
1 
Vincristine Sulfate Injection, USP 
(1 mg/mL, 5 mL) 
Liposomes (SCLI) 
1 
Sphingomyelin/Cholesterol Liposomes 
Injection (103 mg/mL, 1 mL) 
Buffer (SPI) 
1 
Sodium Phosphate Injection 
(14.2 mg/mL, 25 mL) 
 
 
6.1.5  Preparation and Administration 
Marqibo® and its components are to be stored in a controlled refrigerator (2-8cC; 36-46oF) until 
the time of constitution; refrigeration temperature logs (or equivalent records) should be 
maintained. Retain vials in carton until time of use. DO NOT FREEZE 
 
Constitution should take place under strict aseptic conditions following detailed instructions 
included in the kit. After constitution of Marqibo®, the constituted product should be stored in the 
constitution vial or in the infusion bag after being diluted according to instruction into an IV infusion 
bag containing 5% dextrose injection or 0.9% sodium chloride injection to a final total volume of 
100 mL. 
 
The constituted product, whether in the constitution vial or diluted in the infusion bag, should be 
stored at controlled room temperature (15-30cC; 59-86oF) and must be administrated within 12 
hours of the constitution start time. 
 
All unused Marqibo® kits will be destroyed at the site as per the institutional guidelines for 
pharmacy’s cytotoxic agent destruction procedures and according to applicable regulations. 
Destruction on site should only occur with prior authorization from the TACL Operations Center. 
Documentation of local Marqibo® destruction must be provided. Marqibo® is an investigational 
drug. Drugs supplied for clinical investigation should be given by or under the supervision of the 
investigators throughout this study. 
 
Marqibo® will be administered IV over 60 minutes (±10 minutes). Marqibo® may be infused 
through a free running peripheral or central venous catheter, without the use of an inline filter, 

TACL Protocol:  
T2012-002  
Original Version Date: 14-May-2016  
Activated: 
                 28-Jul-2016  
Amendment #1 Date: 16-Mar-2017 
 
 
Amendment #2 Date: 16-Jul-2018 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
T2012-002 Original Version Date: 14-May-2016   
CONFIDENTIAL 
Amendment #1 Date: 16-Mar-2017 
TACL Internal Distribution Only 
Amendment #2 Date: 16-Jul-2018  
40 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
using an infusion pump. For peripheral venous access, a minimum 21-gauge catheter or butterfly 
should be used. It is extremely important that the intravenous needle or catheter be properly 
positioned before any Marqibo® is administered. Leakage into surround tissue during intravenous 
administration of Marqibo® may cause local irritation. If extravasation occurs, the injection should 
be discontinued immediately and managed per institutional procedures. Any remaining portion of 
the dose should be introduced into another vein. Marqibo® should be administered only by 
intravenous infusion and by individuals experienced with the administration of vincristine sulfate. 
In-line filters should not be used and closed transfer filtration devices should not be used in 
preparation without specific review and approval by TACL Operations. Marqibo® should be not 
mixed with or diluted with other drugs or solution other than 5% dextrose injection or 0.9% sodium 
chloride injection. It is not required that the Marqibo® dose be corrected for obese subjects. 
 
The amount (in mg) of study drug to be administered will be determined based on body surface 
area (BSA). In calculating BSA, actual height obtained at screening and weights obtained at the 
onset of induction should be used. There will be no adjustment to “ideal” body weight. 
 
6.1.6  Supplier 
Acrotech Biopharma will supply Marqibo® on this study as well as the equipment necessary for 
preparation on an as needed basis, including a dry heat block, waterbath, thermometer and timer. 
Drug and equipment can be ordered directly from Acrotech Biopharma 
using the forms and procedures provided in the member’s only section of the TACL website. 
 
6.1.7 Drug Accountability 
All study drug supplies must be kept in a locked limited access room. The study drug must not be 
used outside the context of the protocol. Under no circumstances should the investigator or other 
site personnel supply study drug to other Investigators, subjects, or clinics, or allow supplies to be 
used other than directed by this protocol without prior authorization from the Sponsor. 
 
The pharmacist will maintain complete drug accountability records. Periodically throughout the 
study, and again at the end of the study, TACL will require submission of the drug accountability 
record providing a complete accounting of the receipt and disposition of all study drug kits and 
the total number of kits dispense to each subject along with the Marqibo® kit lot number used for 
each individual patient administration. Information recorded during the drug preparation steps are 
to be retained per institutional requirements. 
 
6.1.8 Drug Disposal 
Avoid contact with skin by using gloves. All needles, syringes, vials, and other materials that have 
come in contact with vincristine sulfate should be segregated in plastic bags, sealed, and marked 
as hazardous waste. Incinerate at 1000cC or higher. Sealed containers may explode if a tight seal 
exists. 
 
If incineration is not available, sodium hypochlorite (household bleach) may be added to the vial(s) 
to detoxify the vincristine sulfate. Care must be taken to vent the vial(s) to avoid a pressure build-

TACL Protocol:  
T2012-002  
Original Version Date: 14-May-2016  
Activated: 
                 28-Jul-2016  
Amendment #1 Date: 16-Mar-2017 
 
 
Amendment #2 Date: 16-Jul-2018 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
T2012-002 Original Version Date: 14-May-2016   
CONFIDENTIAL 
Amendment #1 Date: 16-Mar-2017 
TACL Internal Distribution Only 
Amendment #2 Date: 16-Jul-2018  
41 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
up of chlorine gas generated. Decomposition occurs within 10 minutes. Dispose of detoxified vials 
in a safe manner. 
 
Dispose all components of the Marqibo® Kit that did not come into contact with vincristine sulfate 
as per established pharmacy procedures for non-bio hazardous waste. 
 
6.2  
Dexamethasone (Decadron®, Hexadrol®, Dexone®, Dexameth®) NSC#34521 
 
6.2.1 Source and Pharmacology: 
Dexamethasone is a synthetic fluorinated glucocorticoid devoid of mineralocorticoid effects. 
Dexamethasone, 0.75 mg, has potent anti-inflammatory activity equivalent to approximately 5 mg 
of prednisone. Glucocorticoids produce widespread and diverse physiologic effects on 
carbohydrate, protein, and lipid metabolism, electrolyte and water balance, functions of the 
cardiovascular system, kidney, skeletal muscle, and the nervous systems. Glucocorticoids reduce 
the concentration of thymus-dependent lymphocytes (T-lymphocytes), monocytes, and 
eosinophils. Glucocorticoids selectively bind to the cortisol receptors on human lymphoid cells 
which are found in larger numbers on leukemic lymphoblasts. They also decrease binding of 
immunoglobulin to cell surface receptors and inhibit the synthesis and/or release of interleukins, 
thereby decreasing T-lymphocyte blastogenesis and reducing expansion of the primary immune 
response. The specific cellular mechanisms that act to halt DNA synthesis are thought to be 
related to inhibition of glucose transport or phosphorylation, retardation of mitosis, and inhibition 
of protein synthesis. Elimination half-lives for the following age groups have been reported to be: 
infants and children under 2 years of age: 2.3 to 9.5 hours, 8 to 16 years: 2.82 to 7.5 hours, and 
adults (age not specified): 3 to 6 hours. The biologic half-life is 36-72 hours. It is primarily 
metabolized in the liver and excreted by the kidneys. 
 
6.2.2 Toxicity 
 
Common 
Happens to 21-100 children 
out of every 100 
Occasional 
Happens to 5-20 children 
out of every 100 
Rare 
Happens to <5 children 
out of every 100 
Immediate: 
Within 1-2 days 
of receiving drug 
Insomnia, hyperphagia 
Gastritis 
Hyperuricemia 
Prompt: 
Within 
2-3 
weeks, prior to 
the next course 
Immunosuppression, 
personality changes (mood 
swings, euphoria, anxiety, 
depression), 
pituitaryadrenalaxis 
suppression, acne (L) 
Hyperglycemia, facial 
erythema, poor wound 
healing, infections 
(bacterial,fungal, 
parasitic, viral), edema 
Pancreatitis  
(L), 
increased 
intraocular 
pressure 
(L), 
hypertension, 
psychosis, 
vertigo, 
headache 
Delayed: 
Any time later 
Cushing’s syndrome (moon 
facies, truncal obesity) 
Striae and thinning of the 
skin, easy bruising,  
Spontaneous fractures 
(L), 

TACL Protocol:  
T2012-002  
Original Version Date: 14-May-2016  
Activated: 
                 28-Jul-2016  
Amendment #1 Date: 16-Mar-2017 
 
 
Amendment #2 Date: 16-Jul-2018 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
T2012-002 Original Version Date: 14-May-2016   
CONFIDENTIAL 
Amendment #1 Date: 16-Mar-2017 
TACL Internal Distribution Only 
Amendment #2 Date: 16-Jul-2018  
42 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
Common 
Happens to 21-100 children 
out of every 100 
Occasional 
Happens to 5-20 children 
out of every 100 
Rare 
Happens to <5 children 
out of every 100 
during therapy, 
excluding 
the 
above conditions 
 
Muscle 
weakness, 
osteopenia 
growth 
suppression, 
peptic ulcer and GI 
bleeding, pseudotumor 
cerebri (increased 
intracranial pressure 
with 
papilledema, 
headache), 
aseptic 
necrosis 
of 
the 
femoral 
and 
humeral 
heads (L) 
Late: 
Any time after 
completion 
of 
treatment 
 
Cataracts (which may be 
reversible 
on 
discontinuation of 
dexamethasone in 
children) 
 
Unknown Frequency and Timing: dexamethasone crosses the placenta with 54% metabolized by 
enzymes in the placenta. In animal studies, large doses of cortisol administered early in pregnancy 
produced cleft palate, stillborn fetuses, and decreased fetal size. Chronic maternal ingestion during 
the first trimester has shown a 1% incidence of cleft palate in humans. There are no reports of 
dexamethasone excretion into breast milk in humans; however, it is expected due to its low molecular 
weight that it would partition into breast milk. 
(L) Toxicity may also occur later. 
 
6.2.3 Formulation and Stability: 
Available in 0.25, 0.5, 0.75, 1, 1.5, 2, 4, and 6 mg tablets; liquid formulations are available in 
0.5mg/5ml and 0.5mg/0.5ml concentration. Inactive ingredients vary depending on manufacturer 
but tablet formulations may include: calcium or magnesium stearate, corn starch, lactose, and 
various dyes. Liquid formulations may include: 5%-30% alcohol, Benzoic acid, sorbitol, sodium 
saccharin, glycerin, purified water, and various dyes. 
 
Dexamethasone sodium phosphate solution for injection is available as 4 mg/ml, 10 mg/ml, 20 
mg/ml and 24 mg/ml. 4 mg of dexamethasone sodium phosphate is equivalent to 3.33 mg of 
dexamethasone. Vial sizes include 1 ml, 5 ml, 10 ml, 25 ml, 30 ml and are available in multidose 
vials as well as unit of use vials and syringes. Inactive ingredients vary depending on manufacturer 
but include creatinine, sodium citrate, sodium hydroxide to adjust pH, Water for Injection, sodium 
sulfite, bisulfite and metabisulfite, methyl and propyl paraben, benzyl alcohol, and EDTA. 
 
6.2.4 Guidelines for Administration: 
See Treatment and Dose Modifications section of the protocol for dose and schedule. 
 

TACL Protocol:  
T2012-002  
Original Version Date: 14-May-2016  
Activated: 
                 28-Jul-2016  
Amendment #1 Date: 16-Mar-2017 
 
 
Amendment #2 Date: 16-Jul-2018 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
T2012-002 Original Version Date: 14-May-2016   
CONFIDENTIAL 
Amendment #1 Date: 16-Mar-2017 
TACL Internal Distribution Only 
Amendment #2 Date: 16-Jul-2018  
43 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
Dexamethasone Sodium Phosphate for Injection may be given IV, or IM undiluted. For IV use, it 
may be further diluted in dextrose or saline containing solutions. Avoid benzyl alcohol containing 
dexamethasone solutions for use in neonates. Diluted solutions that contain no preservatives 
should be used within 24 hours, but maintain stability for at least 14 days in PVC bags at room 
temperature protected from light. 
 
6.2.5 Supplier: Commercially available. See package insert for further information. 
 
6.3  
Mitoxantrone (Novantrone®, CL 232315, DAD, DHAD, Mitozantrone) NSC #301739 
 
6.3.1 Source and Pharmacology: 
Mitoxantrone is a substituted alkylaminoanthraquinone and is a potent inhibitor of DNA and RNA 
synthesis in vitro and binds strongly to DNA. Mitoxantrone most likely acts through intercalation 
between base pairs of the DNA double helix causing crosslinks and strand breaks. In addition, it 
is a topoisomerase II inhibitor, an enzyme responsible for uncoiling and repairing damaged DNA. 
It has a cytocidal effect on both proliferating and non-proliferating cultured human cells, 
suggesting lack of cell cycle phase specificity. The drug disappears rapidly from plasma (drug 
found only in the 3-minute sample) and < 1% appears in the urine in 24 hours. The mean alpha 
half-life of mitoxantrone is 6 to 12 minutes, the mean beta half -life is 1.1 to 3.1 hours and the 
mean gamma (terminal or elimination) half-life is 23 to 215 hours (median approximately 75 
hours). Primary excretion is biliary with 25% appearing in the feces; renal excretion accounting 
for only 11% of the total dose. Mitoxantrone clearance is reduced by hepatic impairment. Patients 
with severe hepatic dysfunction (bilirubin > 3.4 mg/dL) have an AUC more than three times greater 
than that of patients with normal hepatic function receiving the same dose. Mitoxantrone is 
approximately 95% protein bound. 
 
6.3.2 Toxicity: 
 
Common 
Happens to 21-100 children 
out of every 100 
Occasional 
Happens to 5-20 children 
out of every 100 
Rare 
Happens to <5 children 
out of every 100 
Immediate: 
Within 1-2 days 
of receiving drug 
Nausea, vomiting, diarrhea, 
fever, anorexia, green blue 
discoloration of the urine 
and/or sclera 
Abdominal pain, back 
pain, 
headache, 
phlebitis, 
constipation 
Anaphylaxis, 
angioedema, 
cardiac 
arrhythmias1 
(bradycardia), seizures, 
extravasation reactions 
rare but if occur can 
lead 
to: 
(erythema, 
swelling, pain, burning 
and/or 
blue 
discoloration of the skin 
and 
rarely 
tissue 
necrosis), tumor lysis 

TACL Protocol:  
T2012-002  
Original Version Date: 14-May-2016  
Activated: 
                 28-Jul-2016  
Amendment #1 Date: 16-Mar-2017 
 
 
Amendment #2 Date: 16-Jul-2018 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
T2012-002 Original Version Date: 14-May-2016   
CONFIDENTIAL 
Amendment #1 Date: 16-Mar-2017 
TACL Internal Distribution Only 
Amendment #2 Date: 16-Jul-2018  
44 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
Common 
Happens to 21-100 children 
out of every 100 
Occasional 
Happens to 5-20 children 
out of every 100 
Rare 
Happens to <5 children 
out of every 100 
Prompt: 
Within 
2-3 
weeks, prior to 
the next course 
Myelosuppression 
(L), 
mucositis 
/stomatitis, 
immunosuppression, 
alopecia, fatigue 
Transient 
elevation 
of 
LFTs, 
pruritis 
with 
desquamation of 
the 
skin 
due 
to 
progressive dryness 
Rash, conjunctivitis, (GI) 
hemorrhage, interstitial 
pneumonitis 
Delayed: 
Any time later 
during therapy, 
excluding 
the 
above conditions 
Amenorrhea, 
menstrual 
disorders, 
temporary 
reduction in sperm count 
Cardiotoxicity (decreased 
LVEF)2 (L) 
CHF, hepatotoxicity 
Late: 
Any time after 
completion 
of 
treatment 
 
 
Secondary malignancy 
Unknown Frequency and Timing: Fetal toxicities and teratogenic effects of mitoxantrone have been 
noted in animals. Toxicities include: low birth weight and prematurity. Mitoxantrone is excreted in 
human milk and significant concentrations (18 ng/mL) have been reported for 28 days after the last 
administration. 
1 Rarely clinically significant. 
2 Risk increases with chest radiation and prior anthracycline dosage (L) Toxicity may 
also occur later. 
 
6.3.3 Formulation and Stability: 
The concentrate is a sterile, non-pyrogenic, non-preserved, dark blue aqueous solution containing 
mitoxantrone hydrochloride equivalent to 2 mg/mL mitoxantrone free base, with sodium chloride 
(0.80% w/v), sodium acetate (0.005% w/v), and acetic acid (0.046% w/v) as inactive ingredients 
with 0.14 mEq of sodium per mL. Mitoxantrone is provided as 20 mg (10 mL), 25 mg (12.5 mL) 
and 30 mg (15 mL) vials. Store intact vials at 15°-25°C (59°-77°F). Undiluted mitoxantrone 
injection should be stored not longer than 7 days between 15°-25°C (59°-77°F) or 14 days under 
refrigeration. Refrigeration of the concentrate may result in a precipitate, which redisolves on 
warming to room temperature. DO NOT FREEZE. 
 
6.3.4 Guidelines for Administration: 
 
See Treatment and Dose Modifications sections of the protocol. 
 
Mitoxantrone must be diluted prior to injection. DO NOT GIVE IV PUSH. The dose of mitoxantrone 
should be diluted to ≤ 0.4 mg/mL with either 0.9% Sodium Chloride Injection (USP) or 5% 
Dextrose Injection (USP). The dilution is stable at room temperature for 48 hours with no loss of 

TACL Protocol:  
T2012-002  
Original Version Date: 14-May-2016  
Activated: 
                 28-Jul-2016  
Amendment #1 Date: 16-Mar-2017 
 
 
Amendment #2 Date: 16-Jul-2018 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
T2012-002 Original Version Date: 14-May-2016   
CONFIDENTIAL 
Amendment #1 Date: 16-Mar-2017 
TACL Internal Distribution Only 
Amendment #2 Date: 16-Jul-2018  
45 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
potency. Admixture with heparin may result in precipitation. Mitoxantrone is an irritant: Care 
should be taken to avoid extravasation; the use of a central line is suggested. If it is known or 
suspected that subcutaneous extravasation has occurred, it is recommended that intermittent ice 
packs be placed over the area of extravasation and that the affected extremity be elevated. 
Because of the progressive nature of extravasation reactions, the area of injection should be 
frequently examined and surgery consultation obtained early if there is any sign of a local reaction. 
 
6.3.5 Supplier: Commercially available. See package insert for more detailed information. 
 
6.4  
Methotrexate (MTX, AMETHOPTERIN) NSC #740 (112004) 
 
6.4.1 Source and Pharmacology: 
A folate analogue which inhibits the enzyme dihydrofolate reductase, halting DNA, RNA, and 
protein synthesis. Initial IV half-life is about 1.2 hours, with a second phase of 10.4 hours. About 
50% is bound to protein. Transport into the cell is carrier-mediated. Once in the cell, MTX (Glu)n 
are formed, the number of which are related to the cytocidal effect. Once MTX (Glu)n are formed, 
they do not pass back out of the cell unless converted back to MTX. Af ter oral administration, 
about 60% of a 30 mg/m2 dose is rapidly absorbed from the GI tract, with peak blood levels at 1 
hour. Above this dose, absorption decreases significantly. Absorption can be very erratic, varying 
between 23% and 95%. A 20-fold difference between peak levels of drug has been reported (0.1 
to 2mM). There is significant enterohepatic circulation of MTX: 9% of MTX is excreted in feces. 
MTX is excreted unchanged in the urine, except at high doses when it is partially metabolized to 
hydroxy-MTX and excreted. 
 
6.4.2 Toxicity: 
 
 
Common 
Happens to 21-100 children 
out of every 100 
Occasional 
Happens to 5-20 children 
out of every 100 
Rare 
Happens to <5 children 
out of every 100 
Immediate: 
Within 1-2 days 
of receiving drug 
Nausea, headache 
Arachnoditis: (headache, 
fever, 
vomiting, 
meningismus, 
nuchal 
rigidity, and pleocytosis) 
Anaphylaxis, 
vomiting, seizures(L), 
confusion, back pain, 
rash, bleeding into 
subarachnoid or 
subdural space 
(risk > with platelet 
counts < 
20,000), 

TACL Protocol:  
T2012-002  
Original Version Date: 14-May-2016  
Activated: 
                 28-Jul-2016  
Amendment #1 Date: 16-Mar-2017 
 
 
Amendment #2 Date: 16-Jul-2018 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
T2012-002 Original Version Date: 14-May-2016   
CONFIDENTIAL 
Amendment #1 Date: 16-Mar-2017 
TACL Internal Distribution Only 
Amendment #2 Date: 16-Jul-2018  
46 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
Common 
Happens to 21-100 children 
out of every 100 
Occasional 
Happens to 5-20 children 
out of every 100 
Rare 
Happens to <5 children 
out of every 100 
Prompt: 
Within 
2-3 
weeks, prior to 
the next course 
 
 
 
Myelosuppression, 
ataxia, 
somnolence, 
cranial 
nerve palsy, 
subacute 
myelopathy 
(paraparesis/paraplegia
), speech 
disorders, pain in the 
legs, 
bladder 
dysfunction 
 
Delayed: 
Any time later 
during 
therapy, 
excluding 
the 
above conditions 
 
Learning disability 
(L), 
Cognitive disturbance 
Leukoencephalopathy1 
(L) 
 
Late: 
Any time after 
completion 
of 
treatment 
 
 
Progressive CNS 
deterioration1 
 
Unknown Frequency and Timing: Fetal and teratogenic toxicities:  
 
1 May be enhanced by HDMTX and/or cranial irradiation. (L) 
Toxicity may also occur later. 
 
6.4.3 Formulation and Stability: 
Intact vials may be stored at room temperature (22°-25°C) and are stable for at least 2 years or 
until date of expiration. IT MTX: Available in various dosages in preservative-free liquid, 25 
mg/mL in a 2 mL vial, or as a lyophilized powder. Reconstitute the powder with buffered saline 
solution. The methotrexate solutions may be further diluted with buffered saline or the patient’s 
own CSF. After mixing it should be used within 24 hours, since MTX contains no antibacterial 
preservative. 
 
6.4.4 Guidelines for Administration: 
See Treatment and Dose Modification sections of the protocol. 
 
6.4.5 Supplier: 
All forms of methotrexate are commercially available. See package insert for further information. 

TACL Protocol:  
T2012-002  
Original Version Date: 14-May-2016  
Activated: 
                 28-Jul-2016  
Amendment #1 Date: 16-Mar-2017 
 
 
Amendment #2 Date: 16-Jul-2018 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
T2012-002 Original Version Date: 14-May-2016   
CONFIDENTIAL 
Amendment #1 Date: 16-Mar-2017 
TACL Internal Distribution Only 
Amendment #2 Date: 16-Jul-2018  
47 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
6.5  
Pegaspargase 
(Pegaspargase, 
PEGLA, 
PEG-L-asparaginase, 
polyethylene 
glycol-L-asparaginase, 
Oncaspar®,) NSC #624239. 
 
6.5.1 Source and Pharmacology: 
Pegaspargase is a modified version of the enzyme L-asparaginase. L- asparaginase is modified 
by covalently conjugating units of monomethoxypolyethylene glycol (PEG), molecular weight of 
5000, to the enzyme, forming the active ingredient PEG-L-asparaginase. The L-asparaginase (L-
asparagine amidohydrolase, type EC-2, EC 3.5.1.1) used in the manufacture of Pegaspargase is 
derived from Escherichia coli which is purchased in bulk from Merck, Sharp and Dohme. L-
asparagine is a nonessential amino acid synthesized by the transamination of L-aspartic acid by 
a reaction catalyzed by the enzyme L-asparagine synthetase. The ability to synthesize asparagine 
is notably lacking in malignancies of lymphoid origin. Asparaginase depletes L- asparagine from 
leukemic cells (especially lymphoblasts) by catalyzing the conversion of L-asparagine to aspartic 
acid and ammonia. In predominately L- asparaginase naïve adult patients with leukemia and 
lymphoma, initial plasma levels of L-asparaginase following intravenous administration of 
pegaspargase were determined. Apparent volume of distribution was equal to estimated plasma 
volume. L-asparaginase was measurable for at least 15 days following the initial treatment with 
Pegaspargase. The approximate t½ in adult patients is 5.73 days. The enzyme could not be 
detected in the urine. The half-life is independent of the dose administered, disease status, renal 
or hepatic function, age, or gender. In a study of newly diagnosed pediatric patients with ALL who 
received either a single intramuscular injection of pegaspargase (2500 IU/m2), E. coli L-
asparaginase (25000 IU/m2), or Erwinia (25000 IU/m2), the plasma half-lives for the three forms 
of L-asparaginase were: 5.73 ± 3.24 days, 1.24 ± 0.17 days, and 0.65 ± 0.13 days respectively. 
The plasma half-life of pegaspargase is shortened in patients who are previously hypersensitive 
to native L-asparaginase as compared to nonhypersensitive patients. L-asparaginase is cleared 
by the reticuloendothelial system and very little is excreted in the urine or bile. Cerebrospinal fluid 
levels are < 1% of plasma levels. 
 
6.5.2 Toxicity: 
 

TACL Protocol:  
T2012-002  
Original Version Date: 14-May-2016  
Activated: 
                 28-Jul-2016  
Amendment #1 Date: 16-Mar-2017 
 
 
Amendment #2 Date: 16-Jul-2018 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
T2012-002 Original Version Date: 14-May-2016   
CONFIDENTIAL 
Amendment #1 Date: 16-Mar-2017 
TACL Internal Distribution Only 
Amendment #2 Date: 16-Jul-2018  
48 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
Common 
Happens 
to 
21-100 
children out of every 100 
Occasional 
Happens to 5-20 children 
out of every 100 
Rare 
Happens to <5 children 
out of every 100 
Immediate: 
Within 1-2 days 
of receiving drug 
Allergic reactions (total 
likelihood of local, and or 
systemic 
reaction 
especially 
if 
previous 
hypersensitivity reaction 
to native asparaginase), 
pain 
at 
injection 
site, 
weakness, 
fatigue, 
diarrhea 
Allergic 
reactions 
(total 
likelihood of local, and or 
systemic reaction if no 
previous 
hypersensitivity 
reaction 
to 
native 
asparaginase), rash 
Anaphylaxis, 
hyper/hypotension, 
tachycardia, periorbital 
edema, 
chills, 
fever, 
dizziness, 
dyspnea, 
bronchospasm, 
lip 
edema, 
arthralgia, 
myalgia, urticaria, mild 
nausea/vomiting, 
abdominal 
pain, 
flatulence, somnolence, 
lethargy, headache, 
seizures 
(L), 
hyperuricemia 

TACL Protocol:  
T2012-002  
Original Version Date: 14-May-2016  
Activated: 
                 28-Jul-2016  
Amendment #1 Date: 16-Mar-2017 
 
 
Amendment #2 Date: 16-Jul-2018 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
T2012-002 Original Version Date: 14-May-2016   
CONFIDENTIAL 
Amendment #1 Date: 16-Mar-2017 
TACL Internal Distribution Only 
Amendment #2 Date: 16-Jul-2018  
49 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
Common 
Happens 
to 
21-100 
children out of every 100 
Occasional 
Happens to 5-20 children 
out of every 100 
Rare 
Happens to <5 children 
out of every 100 
Prompt: 
Within 2-3 weeks, 
prior to the next 
course 
Hyperammonemia 
(L), 
coagulation abnormalities 
with prolonged PTT, PT 
and 
bleeding 
times 
(secondary to decreased 
synthesis of fibrinogen, 
AT-III & other clotting 
factors) (L) 
Hyperglycemia, 
abnormal 
liver 
function 
tests, 
pancreatitis (L), increased 
serum lipase/amylase 
Hemorrhage (L), DIC, 
thrombosis, 
anorexia, 
weight 
loss, 
CNS 
ischemic 
attacks, 
edema, azotemia and 
decreased 
renal 
function, 
mild 
leukopenia, 
granulocytopenia, 
thrombocytopenia, 
pancytopenia, hemolytic 
anemia, 
infections 
(sepsis 
with/without 
septic shock, subacute 
bacterial 
endocarditis 
(SBE), 
URI), 
CNS 
changes 
including 
irritability, 
depression, 
confusion, 
EEG 
changes, hallucinations, 
coma 
and 
stupor, 
paresthesias, 
hypertriglyceridemia, 
hyperlipidemia, 
Parkinson- 
like 
syndrome with tremor 
and increase in muscular 
tone, hyperbilirubinemia, 
chest pain 
Delayed: 
Any 
time later 
during 
therapy, 
excluding 
the 
above conditions 
 
 
Renal 
failure, urinary 
frequency, hemorrhagic 
cystitis, 
elevated 
creatinine and BUN, fatty 
liver 
deposits, 
hepatomegaly, liver 
failure 

TACL Protocol:  
T2012-002  
Original Version Date: 14-May-2016  
Activated: 
                 28-Jul-2016  
Amendment #1 Date: 16-Mar-2017 
 
 
Amendment #2 Date: 16-Jul-2018 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
T2012-002 Original Version Date: 14-May-2016   
CONFIDENTIAL 
Amendment #1 Date: 16-Mar-2017 
TACL Internal Distribution Only 
Amendment #2 Date: 16-Jul-2018  
50 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
Common 
Happens 
to 
21-100 
children out of every 100 
Occasional 
Happens to 5-20 children 
out of every 100 
Rare 
Happens to <5 children 
out of every 100 
Unknown Frequency and Timing: Animal reproduction studies have not been conducted with 
pegaspargase. It is not known whether pegaspargase can cause fetal harm when administered to a 
pregnant woman or can affect reproduction capacity. However, fetal toxicities and teratogenic effects 
of asparaginase have been noted in animals. It is unknown whether the drug is excreted in br east 
milk. 
(L) Toxicity may also occur later. 
 
6.5.3 Formulation and Stability 
Each milliliter of pegaspargase contains: PEG-L-asparaginase 750 IU ± 20%, monobasic sodium 
phosphate, USP 1.20 mg ± 5% dibasic sodium phosphate, USP 5.58 mg ± 5%, sodium chloride, 
USP 8.50 mg ± 5% , Water for Injection, USP qs to 1 mL. The specific activity of pegaspargase 
is at least 85 IU per milligram protein. Available in 5 mL vials as Sterile Solution for Injection in 
ready to use single-use vials, preservative free. Keep refrigerated at 2°-8°C (36°- 46°F). Do not 
use if stored at room temperature for more than 48 hours. DO NOT FREEZE. Do not use product 
if it is known to have been frozen. Freezing destroys activity, which cannot be detected visually. 
 
6.5.4 Guidelines for Administration 
For IM administration: the volume at a single injection site should be limited to 2 mL. If the volume 
to be administered is greater than 2 mL, multiple injection sites should be used. For IV 
administration: dilute pegaspargase in 100 mL of 0.9% sodium chloride injection (0.9% NaCl) or 
5% dextrose injection (D5W) and infuse over 1 to 2 hours through a NS or D5W running infusion 
line. Pegaspargase admixed in 100 mL of NS or D5W is stable for 48 hours at room temperature. 
Pegaspargase diluted in 100 mL of 0.9% NaCl is stable for up to 72 hours refrigerated (4ºC [39°F]) 
(refrigerated stability data on file with Sigma-Tau). Avoid excessive agitation. DO NOT SHAKE. 
Do not use if cloudy of if precipitate is present. Have available during and after the infusion: 
antihistamine, epinephrine, oxygen, and IV corticosteroids. Observe patient for at least ONE hour 
after administration for signs of hypersensitivity reactions or per institutional standards.  
 
6.5.5 Supplier: 
Commercially available. See package insert for further information. 
 
6.6  
ASPARAGINASE  Erwinia chrysanthemi (Erwinaze®) or cristantapase (Erwinase®) or Erwinia  
chrysanthemi (recombinant)-rywn (Rylaze®)  
 
6.6.1 Source and Pharmacology: 
L-asparagine is a nonessential amino acid synthesized by the transamination of L-aspartic acid 
by a reaction catalyzed by the enzyme L-asparagine synthetase. Neoplastic cells associated with 
acute lymphoblastic leukemia, acute myeloid leukemia and lymphoblastic lymphosarcoma are 
asparagine-dependent but lack asparagine synthetase activity. The administration of 
Lasparaginase produces an anti-neoplastic effect by catalyzing asparagine into aspartic acid and 
ammonia. As a result, these cells lack the ability to produce the asparagine necessary for protein 

TACL Protocol:  
T2012-002  
Original Version Date: 14-May-2016  
Activated: 
                 28-Jul-2016  
Amendment #1 Date: 16-Mar-2017 
 
 
Amendment #2 Date: 16-Jul-2018 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
T2012-002 Original Version Date: 14-May-2016   
CONFIDENTIAL 
Amendment #1 Date: 16-Mar-2017 
TACL Internal Distribution Only 
Amendment #2 Date: 16-Jul-2018  
51 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
metabolism and survival. Deamination of glutamine may also play a role in the antineoplastic 
activity of asparaginase.  
 
Erwinia chrysanthemi [Erwinaze® or Cristantapase (Erwinase®)] is asparaginase derived from 
cultures of Erwinia chrysanthemi. L-asparaginase is a tetrameric enzyme; each of the four 
identical subunits has a molecular weight of approximately 35 kDa. Asparaginase Erwinia 
chrysanthemi is immunologically distinct from E. coli L-asparaginase and may allow continued 
asparaginase therapy when a hypersensitivity reaction occurs to Escherichia coli-derived 
asparaginase. The package labeling states that there is insufficient information to characterize 
the incidence of antibodies to asparaginase Erwinia chrysanthemi. Several factors are involved in 
immunogenicity assay results and the assessment of antibodies, including assay methodology, 
assay sensitivity and specificity, sample handling, timing of sample collection, concomitant 
medications, and the underlying disease state. The following data have been reported on each of 
the three preparations of asparaginase: 
 
Clinical Pharmacology of 
Asparaginase Formulation 
Fetal toxicities and teratogenic 
effects of mitoxantrone have 
been 
noted 
in 
animals. 
Toxicities include: low birth 
weight 
and 
prematurity. 
Mitoxantrone is excreted in 
human milk and significant 
concentrations (18 ng/mL) 
have been reported for 28 
days 
after 
the 
last 
administration. 
% Anti-Asparaginase 
Antibody positive patients 
Native Escherichia Coli 
26-30 hours 
45-75 
Pegylated-asparaginase 
5.5-7 days 
5-18 
Erwinia Asparaginase 
16 hours (7-13 hrs) 
30-50 
From: Avramis, V; Panosyan, E; Pharmacokinetic/Pharmacodynamic Relationships of 
Asparaginase Formulations: The Past, the Present and Recommendations for the Future. Clin 
Pharmacokinet 2005; 44 (4): 367-393. 
 
Effective asparaginase levels have been defined as activity of ≥ 0.1 International Units per mL. 
Clinical trials with asparaginase Erwinia chrysanthemi (Ewinaze) demonstrated that 100% of 
patients achieved effective asparaginase levels at 48 and 72 hours (n=35 and n=13, respectively) 
following the third total dose when given on a Monday, Wednesday, Friday schedule. No formal 
drug interaction studies have been performed with asparaginase Erwinia chrysanthemi. 
 
 
Asparaginase erwinia chrysanthemi (recombinant)-rywn contains an asparagine specific bacterial 
enzyme (L-asparaginase). L-asparaginase is a tetrameric enzyme that consists of four identical 35 
kDa subunits with a combined molecular weight of 140 kDa. The amino acid sequence is identical to 
native asparaginase Erwinia chrystanthemi (also known as crisantapase). The activity of 

TACL Protocol:  
T2012-002  
Original Version Date: 14-May-2016  
Activated: 
                 28-Jul-2016  
Amendment #1 Date: 16-Mar-2017 
 
 
Amendment #2 Date: 16-Jul-2018 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
T2012-002 Original Version Date: 14-May-2016   
CONFIDENTIAL 
Amendment #1 Date: 16-Mar-2017 
TACL Internal Distribution Only 
Amendment #2 Date: 16-Jul-2018  
52 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
asparaginase erwinia chrysanthemi (recombinant)-rywn is expressed in units, defined as the amount 
of enzyme that catalyzes the conversion of 1μmol of L-asparagine per reaction minute, per mg of 
protein. Asparaginase erwinia chrysanthemi (recombinant)-rywn is produced by fermentation of a 
genetically engineered Pseudomonas fluorescens bacterium containing the DNA which encodes for 
asparaginase Erwinia chrysanthemi. 
 
6.6.2 Toxicity: 
 
Common 
Happens 
to 
21-100 
children out of every 100 
Occasional 
Happens 
to 
5-20 
children out of every 100 
Rare 
Happens to <5 children out 
of every 100 
Immediate: 
Within 1-2 days 
of receiving drug 
 
Allergic reactions 
Anaphylaxis, urticaria 
Local 
injection 
site 
reactions, fever 
Prompt: 
Within 
2-3 
weeks, prior to 
the next course 
 
 
Pancreatitis, 
glucose 
intolerance, 
thrombosis, 
hemorrhage, 
transient 
ischemic 
attack, 
disseminated intravascular 
coagulation, 
hyperbilirubinemia, alanine 
aminotransferase 
increased, 
aspartate 
aminotransferase 
increased, hyperglycemia, 
hyperammonemia, 
vomiting, 
nausea, 
abdominal pain, headache, 
diarrhea, seizure 
Unknown Frequency and Timing: Fetal toxicities and teratogenic effects of L-asparaginase have 
been noted in animals. It is unknown whether the drug is excreted in breast milk. Adequate, well-
controlled studies of asparaginase Erwinia chrysanthemi have NOT been conducted. It is not known 
whether asparaginase Erwinia chrysanthemi will cause fetal harm or affect the ability to reproduce. It 
is not known if asparaginase Erwinia chrysanthemi is excreted into breast milk. The use of 
asparaginase Erwinia chrysanthemi should be avoided in pregnant or lactating patients. 
 
6.6.3 Formulation and Stability 
Asparaginase Erwinia chrysanthemi is supplied as a sterile, white lyophilized powder for 
reconstitution in a clear glass vial with a 3 mL capacity. Each vial contains 10,000 International 
Units of asparaginase Erwinia chrysanthemi and the following inactive ingredients: glucose 
monohydrate (5.0 mg), sodium chloride (0.5 mg). Store between 2°C and 8°C (36° to 46ºF). Store 
intact vials between 2°C and 8°C (36°- 46ºF). Protect from light. 
 
Asparaginase erwinia chrysanthemi (recombinant)-rywn) Rylaze®) injection is supplied as a sterile, 
clear to opalescent, colorless to slightly yellow, preservative-free solution for intramuscular injection. 

TACL Protocol:  
T2012-002  
Original Version Date: 14-May-2016  
Activated: 
                 28-Jul-2016  
Amendment #1 Date: 16-Mar-2017 
 
 
Amendment #2 Date: 16-Jul-2018 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
T2012-002 Original Version Date: 14-May-2016   
CONFIDENTIAL 
Amendment #1 Date: 16-Mar-2017 
TACL Internal Distribution Only 
Amendment #2 Date: 16-Jul-2018  
53 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
Each 0.5 mL contains 10 mg asparaginase erwinia chrysanthemi (recombinant)-rywn and the inactive 
ingredients: polysorbate 80 (0.1 mg), sodium chloride (1.5 mg), sodium phosphate dibasic anhydrous 
(0.8 mg), sodium phosphate monobasic monohydrate (0.6 mg), and trehalose (32.1 mg). Sodium 
hydroxide may be added to adjust the pH. The pH is approximately 7. 
 
6.6.4 Guidelines for Administration 
Follow manufacturer guidelines for preparation and administration.  No more than 2 mL should be 
given at any one injection site. Doses larger than 2 mL should be divided and given in separate 
administration sites. 
 
6.6.5 Supplier: 
 
Commercially available. See package insert for further information. 
 
6.7  
Mercaptopurine 
 
6.7.1 Source and Pharmacology (MP, purinethol®, 6-mercaptopurine) NSC#000755 
Mercaptopurine is an analogue of the purine bases adenine and hypoxanthine. The main intracellular 
pathway for MP activation is catalyzed by the enzyme hypoxanthine-guanine phosphoribosyl transferase 
(HGPRT) which catalyzes the conversion of MP to several active nucleotide metabolites including 
thioinosinic acid, a ribonucleotide which can interfere with various metabolic reactions necessary for 
nucleic acid (RNA and DNA) biosynthesis. It can also cause pseudofeedback inhibition of the first step 
in de novo purine biosynthesis or convert to another ribonucleotide which can cause feedback inhibition. 
Mercaptopurine can be incorporated into DNA in the form of 6-TG nucleotides as well and thus produce 
toxicity. The absorption of an oral dose of MP is incomplete and variable, with only about 16%-50% of 
an administered dose reaching the systemic circulation secondary to a first pass metabolism in the liver. 
Food intake and co-administration with cotrimoxazole (TMP/SMX) significantly reduces absorption of 
MP. After IV administration, MP has a plasma half-life of 21 minutes in children and 47 minutes in adults. 
Approximately 19% is bound to protein. Mercaptopurine is well distributed into most body compartments 
except the CSF. (With high dose IV MP the CSF to plasma ratio is 0.15) MP is metabolized by xanthine 
oxidase in the liver to 6-Thiouric acid an inactive metabolite. In patients receiving both MP and allopurinol 
(a xanthine oxidase inhibitor) the dose of MP must be reduced by 50-75%. Since TPMT, 6-thiopurine 
methyltransferase, is also one of the enzymes involved in the metabolism of  MP, those individuals who 
have an inherited deficiency of the enzyme may be unusually sensitive to the myelosuppressive effects 
of MP and prone to develop rapid bone marrow suppression following the initiation of treatment. 
Mercaptopurine is excreted in urine as metabolites and some unchanged drug; about half an oral dose 
has been recovered in 24 hours. A small proportion is excreted over several weeks.  
 
6.7.2. Toxicology 
 
Incidence 
Toxicities 

TACL Protocol:  
T2012-002  
Original Version Date: 14-May-2016  
Activated: 
                 28-Jul-2016  
Amendment #1 Date: 16-Mar-2017 
 
 
Amendment #2 Date: 16-Jul-2018 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
T2012-002 Original Version Date: 14-May-2016   
CONFIDENTIAL 
Amendment #1 Date: 16-Mar-2017 
TACL Internal Distribution Only 
Amendment #2 Date: 16-Jul-2018  
54 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
Common 
(>20% 
of 
patients)  
Neutrophil count decreased, white blood cell decreased, anorexia, fatigue  
Occasional 
(4 - 20% of 
patients)  
diarrhea, nausea, vomiting, malaise, oligospermia, infection, fever, platelet 
count decreased, anemia, mucositis, stomach pain, ulcerative bowel lesion, 
skin rash, alanine aminotransferase increased, aspartate aminotransferase 
increased  
Rare 
(≤3% 
of 
patients) 
Urticaria, skin hyperpigmentation, alopecia, hyperuricemia, hepatic failure, 
hepatic necrosis, blood bilirubin increased, pulmonary fibrosis, secondary 
malignant neoplasm, renal toxicity, uricosuria, pancreatitis  
 
Pregnancy Category D  
Mercaptopurine can cause fetal harm, including an increased incidence of abortion and stillbirth. Advise 
women to avoid becoming pregnant while receiving mercaptopurine. Mercaptopurine was embryo-lethal 
and teratogenic in several animal species (rat, mouse, rabbit, and hamster). It is not known whether 
mercaptopurine is excreted in human milk; breastfeeding should be avoided.  
 
 
6.7.3 Formulation and Stability: 
Mercaptopurine is available as a 50 mg tablet containing mercaptopurine and the inactive 
ingredients corn and potato starch, lactose, magnesium stearate, and stearic acid. Store at 15°-
25°C (59°-77°F) in a dry place. In the United States, mercaptopurine is also available as an oral 
suspension in a concentration of 20 mg/mL (2000 mg/100 mL per bottle). The oral suspension is 
a pink to brown viscous liquid supplied in amber glass multiple-dose bottles with a child resistant 
closure. It should be stored at 15°-25°C (59°-77°F) in a dry place.  
NOTE: the concentration of the commercially available suspension (20 mg/mL) and the compounded 
suspension (50 mg/mL) are NOT the same; doses should be prescribed in the milligrams required, not 
mL.  
 
 
6.7.4 Guidelines for Administration 
 
Guidelines for Administration: See Treatment and Dose Modifications sections of the protocol.  
Mercaptopurine should be taken consistently at the same time every day. If allopurinol is also given, the 
oral dose of mercaptopurine should be reduced by 67-75%. Patients with severe myelosuppression 
should have their thiopurine S-methyltransferase (TPMT) status and/or their thiopurine metabolite 
concentrations evaluated, so that the dose of mercaptopurine be reduced in patients with a TPMT defect. 
Patients with the rare homozygous deficient TPMT phenotype may tolerate only 1/10th to 1/20th the 

TACL Protocol:  
T2012-002  
Original Version Date: 14-May-2016  
Activated: 
                 28-Jul-2016  
Amendment #1 Date: 16-Mar-2017 
 
 
Amendment #2 Date: 16-Jul-2018 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
T2012-002 Original Version Date: 14-May-2016   
CONFIDENTIAL 
Amendment #1 Date: 16-Mar-2017 
TACL Internal Distribution Only 
Amendment #2 Date: 16-Jul-2018  
55 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
average mercaptopurine dose. TPMT testing and thiopurine metabolite measurements are commercially 
available.  
6.7.5 Supplier: 
 
Commercially available. See package insert for further information. 
 
Suspension: 
For children unable to swallow the tablets whole, a 50 mg/mL oral suspension can be compounded. The 
suspension is prepared by crushing 50 mercaptopurine 50 mg tablets in a mortar and adding 8.5 mL 
sterile water for irrigation. The mixture is triturated to form a smooth paste. Next, 16.5 mL simple syrup 
(pH=7) are added with continuous mixing and finally cherry syrup (pH=7.1) is added to a total volume of 
50 mL. The suspension is stable in amber glass bottles at room temperature (19oC -23oC) for up to 5 
weeks. The suspension should be shaken well before each use. Procedures for proper handling and 
disposal of cytotoxic drugs should be used when preparing the suspension. (Aliabadi HM, Romanick M, 
Desai S et al. Effect of buffer and antioxidant on stability of mercaptopurine suspension. Am J Heath-
Syst Pharm. 65:441-7, 2008).  
Supplier: The tablets are commercially available from various manufacturers. In the United States, the 
commercially available oral suspension is available through AnovoRx Distribution, LLC (1-888-470- 
0904). See package insert for further information. PLEASE NOTE there is a difference in the 
concentration of the commercially available (20 mg/mL) and extemporaneously compounded (50 
mg/mL) oral suspensions.  
 
 
7.0  
REQUIRED OBSERVATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
 
7.1  
Clinical and Laboratory Studies 
All entry/eligibility studies must be performed within one week prior to study enrollment 
(“PreEnrollment”) unless specified otherwise (e.g., Disease evaluation is required within two 
weeks prior to study enrollment. Obtain other studies as needed for good patient care.) Some 
evaluations will need to be performed within 3 days prior to starting therapy (“Pre-Treatment”). 
 
STUDIES TO BE 
OBTAINED 
 
Pre- 
Enrollment* 
Pre-Treatment 
(within 3 days 
prior to starting 
protocol therapy) 
During 
Course 
1 
(Cohort 
A 
and B) 
During 
Course 
1 
(Cohort C) 
Final Visit/ 
Follow-up 
History 
X 
X 
 
 
X 
Physical Exam 
X 
X 
Weekly 
Weekly 
X 
Vital Signs 
X 
X 
Weekly 
Weekly 
X 
Height, Weight, BSA X 
X 
 
 
X 

TACL Protocol:  
T2012-002  
Original Version Date: 14-May-2016  
Activated: 
                 28-Jul-2016  
Amendment #1 Date: 16-Mar-2017 
 
 
Amendment #2 Date: 16-Jul-2018 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
T2012-002 Original Version Date: 14-May-2016   
CONFIDENTIAL 
Amendment #1 Date: 16-Mar-2017 
TACL Internal Distribution Only 
Amendment #2 Date: 16-Jul-2018  
56 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
STUDIES TO BE 
OBTAINED 
 
Pre- 
Enrollment* 
Pre-Treatment 
(within 3 days 
prior to starting 
protocol therapy) 
During 
Course 
1 
(Cohort 
A 
and B) 
During 
Course 
1 
(Cohort C) 
Final Visit/ 
Follow-up 
CBC, 
differential, 
platelets 
X 
X 
Twice weekly 
including at 
least within 1 
day prior to 
Marqibo® 
doses #2, 3 
and 4 
Twice 
weekly 
X 
Chemistries1 
X 
X 
Twice 
Weekly, 
including at 
least within 1 
day prior to 
Marqibo® 
doses #2, 3 
and 4 
Twice 
weekly 
X 
Electrolytes2 
X 
X 
Twice 
Weekly, 
including at 
least within 1 
day prior to 
Marqibo® 
doses #2, 3 
and 4 
Twice 
weekly 
X 
HIV 
X^ 
 
 
 
 
HBsAg, HCV 
X^ 
 
 
 
 
Urine pregnancy or 
Serum β-HCG (for 
females 
of 
childbearing 
potential) 
X 
 
If pregnancy 
is suspected 
If 
pregnancy 
is 
suspected 
 
Echocardiogram/  
MUGA/Cardiac MRI X^ 
 
 
 
 

TACL Protocol:  
T2012-002  
Original Version Date: 14-May-2016  
Activated: 
                 28-Jul-2016  
Amendment #1 Date: 16-Mar-2017 
 
 
Amendment #2 Date: 16-Jul-2018 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
T2012-002 Original Version Date: 14-May-2016   
CONFIDENTIAL 
Amendment #1 Date: 16-Mar-2017 
TACL Internal Distribution Only 
Amendment #2 Date: 16-Jul-2018  
57 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
STUDIES TO BE 
OBTAINED 
 
Pre- 
Enrollment* 
Pre-Treatment 
(within 3 days 
prior to starting 
protocol therapy) 
During 
Course 
1 
(Cohort 
A 
and B) 
During 
Course 
1 
(Cohort C) 
Final Visit/ 
Follow-up 
Neurological 
Examination/ 
Completion 
of 
Neurological Exam 
Form (Appendix 4). 
X 
X 
Weekly 
including at 
least within 1 
day prior to 
Marqibo® 
doses #2, 3 
and 4 
Weekly 
X 
EKG 
X 
 
Day 8 (+/- 2 
days) [cohort 
A only] 
 
 
CSF Cell count and 
Differential (with IT 
Therapy if needed as 
per Section 4.1) 
 
X^ 
 
At the time of 
LP 
for 
IT 
therapy and at 
restaging on 
day 29† (+/- 2 
days) 
At the time 
of LP for IT 
therapy 
if 
given and at 
restaging 
on day 14 
(+2) or day 
29 (+/-2) if 2 
cycles are 
given§ 
 
Bone 
marrow 
aspirate 
and/or 
biopsy for response 
assessment (Section 
7.3) 
X^ 
 
Day 29 (+/- 2 
days) 
Day 14 (+2) 
or day 29 
(+/-2 days) §  
Bone marrow sample 
for MRD 
X^# 
Bone marrow 
need not be 
repeated for 
this purpose. 
 
Day 29 (+/- 2 
days) 
 
 
Pharmacokinetic 
Studies 
(required) 
May 
be collected 
through the line used 
for 
Marqibo® 
infusion. 
 
 
Immediately 
prior to 
Marqibo 
administration 
for Marqibo 
doses #1, 2, 
and 3 for arm 
A and B. 
Arm C will 
be obtained 
prior 
to 
Dose 1 and 
a 
trough 
level on day 
8, 
during 
each cycle. 
 

TACL Protocol:  
T2012-002  
Original Version Date: 14-May-2016  
Activated: 
                 28-Jul-2016  
Amendment #1 Date: 16-Mar-2017 
 
 
Amendment #2 Date: 16-Jul-2018 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
T2012-002 Original Version Date: 14-May-2016   
CONFIDENTIAL 
Amendment #1 Date: 16-Mar-2017 
TACL Internal Distribution Only 
Amendment #2 Date: 16-Jul-2018  
58 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
STUDIES TO BE 
OBTAINED 
 
Pre- 
Enrollment* 
Pre-Treatment 
(within 3 days 
prior to starting 
protocol therapy) 
During 
Course 
1 
(Cohort 
A 
and B) 
During 
Course 
1 
(Cohort C) 
Final Visit/ 
Follow-up 
 
Peripheral Blood for 
Pharmacokinetic 
Studies (optional) 
 
 
 
Day 1 (3 blood 
samples) 
Day 1 (3 
blood 
samples) 
 
Follow-up visit 
 
 
 
 
Q 6months 
*Required for verification of eligibility. FAX or email all results to the TACL Operations Center 
with study registration eligibility. If a patient has labs done prior to study entry that establish 
eligibility, then abnormal Day 1 labs do not deem them ineligible. 
#Optional 
^Within 2 weeks prior to enrollment is acceptable 
†IT chemotherapy is not required at the time of day 29 LP, but can be given per investigator 
discretion. 
§Cohort C disease restaging will be done after cycle 1, if only one cycle is administered. If a 
second cycle is planned, restaging may be done after cycle 2. Please see section 7.3 for 
additional guidance. A lumbar puncture will only be required after 2 cycles; and is optional after 
cycle 1.  
1: BUN, creatinine, ALT, AST, LDH, alkaline phosphatase, glucose, total and direct bilirubin, 
albumin, total protein, uric acid 
2: Sodium, potassium, chloride, bicarbonate, calcium, magnesium, phosphorus 
 
7.2 
Required Supportive Care Therapies During Protocol Treatment 
 
The following supportive care measures are required by protocol: 
• 
Antifungal prophylaxis (mandatory only for Cohorts A and B): 
o Non-azole based anti-fungal prophylaxis is mandated in all subjects enrolled in 
Cohorts A and B from the start of therapy until day 29, and ideally until neutrophil 
count recovery. All subjects are encouraged to continue antifungal prophylaxis 
beyond the treatment period especially if neutrophil count recovery has not 
occurred. Any exceptions must be discussed with the Study Chair or Vice Chair. 
(See protocol section 5.2).  

TACL Protocol:  
T2012-002  
Original Version Date: 14-May-2016  
Activated: 
                 28-Jul-2016  
Amendment #1 Date: 16-Mar-2017 
 
 
Amendment #2 Date: 16-Jul-2018 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
T2012-002 Original Version Date: 14-May-2016   
CONFIDENTIAL 
Amendment #1 Date: 16-Mar-2017 
TACL Internal Distribution Only 
Amendment #2 Date: 16-Jul-2018  
59 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
o All azole therapy must be discontinued at least 1 week prior to the start of initiation 
of protocol therapy with Marqibo®. 
• 
Pneumocystis prophylaxis: 
o PJP prophylaxis is required, with agents and dosing provided according to 
institutional guidelines. (See protocol section 5.2) 
• 
Bowel prophylaxis 
o All patients must receive prophylaxis against constipation starting with the first 
dose of Marqibo unless there is diarrhea. (See protocol section 5.5 and Appendix 
6) 
 
 
7.3  
Disease Evaluations During Therapy 
 
All patients should have a bone marrow aspirate/biopsy and lumbar puncture and CBC to assess 
response on day 29 (+/- 2 days)**.  
 
**For cohort C: Restaging studies should be performed on day 14 (+ 2 days) of cycle 1, with the 
exception of those patients who proceed to a second cycle. Cohort C, cycle 2 may start on Day 15 
– 22 of cycle 1. If a second cycle is administered, a single restaging on day 14 (+2 days) of cycle 2 
is required. In summary, a day 14 (+2 days) evaluation is required in all subjects at the completion 
of treatment on cohort C, either after cycle 1 (if a second cycle is not administered), or after cycle 2. 
A day 14 evaluation will not be required in either scenario in the presence of circulating peripheral 
blasts.  
 
A bone marrow procedure need not be performed if the patient has an absolute peripheral blast 
count (APBC) greater than or equal to 2,500/µL in the peripheral blood. 
 
If the marrow is hypoplastic, and counts have not recovered to ANC > 500/µL and platelets > 
50,000/µL repeat CBC weekly until recovery or progression. 
 
If the patient has a M1 marrow but has not achieved an ANC > 500/µL and platelets > 50,000/µL, 
repeat CBC weekly and bone marrow every 1-4 weeks until count recovery or relapse. 
 
 
 
7.4  
Research Studies 
 
Participation in pharmacokinetic (PK) studies is mandatory for a limited sample set, for which 
samples can be drawn from the same line used to administer Marqibo®. Institutional guidelines 
should be followed in regard to maximum blood draw limits for pediatric patients. 
 
Participation in the collection of the Dose 1 PK specimens is encouraged but is voluntary 
and patients may still participate in the therapeutic part of the study if they decline participation in 

TACL Protocol:  
T2012-002  
Original Version Date: 14-May-2016  
Activated: 
                 28-Jul-2016  
Amendment #1 Date: 16-Mar-2017 
 
 
Amendment #2 Date: 16-Jul-2018 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
T2012-002 Original Version Date: 14-May-2016   
CONFIDENTIAL 
Amendment #1 Date: 16-Mar-2017 
TACL Internal Distribution Only 
Amendment #2 Date: 16-Jul-2018  
60 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
the research samples. Institutions are encouraged to talk to their patients about participation. The 
more detailed PK studies, require samples to be drawn from a line separate from the one used to 
administer Marqibo®. 
 
7.4.1 Bone Marrow MRD 
 
Samples 
requested: 
Bone Marrow Sample for MRD 
• 
Pre-treatment: optional* 
• 
Day 29 (+/- 2 days) 
Sample should also be submitted if the bone marrow procedure is 
repeated after day 29 to document marrow and count recovery.* Repeat 
bone marrow for this purpose is not required. For patients with circulating 
blasts, 10 mL of peripheral blood in a heparinized tube may be submitted. 
For all patients, prior flow cytometry report should be submitted. 
 
*Bone Marrow MRDs are performed as part of standard of care, however, 
the information from them will be used for research purposes. 
 
Not required for cohort C.  
Bone 
marrow 
Collection 
procedure: 
• 
Collect minimum of 2 mL of marrow into a syringe and place marrow 
into a large purple EDTA tube that are commonly used in all hospitals. 
Mix well. 
• 
Use multiple syringes and tubes as needed. Reposition marrow 
aspirate needle as least once during procedure to ensure the 
maximum quality of marrow 
Specimen Labeling: Please refer to the TACL MRD Lab Manual for instructions regarding 
specimen labeling.  
Specimen 
Packaging 
and 
Shipping: 
 
 
 
Please refer to the TACL MRD Lab Manual for instructions regarding 
specimen packaging and shipping.  
 
*Results from MRD assessments must be forwarded to TACL Operations at tacl@chla.usc.edu 
 
7.4.2  Marqibo® Pharmacokinetic Studies (Mandatory and Optional Studies) 
 
Participation in PK studies is mandatory for a limited set, for which samples can be drawn 
from the same line used to administer Marqibo®. These studies include a baseline level 
drawn prior to the first dose and trough levels prior to the second and third dose of 

TACL Protocol:  
T2012-002  
Original Version Date: 14-May-2016  
Activated: 
                 28-Jul-2016  
Amendment #1 Date: 16-Mar-2017 
 
 
Amendment #2 Date: 16-Jul-2018 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
T2012-002 Original Version Date: 14-May-2016   
CONFIDENTIAL 
Amendment #1 Date: 16-Mar-2017 
TACL Internal Distribution Only 
Amendment #2 Date: 16-Jul-2018  
61 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
Marqibo®. Participation in more detailed PK studies, which require samples to be drawn 
from a separate line than the one used to administer Marqibo® are voluntary. (Appendix 
7). 
 
The mandatory PK samples will be collected at the following time points for arm A and B.  
• 
Generally performed 30-60 minutes before start of dose 1 infusion (SOI) ±10 
minutes, but may be performed with routine morning labs as long as it is before 
start of infusion. 
• 
Pre-dose #2 (trough level), up to 1 hour pre-dose is acceptable 
• 
Pre-dose #3 (trough level), up to 1 hour pre-dose is acceptable 
 
For cohort C, the mandatory PK samples will be drawn 30-60 minutes before start of dose 
1 infusion (SOI) ±10 minutes, but may be performed with routine morning labs as long as 
it is before start of infusion; and a trough level will be drawn anytime on day 8.  
 
 
The voluntary PK samples will be collected at the following time points (all cohorts): 
 
• 
End of Infusion (EOI) of dose 1 ±5 minutes 
• 
3 hours (EOI + 2 hours) ±15 minutes 
• 
25 hours (EOI + 24 hours) ±30 minutes 
 
Analysis will be conducted in the laboratory of the NCI POB Pharmacology and 
Experimental  Therapeutics program. Quantification of total plasma vincristine will be 
performed by a qualified LC/MS/MS. 
 
Samples 
requested: 
Mandatory (Arm A & B) 
• 
Pre-dose 1 
• 
Pre-dose #2 (trough level) 
• 
Pre-dose #3 (trough level) 
 
May be collected through the 
line used for Marqibo® infusion 
 
Mandatory (Arm C) 
• 
Pre-dose 1 
• 
Day 8 will have a trough level 
 
Voluntary (all cohorts) 
• 
End of infusion (EOI) of dose 
1 
• 
3 hours (EOI + 2 hours) 
• 
25 hours (EOI + 24 hours) 
 
Must be collected from a 
separate line from that used for 
Marqibo® infusion. 

TACL Protocol:  
T2012-002  
Original Version Date: 14-May-2016  
Activated: 
                 28-Jul-2016  
Amendment #1 Date: 16-Mar-2017 
 
 
Amendment #2 Date: 16-Jul-2018 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
T2012-002 Original Version Date: 14-May-2016   
CONFIDENTIAL 
Amendment #1 Date: 16-Mar-2017 
TACL Internal Distribution Only 
Amendment #2 Date: 16-Jul-2018  
62 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
Sample Collection 
procedure: 
• 
Peripheral blood samples of 3 mL will be collected in 
lavender-top (EDTA) vacutainers at each of the time points 
indicated above. 
• 
Invert the lavender-top vacutainer 10 times to mix 
completely 
• 
If blood samples are taken via an indwelling central venous 
cannula, an appropriate amount of fluid should be removed 
from the cannula to clear the line before each blood sample 
is taken.Place the samples on ice until centrifugation 
Specimen 
Processing 
• 
Plasma: should be separated by centrifugation at 10C (10 
min at 1000 g or 2500 rpm) within four hours after 
collection. Separated plasma should be transferred to 
screw-capped polyproplyene tubes (i.e. Nunc 3.6 ml 
#379189, 366524 or equivalent). Plasma samples should 
be stored in the dark at less than -70° C. 
Specimen labeling: 
• 
Specimens should be labeled with the TACL registration 
number,date and time of sampling and the sample number 
(see appendix 7). 
 

TACL Protocol:  
T2012-002  
Original Version Date: 14-May-2016  
Activated: 
                 28-Jul-2016  
Amendment #1 Date: 16-Mar-2017 
 
 
Amendment #2 Date: 16-Jul-2018 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
T2012-002 Original Version Date: 14-May-2016   
CONFIDENTIAL 
Amendment #1 Date: 16-Mar-2017 
TACL Internal Distribution Only 
Amendment #2 Date: 16-Jul-2018  
63 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
Specimen 
Packaging 
and 
Shipping: 
 
 
 
• 
Participating sites should ship samples on dry ice using 
priority Federal Express. 
• 
Samples should be shipped Mon, Tues or Wed only and 
should not be sent on the day preceding a holiday. Lab 
receives samples Tuesday through mid-Friday. 
• 
All samples should be batched per patient 
• 
Send a notification email to marqibo@mail.nih.gov when 
sending samples. 
• 
Include the completed pharmacokinetic 
• 
 worksheet (Appendix7) 
• 
Ship samples to: 
 
Figg Lab 
Clinical Pharmacology Program 
National Cancer Institute 
9000 Rockville Pike 
Building 10, Room 5A08 
Bethesda, MD 20892 
(O) 240-760-6180 
(F) 301-402-8606 
 
For specimen shipping, please request a label from TACL 
Operations at least 24 hours in advance of shipment. Please call 
the TACL Operations Center for any questions at 323-361-3022. 
 
 
7.5  
Required Observations Following Completion of Protocol Therapy 
 
When a patient discontinues the study, a Final Visit will be conducted. Following discontinuation 
of the study drug, the patient will be treated in accordance with the investigator's best clinical 
judgment. If a patient discontinues from the study due to an adverse event considered possibly 
or probably related to study drug, a Follow-up Visit must be conducted no later than 30 days after 
the last dose of anti-cancer therapy administered as part of this protocol. Safety assessments will 
be conducted at least every 30 days, until all toxicities resolve, return to baseline or become 
clinically satisfactory, stable, or are considered irreversible. 
 
Upon completing protocol therapy or exiting the study, all patients will be followed for life or until 
otherwise notified by the study committee that the study is closed. Sites should submit follow-up 
a minimum of every 6 months. Events such as patient death, relapse or development of toxicity 
related to this therapy should be reported right away. The purpose is to assess safety, remission 
status, administration of alternative therapies, and survival. 

TACL Protocol:  
T2012-002  
Original Version Date: 14-May-2016  
Activated: 
                 28-Jul-2016  
Amendment #1 Date: 16-Mar-2017 
 
 
Amendment #2 Date: 16-Jul-2018 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
T2012-002 Original Version Date: 14-May-2016   
CONFIDENTIAL 
Amendment #1 Date: 16-Mar-2017 
TACL Internal Distribution Only 
Amendment #2 Date: 16-Jul-2018  
64 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
The following data will be collected: 
1) Disease status information 
2) Anti-cancer therapy received after exiting the protocol 
3) All adverse events thought to be related to this study’s treatment 
4) Date and cause of death 
 
 
8.0  
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY, OFF STUDY CRITERIA AND 
STUDY TERMINATION 
 
8.1  
Criteria for Removal from Protocol Therapy 
a. Completion of protocol therapy 
b. Progressive disease 
c. Patient/parent withdrawal or refusal after beginning protocol therapy 
d. Patient/parent withdrawal or refusal before beginning protocol therapy 
e. Patient off treatment for other complicating disease 
f. Non-compliance with protocol regimen and procedures 
g. Unacceptable toxicity 
h. Investigator determination 
i. Female patient becomes pregnant or begins breast-feeding 
 
8.2  
Off Study Criteria 
a. Death 
b. Patient Lost to follow-up 
c. Patient withdraws consent, refuses follow-up 
 
8.3  
Termination of the Study by TACL 
The TACL Consortium may terminate this study prematurely, either in its entirety or at an 
investigative site, for reasonable cause provided that written notice is submitted in 
advance of the intended termination. Advance notice is not required if the study is stopped 
due to safety concerns. 
 
 
9.0  
STATISTICAL CONSIDERATIONS 
 
The Phase I sample size for each dose level and each of the three cohorts is 6 evaluable patients 
for the primary endpoint, consistent with the sample size typically sufficient to demonstrate regimen 
tolerability in Phase I trials. The maximum sample size in any cohort at a particular dose level is 12 
evaluable patients, including 6 evaluable patients for expansion. 
 
As of Protocol Amendment #3, Cohort A will enroll at DL1 only. Cohort B will utilize DL1 and Cohort 
C will continue treatment at DL2. Dose escalation for Cohort B and de-escalation for Cohort C may 
still occur per study design.  

TACL Protocol:  
T2012-002  
Original Version Date: 14-May-2016  
Activated: 
                 28-Jul-2016  
Amendment #1 Date: 16-Mar-2017 
 
 
Amendment #2 Date: 16-Jul-2018 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
T2012-002 Original Version Date: 14-May-2016   
CONFIDENTIAL 
Amendment #1 Date: 16-Mar-2017 
TACL Internal Distribution Only 
Amendment #2 Date: 16-Jul-2018  
65 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
The focus of the study design and statistical analysis is to determine whether Marqibo® can be 
substituted for standard vincristine and successfully administered to patients with relapsed ALL in 
three different treatment cohorts: (A) treatment with the UK ALL R3 regimen;  (B) treatment with 
UK ALL R3 regimen without mitoxantrone, and (C) treatment with ALL maintenance therapy. 
Secondary objectives include estimating rates of serious toxicities and therapy delays in each of 
these cohorts.  Achievement of response and achievement of an MRD undetectable status will 
only be evaluated in Cohorts A and B, as Cohort C is not being used to eradicate disease, rather 
is only intended for the purposes of disease stabilization. 
 
9.1  
Endpoints 
 
9.1.1 Primary Endpoint 
Cohort A 
The primary endpoint in Cohort A is whether a patient is successfully treated with UK ALL 
R3/Marqibo® at nearly full dose without inordinate delays in the resolution of hematologic 
and non-hematologic toxicity that preclude timely continuation with subsequent treatment. 
Specifically, a patient will be considered successfully treated if: 
a. The patient has received 16 of 20 prescribed doses of Dexamethasone, 2 of 2 
prescribed doses of Mitoxantrone, 3 of 4 prescribed doses of Marqibo®, and 1 of 2 
doses of pegaspargase. 
b. The patient has not experienced a dose limiting toxicity (DLT) as defined in section 4.2. 
A patient will be considered NOT successfully treated if (s)he has experienced a dose 
limiting toxicity (DLT) as defined in section 4.2, or has received fewer than the minimum 
numbers of prescribed doses as described in (a) above for reasons not unequivocally 
unrelated to treatment toxicity (see section 9.3.1) 
 
Cohort B 
The primary endpoint in Cohort B is whether a patient is successfully treated with UK ALL 
R3/Marqibo® without mitoxantrone at nearly full dose without inordinate delays in the 
resolution of hematologic and non-hematologic toxicity that preclude timely continuation 
with subsequent treatment. 
Specifically, a patient will be considered successfully treated if: 
a. The patient has received 16 of 20 prescribed doses of Dexamethasone, 3 of 4 
prescribed doses of Marqibo® and 1 of 2 doses of pegaspargase. 
b. The patient has not experienced a dose limiting toxicity (DLT) as defined in section 4.2 
A patient will be considered NOT successfully treated if (s)he has experienced a dose 
limiting toxicity (DLT) as defined in section 4.2, or has received fewer than the minimum 
numbers of prescribed doses as described in (a) above for reasons not unequivocally 
unrelated to treatment toxicity (see section 9.3.1) 

TACL Protocol:  
T2012-002  
Original Version Date: 14-May-2016  
Activated: 
                 28-Jul-2016  
Amendment #1 Date: 16-Mar-2017 
 
 
Amendment #2 Date: 16-Jul-2018 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
T2012-002 Original Version Date: 14-May-2016   
CONFIDENTIAL 
Amendment #1 Date: 16-Mar-2017 
TACL Internal Distribution Only 
Amendment #2 Date: 16-Jul-2018  
66 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
Cohort C 
The primary endpoint in Cohort C is whether a patient is successfully treated with one 
cycle (14 days) of the modified maintenance treatment at nearly full dose without 
inordinate delays in the resolution of non-hematologic toxicity that preclude timely 
continuation with subsequent treatment. 
Specifically, a patient will be considered successfully treated if  during the first course of 
modified maintenance treatment: 
a. The patient has received 8 of 10 prescribed doses of dexamethasone, and 1 of 1 
prescribed doses of Marqibo®, 1 or 2 prescribed doses of Methotrexate, and at least 
50% of doses of mercaptopurine 
b. The patient has not experienced a dose limiting toxicity (DLT) as defined in section 4.2 
A patient will be considered NOT successfully treated if (s)he has experienced a dose 
limiting toxicity (DLT) as defined in section 4.2, or has received fewer than the minimum 
numbers of prescribed doses as described in (a) above for reasons not unequivocally 
unrelated to treatment toxicity (see section 9.3.1) 
 
9.1.2 Exploratory Endpoints 
a. Occurrence of toxicity, as graded using the NCI’s Common Terminology Criteria for 
Adverse Events (CTCAE 4.03). 
b. (Cohorts A and B) Achievement of CR or CRi during the course of therapy. 
c. (Cohorts A and B) In those who achieve CR or CRi, achievement of MRD negative 
status (i.e., <10-4 blasts by flow cytometry in a central lab). 
d. Pharmacokinetic assessment of Marqibo® 
 
9.1.3 Safety Endpoints 
Toxic Death (TD):  Any death that is not clearly related to disease progression or to 
external causes (e.g. accident) that occurs during protocol therapy or during recovery 
following protocol therapy, or prior to commencing subsequent non-protocol course of 
therapy, will be considered a toxic death for the purposes of this study. 
 
9.2  
Study Design 
 
An open label design over two Marqibo® dose levels will be used to evaluate its substitution for 
vincristine in three different treatment cohorts: (A)  patients treated with UK ALL R3, (B) patients 
treated with UK ALL R3 that omits Mitoxantrone, and (C) patients treated with a modified ALL 
maintenance regimen.  Prior data on relapse ALL patients treated with standard UK ALL R3 and 
with COG protocol therapies (section 2.3) suggest that approximately 10% of patients treated in 
first relapse will experience grade 3 or higher toxicity sufficient to prevent the start of subsequent 
therapy by day 49. Data from patients treated in second or greater relapse, which will represent 

TACL Protocol:  
T2012-002  
Original Version Date: 14-May-2016  
Activated: 
                 28-Jul-2016  
Amendment #1 Date: 16-Mar-2017 
 
 
Amendment #2 Date: 16-Jul-2018 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
T2012-002 Original Version Date: 14-May-2016   
CONFIDENTIAL 
Amendment #1 Date: 16-Mar-2017 
TACL Internal Distribution Only 
Amendment #2 Date: 16-Jul-2018  
67 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
the majority of patients on this study, suggest higher delay rates, but are imprecise due to the 
small number of patients. 
 
For Cohort A, the original design criteria for escalation to DL2 (≤ 2/6 not successfully treated at 
DL1) has been satisfied.  Hence, following Amendment #2, a minimum of 6 and a maximum of 12 
patients (including 6 for expansion) who are evaluable for the primary endpoint will be enrolled at 
DL2. Following Amendment #3, Cohort A was dose de-escalated to DL1 given the development 
of two DLTs at DL2. 
 
Since treatments in Cohorts B and C were expected to be less toxic than Cohort A, as detailed 
below Cohorts B and C initially opened to accrual at DL2.   
 
For Cohort B, dosing began at DL2. The cohort was subsequently de-escalated to DL1 after 2 
patients were enrolled. The decision to dose de-escalate was an elective decision made by the 
study committee in the context of known hepatic toxicity associated with Marqibo®, the 
development of hepatic DLT in one subject on this cohort, and a second subject who was close 
to meeting criteria for DLT based on hepatic function tests. Cohort B will remain open to accrual 
at DL1 with 6-12 evaluable patients. Cohort B may be re-escalated to DL2 pending further 
experience at DL1 (≤ 2/6 not successfully treated in the first 6 evaluable patients).  
 
For Cohort C, dosing began at DL2. Cohort C will remain open to accrual at DL2 with 6-12 
evaluable patients, provided the primary endpoint conditions are met, ie, ≤ 2/6 not successfully 
treated in the first 6 evaluable patients at this dose level. If Cohort C is de-escalated, the cohort 
may continue to accrue at DL1 between 6 to 12 evaluable patients at that dose level. 
 
The occurrence of unsuccessful treatment, following the definition in Section 9.1.1, will be 
monitored in real time during the Phase I and expansion accruals.  The design will not be 
prescriptive.  Rather, if at any time after the third patient is enrolled either within a single cohort 
or in all cohorts combined, if nominally more than 1/3 of evaluable patients within a single cohort 
or in all cohorts combined are not successfully treated the study will be suspended pending review 
by the study committee of the types and severity of toxicities in all three cohorts, with possible 
determinations to continue at the specified dose level in all three cohorts, to de-escalate the dose 
of Marqibo® to DL1 in one or more cohorts, or to halt the study in one or more or cohorts, with 
appropriate amendments as necessary. In addition, during Phase I, the decision to de-escalate 
will be considered separately for each cohort and dose level when more than 1 patient is treated 
unsuccessfully after the first 6 evaluable patients have been enrolled. And the decision to escalate 
during Phase I will be considered separately for each cohort and dose level when no more than 
1 patient is treated unsuccessfully after the first 6 evaluable patients have been enrolled. Accrual 
to the study will be halted, before reopening for expansion, once at least 6 evaluable patients 
have been treated at the final tested dose level in each of the three cohorts. 
Treatment success, as defined in in Section 9.1.1, during the first course of treatment will continue 
to be monitored during the expansion. Assuming a treatment failure rate that exceeds 10% (i.e., 
p0>0.10) is unacceptable, a Bayesian monitoring rule based on a pessimistic Beta (1,4) prior 
distribution will be used to judge the empirical evidence from both the Phase I and expansion 

TACL Protocol:  
T2012-002  
Original Version Date: 14-May-2016  
Activated: 
                 28-Jul-2016  
Amendment #1 Date: 16-Mar-2017 
 
 
Amendment #2 Date: 16-Jul-2018 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
T2012-002 Original Version Date: 14-May-2016   
CONFIDENTIAL 
Amendment #1 Date: 16-Mar-2017 
TACL Internal Distribution Only 
Amendment #2 Date: 16-Jul-2018  
68 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
cohorts. This prior has mean 0.20, median 0.16, and 90% of support under 0.48. A posterior 
probability of greater than 80% that p0>0.10 will be considered statistical evidence that the 
treatment failure rates may exceed 10%.  Operationally, this criterion will be satisfied if 2 or more 
of the first 5 evaluable patients in the expansion cohort experience a treatment failure as defined 
by the protocol, and subsequently, if 3 or more of the first 6 evaluable patients have a treatment 
failure. If this criterion is satisfied, the study will be suspended to accrual pending review of 
toxicities by the study committee, in consultation with the Data and Safety Monitoring Committee, 
to determine whether the study should continue as planned, be amended, or be terminated. 
 
 
9.3  
Patient Evaluability 
 
9.3.1  
Definition of a patient evaluable for the primary endpoint 
 
A patient will be considered evaluable for the treatment success endpoint (section 9.1.1) 
if (s)he receives any portion of treatment, except if treatment or follow-up is terminated for 
reasons unequivocally unrelated to treatment toxicity (e.g., if a drug is omitted from the 
regimen for reasons aside from toxicity, or treatment is terminated because of problems 
unequivocally related to disease progression).  Patient who are not evaluable for the 
primary endpoint will be replaced. 
 
9.3.2  
Definition of a patient evaluable for toxicity: 
 
Any patient who receives at least one dose of any drug on study will be considered 
evaluable for toxicity. 
 
9.3.3.  
Definition of a patient evaluable for response: 
 
A patient will be considered evaluable for response if the patient receives all or part of 
protocol therapy and the patient is under follow-up for a sufficient period to evaluate the 
disease at the end of protocol therapy or to meet the definition of progressive disease. A 
patient who dies as a result of toxicity after receiving all or part of protocol therapy, or who 
is removed from therapy for problems possibly related to disease progression, will be 
considered a non-responder. 
 
 
9.4 
Definition of toxic death (TD) 
 
Any death that is not clearly related to disease progression that occurs during protocol therapy 
or during recovery following protocol therapy, or prior to commencing subsequent non-protocol 
course of therapy, will be considered a toxic death for the purposes of this study.  
 

TACL Protocol:  
T2012-002  
Original Version Date: 14-May-2016  
Activated: 
                 28-Jul-2016  
Amendment #1 Date: 16-Mar-2017 
 
 
Amendment #2 Date: 16-Jul-2018 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
T2012-002 Original Version Date: 14-May-2016   
CONFIDENTIAL 
Amendment #1 Date: 16-Mar-2017 
TACL Internal Distribution Only 
Amendment #2 Date: 16-Jul-2018  
69 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
9.4  
Statistical Analysis 
 
9.4.1 Treatment success rate:  Given the small sample size in each cohort, the treatment success 
rate will only be estimable imprecisely within each cohort and overall.   
 
9.4.2 Toxicity: The analysis of toxicity will be primarily descriptive, comprising tabulation of the 
fraction of patients who experience grade 3 or grade 4 toxicities. 
 
9.4.3 Efficacy: Given the small sample size in each cohort, the CR/CRi rates and the MRD-
negative rates will only be estimable imprecisely within each cohort and overall.. 
 
9.4.4 Pharmacokinetics analysis: The precision with which a detailed pharmacokinetic analysis of 
vincristine levels after exposure to Marqibo® in the context of UK ALL R3 treatment or 
maintenance therapy in this population of patients can be performed will depend on the 
number of patients who participate in the optional Day 1 PK component of this study, which 
includes sampling at end of infusion, 3 hours and 24 hours in addition to the mandatory 
day 8 and day 15 samples (applicable to only the UK ALL R3 with or without mitoxantrone 
arms A & B). Patients enrolled to arm C will only have pre-dose #1 (30 minutes before 
start of infusion (SOI) and a trough level at day 8 during the first cycle. Assuming first order 
elimination, these pharmacokinetic analyses will include estimation of total vincristine 
concentration, area under the curve through 168 hours, and, the half -life of vincristine 
when Marqibo® is given with combination therapy.  However, the two mandatory samples 
at day 8 and 15 taken prior to the second and third dose of Marqibo®, representing 
vincristine trough levels, will be obtained on all patients.  There are no data currently 
available to estimate interpatient variability of vincristine levels from Marqibo® in children, 
but data from 23 in adults indicate that the coefficient of variation (CV) of vincristine at 
trough levels will be approximately 100%.  Hence, assuming that the study proceeds to 
the second stage, and that 25/30 patients are evaluable for PK assessment, the precision 
of the estimate of mean trough levels of vincristine at each of these times point will be 
CV=17%, resulting in a 95% confidence interval with bounds within 40% of the population 
value.  This provides sufficient precision for meaningful comparison of vincristine 
concentration in this study to published adult study as well as the ongoing Marqibo® Phase 
I study in children.  These analyses will be based on the total vincristine exposure and will 
not include distinguishing between the free and liposomal bound components. 
 
9.5  
Interim Monitoring of Toxic Death 
 
The occurrence of toxic death (TD) per 9.3.4 will be a primary endpoint for safety monitoring. 
Based on prior studies, a 10% TRM rate in patients with advanced ALL is expected (see section 
2.3). Hence a population toxic death rate that exceeds 10% will be considered unacceptable. No 
formal statistical monitoring will be employed. Rather, an observed TD rate that exceeds 10% at 
any time in any cohort will result in immediate suspension of the study, at which time the cause 
and circumstances of the death and its attribution to the study regimen will be reviewed with the 
study committee and with the Data and Safety Monitoring Committee (DSMC) to determine 

TACL Protocol:  
T2012-002  
Original Version Date: 14-May-2016  
Activated: 
                 28-Jul-2016  
Amendment #1 Date: 16-Mar-2017 
 
 
Amendment #2 Date: 16-Jul-2018 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
T2012-002 Original Version Date: 14-May-2016   
CONFIDENTIAL 
Amendment #1 Date: 16-Mar-2017 
TACL Internal Distribution Only 
Amendment #2 Date: 16-Jul-2018  
70 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
whether modifications to or termination of the study is warranted. Operationally, this criterion will 
be satisfied if within a cohort, a TD is observed, and the nominal rate exceeds 10%. 
 
9.6  
Inclusion of Women and Minorities 
 
The study is open to all participants regardless of gender or ethnicity. Review of accrual to past 
studies of new agents demonstrates the accrual of both genders and all NIH-identified ethnicities 
to such studies. The small number of patients entered into this trial will obviate any analysis of 
variation in response rate with gender or ethnicity. 
 
 
10.0  RESPONSE CRITERIA 
 
10.1  Bone Marrow Status Definitions 
 
M1 Marrow 
Less than 5% blasts in a bone marrow aspirate and at least 200 cells counted. 
 
M2 Marrow 
5-25% blasts in a bone marrow aspirate with at least 200 cells counted. 
 
M3 Marrow 
Greater than 25% blasts in a bone marrow aspirate with at least 200 cells counted. 
 
10.2  Bone Marrow Response Criteria 
 
10.2.1 Complete Remission (CR) 
Attainment of M1 bone marrow with no evidence of circulating blasts or extramedullary disease 
and with recovery of peripheral counts (ANC ≥ 500/µL and PLT count ≥ 50,000 µL). Qualifying 
marrow and peripheral counts should be performed within 1 week of each other. 
 
10.2.2 Complete Remission with Incomplete Blood Count Recovery (CRi) 
Attainment of M1 bone marrow with no evidence of circulating blasts or extramedullary disease, 
but with insufficient recovery of absolute neutrophil count (ANC < 500/µL) or platelets (< 50,000/ 
µL). 
 
10.2.3  Partial Remission (PR) 
Complete disappearance of circulating blasts and achievement of M2 marrow status, without new 
sites of extramedullary disease, and with recovery of absolute neutrophil count (ANC > 500/µL). 
 
10.2.4 Stable Disease (SD) 
Patient does not satisfy the criterion for PD, and fails to qualify for CR, CRi, or PR. 
 

TACL Protocol:  
T2012-002  
Original Version Date: 14-May-2016  
Activated: 
                 28-Jul-2016  
Amendment #1 Date: 16-Mar-2017 
 
 
Amendment #2 Date: 16-Jul-2018 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
T2012-002 Original Version Date: 14-May-2016   
CONFIDENTIAL 
Amendment #1 Date: 16-Mar-2017 
TACL Internal Distribution Only 
Amendment #2 Date: 16-Jul-2018  
71 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
10.2.5 Progressive Disease (PD) 
An increase of at least 25% in the absolute number of circulating leukemic cells, development of 
new sites of extramedullary disease, or other laboratory or clinical evidence of PD, with or without 
recovery of ANC or platelets. 
 
10.2.6 Toxic Death (TD) 
Any patient who dies after receiving therapy on this protocol prior to receiving subsequent therapy. 
 
10.2.7 Not evaluable (NE) 
Patient does not satisfy the criterion for PD or ID, and either did not have a marrow evaluation, 
had inadequate marrow cell count, or had insufficient recovery of ANC to be classified as CR, 
CRp, PR, or SD. 
 
10.3  CNS Status Definitions 
CNS 1: In cerebral spinal fluid (CSF), absence of blasts on cytospin preparation, 
regardless of the number of white blood cells (WBCs). 
 
CNS 2: In CSF, presence < 5/μL WBCs and cytospin positive for blasts, or ≥ 5 /μL WBCs 
but negative by Steinherz/Bleyer algorithm: 
 
CNS 2a: < 10/μL RBCs; < 5/μL WBCs and cytospin positive for blasts; 
CNS 2b: ≥ 10/μL RBCs; < 5/μL WBCs and cytospin positive for blasts; and CNS 
2c: ≥ 10/μL RBCs; ≥ 5/μL WBCs and cytospin positive for blasts but negative by 
Steinherz/Bleyer algorithm (see below) 
 
CNS 3: In CSF, presence of ≥ 5/μL WBCs and cytospin positive for blasts and/or clinical 
signs of CNS leukemia: 
CNS 3a: < 10/μL RBCs; ≥ 5/μL WBCs and cytospin positive for blasts; 
CNS 3b: ≥ 10/μL RBCs, ≥ 5/μL WBCs and positive by Steinherz/Bleyer algorithm  
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 patient has leukemic cells in the peripheral blood and the lumbar puncture is 
traumatic and contains ≥ 5 WBC/µL and blasts, the following Steinherz/Bleyer algorithm 
should be used 
 
CSF WBC > 2X Blood WBC 
CSF RBC          Blood RBC 
 
A patient with CSF WBC ≥ 5/µL blasts, whose CSF WBC/RBC is 2X greater than the blood 
WBC/RBC ratio, has CNS disease at diagnosis. 
 

TACL Protocol:  
T2012-002  
Original Version Date: 14-May-2016  
Activated: 
                 28-Jul-2016  
Amendment #1 Date: 16-Mar-2017 
 
 
Amendment #2 Date: 16-Jul-2018 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
T2012-002 Original Version Date: 14-May-2016   
CONFIDENTIAL 
Amendment #1 Date: 16-Mar-2017 
TACL Internal Distribution Only 
Amendment #2 Date: 16-Jul-2018  
72 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
Example: CSF WBC = 60/µL; CSF RBC = 1500/µL; blood WBC =46000/µL;   
blood RBC = 3.0 X 
106/µL: 
 
 
CSF calculation    Blood calculation      
 
60     = 0.04          46000     = 0.015 x 2 = .03 
 
1500 
3.0 X 106 
 
 
Therefore this patient has CNS disease because 0.04 > 0.03 
 
10.4  CNS Response Criteria 
 
Only subjects with CNS 1 or 2 status will be enrolled. Those with active CNS disease (CNS 3) are 
excluded until they achieve CNS 1 or 2 status. CNS status will only be evaluated for progressive 
disease, defined as below. 
 
10.4.1 Progressive Disease (PD): Any subject who develops CNS 3 disease will be considered 
to have progressive disease. 
 
 
11.0  ADVERSE EVENT REPORTING REQUIREMENTS 
 
11.1  Definitions 
 
Adverse Event: An adverse event means any untoward medical occurrence associated with the 
use of a drug in humans, whether or not considered drug related. 
 
Suspected Adverse Reaction: Any adverse event for which there is a reasonable possibility that 
the drug caused the adverse event. Reasonable possibility means there is evidence to suggest a 
causal relationship between the drug and the adverse event. 
 
Unexpected Adverse Event or Unexpected Suspected Adverse Reaction: An adverse event 
or suspected adverse reaction is considered “unexpected” if it is not listed in the investigator 
brochure or is not listed at the specificity or severity that has been observed; or, if an investigator 
brochure is not available, is not consistent with the risk information described in the general 
investigational plan. 
 
Serious Adverse Events or Serious Suspected Adverse Reactions: An adverse event or 
suspected adverse reaction is considered serious if, in the view of either the investigator  or 
sponsor, it results in any of the following outcomes: 
 
Death of Patient 
An event that results in the death of a patient. 

TACL Protocol:  
T2012-002  
Original Version Date: 14-May-2016  
Activated: 
                 28-Jul-2016  
Amendment #1 Date: 16-Mar-2017 
 
 
Amendment #2 Date: 16-Jul-2018 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
T2012-002 Original Version Date: 14-May-2016   
CONFIDENTIAL 
Amendment #1 Date: 16-Mar-2017 
TACL Internal Distribution Only 
Amendment #2 Date: 16-Jul-2018  
73 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
Life-Threatening 
An event that, in the opinion of the investigator, would have resulted in 
immediate fatality if medical intervention had not been taken. This does not 
include an event that would have been fatal if it had occurred in a more severe 
form. 
Hospitalization 
An event that results in an admission to the hospital for any length of time. 
This does not include an emergency room visit or admission to an outpatient 
facility. 
Prolongation of 
Hospitalization 
An event that occurs while the study patient is hospitalized and prolongs the 
patient’s hospital stay. 
Congenital 
Anomaly 
An anomaly detected at or after birth, or any anomaly that results in fetal loss. 
Persistent or 
Significant 
Disability/ 
Incapacity 
An event that results in a condition that substantially interferes with the 
activities of daily living of a study patient. Disability is not intended to include 
experiences of relatively minor medical significance such as headache, 
nausea, vomiting, diarrhea, influenza, or accidental trauma (e.g., sprained 
ankle). 
Important 
Medical Event 
Requiring 
Medical or 
Surgical 
Intervention to 
Prevent Serious 
Outcome 
An important medical event that may not be immediately life-threatening or 
result in death or hospitalization, but based on medical judgment may 
jeopardize the patient and may require medical or surgical intervention to 
prevent any of the outcomes listed above (i.e., death of patient, life-
threatening, hospitalization, prolongation of hospitalization, congenital 
anomaly, or persistent or significant disability/incapacity). Examples of such 
events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result 
in inpatient hospitalization, pregnancy, or the development of drug 
dependency or drug abuse. 
 
Grade 3 fever and neutropenia is not an SAE unless a new hospitalization is required or is associated 
with another medical complication deemed medically important or life threatening. 
 
11.2  Data Collection 
Adverse events and suspected adverse reactions will be collected and reported on the electronic 
CRFs beginning with the first dose of study therapy until 30 days following the last dose of study 
therapy (or until the patient begins another therapy). The investigator will evaluate all adverse 
events and suspected adverse reactions as to their severity and relationship to Marqibo® as well 
as the regimen as a whole. Serious adverse events and suspected adverse reactions will require 
expedited reporting to the TACL Operations Center as described below. 
 
11.3  Reporting Serious Adverse Events or Serious Suspected Adverse Reactions 
 
11.3.1 The following serious adverse events or serious suspected adverse reactions requires 
expedited reporting: 

TACL Protocol:  
T2012-002  
Original Version Date: 14-May-2016  
Activated: 
                 28-Jul-2016  
Amendment #1 Date: 16-Mar-2017 
 
 
Amendment #2 Date: 16-Jul-2018 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
T2012-002 Original Version Date: 14-May-2016   
CONFIDENTIAL 
Amendment #1 Date: 16-Mar-2017 
TACL Internal Distribution Only 
Amendment #2 Date: 16-Jul-2018  
74 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
• 
All Grade 5 events regardless of causality. 
• 
All Grade 4 events that are possibly, probably or definitely related to Marqibo® or the 
regimen as a whole.  Exclude reporting of hematologic toxicity as a serious adverse 
event unless the event meets the criteria of hematologic dose limiting toxicity per 
protocol section 4.2.1.2:  The absence of peripheral blood count recovery (ANC > 
500/μL and platelet count > 20,000/μL) 7 weeks (49 days) after the start of 
chemotherapy in 
the 
absence of 
persistent leukemia 
or 
documented 
myelosuppressive infection. 
• 
All unexpected Grade 3 events that are possibly, probably or definitely related to 
Marqibo® or the regimen as a whole. 
 
11.3.2 Steps for Reporting 
 
Step 1: Identify the adverse event or suspected adverse reaction using the NCI Common 
Terminology Criteria for Adverse Events (CTCAE), version 4.03. 
The CTCAE provides descriptive terminology and a grading scale for each adverse event 
listed. 
A 
copy 
of 
the 
CTCAE 
can 
be 
downloaded 
at 
http://evs.nci.nih.gov/ftp1/CTCAE/About.html. 
 
Step 2: Grade the event using the NCI CTCAE version 4.03. 
 
Step 3: Determine if the adverse event or suspected adverse reaction meets the criteria of 
being “serious”. 
 
Step 4: Determine whether the adverse event or suspected adverse reaction is related to the 
protocol therapy. 
 
The investigator will assess the causal relationship between the investigational product and the 
regimen as a whole and the adverse event. The investigator will use his/her clinical expertise and 
judgment to select the attribution category below that best fits the circumstances of the AE. 
 
Attribution categories are as follows: Unrelated, Unlikely, Possible, Probable, and Definite. 
 
Unrelated: 
• 
The adverse event is clearly unrelated to the investigational agent(s). 
• 
Does not follow a known response pattern to the suspect investigational product (if 
response pattern is previously known). 
• 
Can be explained by the known characteristics of the patient’s clinical state or therapy 
administered to the patient. 
 
Unlikely: 
• 
The adverse event is doubtfully related to the investigational agent(s). 
• 
May or may not follow a reasonable temporal sequence from administration of the 
investigational product. 

TACL Protocol:  
T2012-002  
Original Version Date: 14-May-2016  
Activated: 
                 28-Jul-2016  
Amendment #1 Date: 16-Mar-2017 
 
 
Amendment #2 Date: 16-Jul-2018 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
T2012-002 Original Version Date: 14-May-2016   
CONFIDENTIAL 
Amendment #1 Date: 16-Mar-2017 
TACL Internal Distribution Only 
Amendment #2 Date: 16-Jul-2018  
75 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
• 
Likely explained by the known characteristics of the patient’s clinical state or other 
therapy administered to the patient. 
 
Possibly Related: 
• 
The adverse event may be related to the investigational agent(s). 
• 
Follows a reasonable temporal sequence from administration of the investigational 
product. 
• 
May also be reasonably explained by the patient’s clinical state or therapy 
administered to the patient. 
• 
May follow a known response pattern to the investigational product (if response pattern 
is previously known) 
 
Probably Related: 
• 
The adverse event is likely related to the investigational agent(s). 
• 
Follows a reasonable temporal sequence from administration of the investigational 
product. 
• 
May follow a known response pattern to the investigational product (if response pattern 
is previously known) 
• 
Could not be reasonably explained by the known characteristics of the patient’s clinical 
state or other modes of therapy administered to the patient, if applicable; 
 
Definitely Related: 
• 
The adverse event is clearly related to the investigational agent(s). 
• 
Follows the temporal sequence from administration of the investigational product 
• 
Follows a known response pattern to the investigational product. 
• 
Cannot be explained by the known characteristics of the patient’s clinical state or other 
therapy administered to the patient. 
• 
Is confirmed by improvement of symptoms on stopping or slowing administration of 
the investigational product and re-emergence of symptoms on restarting 
administration of the investigational product, (if applicable). 
 
Step 5:  
Determine if the adverse event or suspected adverse reaction is 
“unexpected”. 
 
Step 6: Notify the TACL Operations Center by telephone or email 
 
The following information should be submitted within 24 hours of event notification by either 
telephone (323) 361-3022 or Email TACL@chla.usc.edu. 
 
1. 
Patient TACL study ID and initials 
2. 
Event description 
3. 
Severity (CTCAE Grade) 
4. 
Onset date 
5. 
Reason event is considered serious 

TACL Protocol:  
T2012-002  
Original Version Date: 14-May-2016  
Activated: 
                 28-Jul-2016  
Amendment #1 Date: 16-Mar-2017 
 
 
Amendment #2 Date: 16-Jul-2018 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
T2012-002 Original Version Date: 14-May-2016   
CONFIDENTIAL 
Amendment #1 Date: 16-Mar-2017 
TACL Internal Distribution Only 
Amendment #2 Date: 16-Jul-2018  
76 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
6. 
Dose of study drug and dates of administration 
7. 
Investigator opinion of relationship to DRUG and the regimen as a whole 
8. 
Name and phone number of physician in charge of the case 
9. 
Name and phone number of CRA or Research nurse working with the case 
 
Step 7: Submit a written report to the TACL Operations Center 
 
Complete the TACL SAE Notification Form within 72 hours of learning of the event. The completed 
form can emailed to TACL@chla.usc.edu. The form may also be faxed to 323-361-4505. A follow-
up SAE Notification Form must be submitted upon resolution of the event or interimly (prior to 
resolution) as requested by the study committee and/or TACL Operations Center. Please confirm 
via email or phone that the TACL Operations Center has received this notification. These serious 
adverse events will be reported to the FDA by the TACL Operations Office using the MedWatch 
form as required per federal regulations. 
 
11.4  Institutional Reporting to the IRB 
 
All SAEs should be reported to the treating institution’s IRB or Ethics board per institutional 
guidelines. The TACL Operations Center will also report SAE’s to the CHLA IRB as required. The 
TACL Operations Center will distribute SAE’s to all TACL sites as appropriate for submission to 
their institutional IRB or Ethics board. 
 
12.0  DATA AND SAFETY MONITORING 
 
12.1  Data Submission 
All study data will be submitted via electronic data capture forms using the DataLabs/TACL 
Website. All toxicities grades 1-5, heme and non-heme with grade fluctuations should be reported 
in the eCRF. Please refer to the TACL web site https://tacl.chla.usc.edu) for T2012-002 CRF 
Completion Guide or contact the TACL Operations Center at (323) 361-3022 if you need 
assistance. 
 
The following are required to be submitted to the Operations Center for all patients 
entered: 
Copies of following: Roadmaps and Bone Marrow Reports (include both aspirate and 
biopsy reports). These de-identified forms are to be emailed to the TACL Operations Office 
at tacl@chla.usc.edu at the end of the study course. 
 
12.2  Weekly Safety Review 
The TACL Operations Center (TOC) conducts weekly (as needed) patient safety and review 
meetings with the protocol chair, protocol vice-chair, research coordinators and other 
administrative TACL team members to review all data submitted, non-serious adverse events and 
other correspondence pertaining to patients. Serious adverse events will be immediately 
evaluated by the study team and determination regarding notification of participating sites will be 
made. All serious adverse events will be sent to the CHLA IRB and DSMC if required. Any interim 

TACL Protocol:  
T2012-002  
Original Version Date: 14-May-2016  
Activated: 
                 28-Jul-2016  
Amendment #1 Date: 16-Mar-2017 
 
 
Amendment #2 Date: 16-Jul-2018 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
T2012-002 Original Version Date: 14-May-2016   
CONFIDENTIAL 
Amendment #1 Date: 16-Mar-2017 
TACL Internal Distribution Only 
Amendment #2 Date: 16-Jul-2018  
77 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
results that would affect patient safety would be immediately communicated to all participating 
TACL sites. All correspondence with sites will be transmitted via email, and all information also 
being posted on a member’s only section of the TACL website. 
 
12.3  Data Safety and Monitory Committee 
This study will be monitored by the CHLA Hematology/Oncology/BMT Data and Safety Monitoring 
Committee (DSMC), which meets every six months to review progress and safety of studies under 
its purview.  In advance of the DSMC meetings, a study progress report will be prepared by the 
TACL Operations Center, study statistician and study PI detailing patient accrual, toxicities, 
deaths on study, current study status, responses, summary of amendments to protocol/consent, 
lists of any publications from study, and plans for study in coming year. Any publications from the 
study (abstract or manuscript) will be attached to the DSMC report. After DSMC review, the DSMC 
will issue a confidential report to the study PI and TACL Operations Center. 
 
Not more than 8 weeks after the DSMC meeting, a DSMC public report will also be created after 
approval of the confidential report and resolution of any issues by the PI. The public report will 
provided to the participating sites, and can be filed at the IRB at each site if required per local IRB 
guidelines. 
 
 
13.0  REFERENCES 
 
1. 
Ko RH, Ji L, Barnette P, Bostrom B, Hutchinson R, Raetz E et al. Outcome of 
patients treated for relapsed or refractory acute lymphoblastic leukemia: a 
Therapeutic Advances in Childhood Leukemia Consortium study. J Clin Oncol 
2010; 28(4): 648-654. e-pub ahead of print 2009/10/21; doi: JCO.2009.22.2950 
[pii]10.1200/JCO.2009.22.2950 
 
2. 
Weiden PL, Wright SE. Vincristine neurotoxicity. N Engl J Med 1972; 286(25): 
1369-1370. e-pub ahead of print 1972/06/22; 
 
3. 
Webb MS, Harasym TO, Masin D, Bally MB, Mayer LD. Sphingomyelin- 
cholesterol liposomes significantly enhance the pharmacokinetic and therapeutic 
properties of vincristine in murine and human tumour models. Br J Cancer 1995; 
72(4): 896-904. e-pub ahead of print 1995/10/01; 
 
4. 
Shah NN, Cole DE, Lester-McCully CM, Wayne AS, Warren KE, Widemann BC. 
Plasma and cerebrospinal fluid pharmacokinetics of vincristine and vincristine 
sulfate liposomes injection (VSLI, marqibo(R)) after intravenous administration in 
Non-human primates.  
Invest  
New  Drugs  2016;  34(1):  61-65.  
doi: 
10.1007/s10637-015-0311-x 
 

TACL Protocol:  
T2012-002  
Original Version Date: 14-May-2016  
Activated: 
                 28-Jul-2016  
Amendment #1 Date: 16-Mar-2017 
 
 
Amendment #2 Date: 16-Jul-2018 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
T2012-002 Original Version Date: 14-May-2016   
CONFIDENTIAL 
Amendment #1 Date: 16-Mar-2017 
TACL Internal Distribution Only 
Amendment #2 Date: 16-Jul-2018  
78 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
5. 
Thomas DA, Kantarjian HM, Stock W, Heffner LT, Faderl S, Garcia-Manero G et 
al. Phase 1 multicenter study of vincristine sulfate liposomes injection and 
dexamethasone in adults with relapsed or refractory acute lymphoblastic leukemia. 
Cancer 2009; 115(23): 5490-5498. e-pub ahead of print 2009/08/27; doi: 
10.1002/cncr.24632 
 
6. 
U.S. Food and Drug Administration, FDA News Release, Aug. 9, 2012. 
http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm315027.htm. In. 
 
7. 
O'Brien S, Thomas DA, Heffner LT, Stock W, Messerschmidt GL, Hagey A et al. 
Marqibo(R) (vincristine sulfate liposomes injection; VSLI) In the Treatment of Adult 
Patients with Advanced, Relapsed/Refractory Acute Lymphoblastic Leukemia 
(ALL): A Combined Analysis of the VSLI-06 and RALLY Studies. ASH Annual 
Meeting Abstracts 2010; 116(21): 2143. 
 
8. 
Herzog CE, Russo ML, Kuttesch J. Phase II Study of Sphingosomal Vincristine 
(SV), 
in 
Pediatric 
Malignancies 
(American 
Society 
of 
Pediatric 
Hematology/Oncology 18th Annual Meeting Abstract, #393). Pediatr Blood Cancer 
2005; 44(Supplement 6): 540. 
 
9. 
Shah NN, Merchant MS, Cole DE, Jayaprakash N, Bernstein D, Delbrook C et al. 
Vincristine Sulfate Liposomes Injection (VSLI, Marqibo(R)): Results From a Phase 
I Study in Children, Adolescents, and Young Adults With Refractory Solid Tumors 
or Leukemias. Pediatr Blood Cancer 2016; 63(6): 997-1005. doi: 
10.1002/pbc.25937 
 
10. 
Parker C, Waters R, Leighton C, Hancock J, Sutton R, Moorman AV et al. Effect 
of mitoxantrone on outcome of children with first relapse of acute lymphoblastic 
leukaemia (ALL R3): an open-label randomised trial. Lancet 2010; 376(9757): 
2009-2017.  
e-pub  ahead  
of  
print  2010/12/07;  doi: 
10.1016/S01406736(10)62002-8 
 
11. 
Abelev B, Adam J, Adamova D, Adare AM, Aggarwal MM, Aglieri Rinella G et al. 
Production of muons from heavy flavor decays at forward rapidity in pp and PbPb 
collisions at sqrt[s(NN)]=2.76 TeV. Phys Rev Lett 2012; 109(11): 112301. epub 
ahead of print 2012/09/26; 
 
12. 
Sun W, Orgel E, Malvar J, Sposto R, Wilkes JJ, Gardner R et al. Treatmentrelated 
adverse events associated with a modified UK ALLR3 induction chemotherapy 
backbone for childhood relapsed/refractory acute lymphoblastic leukemia. Pediatr 
Blood Cancer 2016; 63(11): 1943-1948. doi: 

TACL Protocol:  
T2012-002  
Original Version Date: 14-May-2016  
Activated: 
                 28-Jul-2016  
Amendment #1 Date: 16-Mar-2017 
 
 
Amendment #2 Date: 16-Jul-2018 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
T2012-002 Original Version Date: 14-May-2016   
CONFIDENTIAL 
Amendment #1 Date: 16-Mar-2017 
TACL Internal Distribution Only 
Amendment #2 Date: 16-Jul-2018  
79 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
10.1002/pbc.26129 
 
13. 
Raetz EA, Borowitz MJ, Devidas M, Linda SB, Hunger SP, Winick NJ et al. 
Reinduction platform for children with first marrow relapse of acute lymphoblastic 
Leukemia: A Children's Oncology Group Study[corrected]. J Clin Oncol 2008; 
26(24):  3971-3978.  e-pub  ahead  
of  
print  2008/08/20;  doi: 
10.1200/JCO.2008.16.1414 
 
14. 
Horton TM, Sposto R, Brown P, Reynolds CP, Hunger SP, Winick NJ et al. Toxicity 
assessment 
of molecularly targeted 
drugs incorporated 
into multiagent 
chemotherapy regimens for pediatric acute lymphocytic leukemia (ALL): review 
from an international consensus conference. Pediatr Blood Cancer 2010; 54(7): 
872-878. e-pub ahead of print 2010/02/04; doi: 10.1002/pbc.22414 
 
15. 
Jeha S, Gaynon PS, Razzouk BI, Franklin J, Kadota R, Shen V et al. Phase II study 
of clofarabine in pediatric patients with refractory or relapsed acute lymphoblastic 
leukemia. J Clin Oncol 2006; 24(12): 1917-1923. e-pub ahead of print 2006/04/20; 
doi: 10.1200/JCO.2005.03.8554 
 
16. 
Messinger YH, Gaynon PS, Sposto R, van der Giessen J, Eckroth E, Malvar J et 
al. Bortezomib with chemotherapy is highly active in advanced B-precursor acute 
lymphoblastic leukemia: Therapeutic Advances in Childhood Leukemia & 
Lymphoma (TACL) Study. Blood 2012; 120(2): 285-290. e-pub ahead of print 
2012/06/02; doi: 10.1182/blood-2012-04-418640 
 
17. 
Wexler LH. Ameliorating anthracycline cardiotoxicity in children with cancer: 
clinical trials with dexrazoxane. Semin Oncol 1998; 25(4 Suppl 10): 86-92. 
 
18. 
Woodlock TJ, Lifton R, DiSalle M. Coincident acute myelogenous leukemia and 
ischemic heart disease: use of the cardioprotectant dexrazoxane during induction 
chemotherapy. Am J Hematol 1998; 59(3): 246-248. 
 
19. 
Herman EH, Zhang J, Rifai N, Lipshultz SE, Hasinoff BB, Chadwick DP et al. The 
use of serum levels of cardiac troponin T to compare the protective activity of 
dexrazoxane against doxorubicin- and mitoxantrone-induced 
cardiotoxicity. 
Cancer Chemother Pharmacol 2001; 48(4): 297-304. 
 
20. 
Bernitsas E, Wei W, Mikol DD. Suppression of mitoxantrone cardiotoxicity in 
multiple sclerosis patients by dexrazoxane. Ann Neurol 2006; 59(1): 206-209. 
doi: 10.1002/ana.20747 
 

TACL Protocol:  
T2012-002  
Original Version Date: 14-May-2016  
Activated: 
                 28-Jul-2016  
Amendment #1 Date: 16-Mar-2017 
 
 
Amendment #2 Date: 16-Jul-2018 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
T2012-002 Original Version Date: 14-May-2016   
CONFIDENTIAL 
Amendment #1 Date: 16-Mar-2017 
TACL Internal Distribution Only 
Amendment #2 Date: 16-Jul-2018  
80 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
21. 
Feijen EA, Leisenring WM, Stratton KL, Ness KK, van der Pal HJ, Caron HN et al. 
Equivalence Ratio for Daunorubicin to Doxorubicin in Relation to Late Heart Failure 
in Survivors of Childhood Cancer. J Clin Oncol 2015; 33(32): 3774-3780. 
doi: 10.1200/JCO.2015.61.5187 
 
22. 
Bedikian AY, Silverman JA, Papadopoulos NE, Kim KB, Hagey AE, Vardeleon A 
et al. Pharmacokinetics and Safety of Marqibo (Vincristine Sulfate Liposomes 
Injection) in Cancer Patients With Impaired Liver Function. The Journal of Clinical 
Pharmacology 2011; 51(8): 1205-1212. doi: 10.1177/0091270010381499 
 
 
 
 
 
 
 
 
 
 
 
 

TACL Protocol:  
T2012-002  
Original Version Date: 14-May-2016  
Activated: 
                 28-Jul-2016  
Amendment #1 Date: 16-Mar-2017 
 
 
Amendment #2 Date: 16-Jul-2018 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
T2012-002 Original Version Date: 14-May-2016   
CONFIDENTIAL 
Amendment #1 Date: 16-Mar-2017 
TACL Internal Distribution Only 
Amendment #2 Date: 16-Jul-2018  
81 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
14.0  SAMPLE INFORMED CONSENT 
Local IRB changes to this document are allowed. Changes within the document should not 
substantially alter the meaning or intent of the consent document. If the institution or IRB insists 
on making deletions or more substantive modifications to the consent, especially in the risks 
sections, they should be reviewed and approved by the TACL Operations Center. 
 
SAMPLE INFORMED ASSENT*/CONSENT DOCUMENT / PARENTAL PERMISSION FOR 
PARTICIPATION IN RESEARCH *Assent for patients >13 years of age *Assent for patients <13 
years of age should be written per institutional guidelines 
 
TACL Protocol T2012-002:  A Pilot Study of Vincristine Sulfate Liposome Injection (Marqibo®) in 
Combination with UK ALL R3 Induction Chemotherapy for Children, Adolescents, and Young 
Adults with Relapse of Acute Lymphoblastic Leukemia 
IND 128316 
 
Subject Name: 
 
Medical Record #: 
 
Physician: 
 
 
When we say “you” in this consent form, we mean you or your child; “we” means the doctors 
and other staff. 
 
This is a clinical trial, a type of research study. Your study doctor will explain the clinical trial to 
you. Clinical trials include only people who choose to take part. Please take your time to make 
your decision about taking part. You may discuss your decision with your friends and family. You 
can also discuss it with your health care team. If you have any questions, you can ask your study 
doctor for more explanation. 
 
This study is being carried out by the Therapeutic Advances in Childhood Leukemia & Lymphoma 
(TACL) Consortium. TACL is a group of Universities and Children’s Hospitals that are working 
together to find treatments for children with leukemia and lymphoma. Funding for this research is 
provided by Acrotech Biopharma and Gateway for Cancer Research. 
 
You are being asked to take part in this research study because your acute lymphoblastic 
leukemia or lymphoma (ALL) has relapsed. Relapse means your leukemia has come back after 
treatment. Marqibo® is a drug approved by the FDA (Food and Drug Administration) for the 
treatment of ALL in adults. This study is being done to find out if Marqibo® can be safely given 
during treatment with standard chemotherapy drugs. 
 

TACL Protocol:  
T2012-002  
Original Version Date: 14-May-2016  
Activated: 
                 28-Jul-2016  
Amendment #1 Date: 16-Mar-2017 
 
 
Amendment #2 Date: 16-Jul-2018 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
T2012-002 Original Version Date: 14-May-2016   
CONFIDENTIAL 
Amendment #1 Date: 16-Mar-2017 
TACL Internal Distribution Only 
Amendment #2 Date: 16-Jul-2018  
82 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
It is important for you to know why this study is being done before you decide to take part in this 
research study. This consent will tell you about the study. This consent will also tell you about 
risks and side effects that might happen to you if you take part in this study. You also need to 
know you do not have to take part in this study. You can talk to your doctor about other cancer 
treatments. Because all of the drugs used in this study are each available to doctors, it is possible 
for you to receive these drugs without taking part in this study. Taking part in this study is voluntary. 
Why is this study being done? 
 
The goals of this study are: 
 
• 
To evaluate the side effects (good and/or bad) of giving Marqibo® with other 
chemotherapy using the standard drugs dexamethasone, pegaspargase and 
mitoxantrone. 
 
• 
To evaluate the pharmacokinetics of Marqibo® when it is given with other 
chemotherapy agents 
 
• 
To measure how effective the combination Marqibo® with standard chemotherapy 
drugs is at treating children and young adults with relapsed ALL 
 
 
How many people will take part in this study? 
 
It is expected that approximately 25 – 38 children and young adults will take part in this study. 
 
 
What will happen if I take part in this research study? 
 
Before you begin the study… 
 
You will need to have the following exams, tests or procedures to find out if you can be in the 
study. These exams, tests or procedures are part of your regular cancer care and may be done 
even if you do not join the study. If you have had some of them recently, they may not need to 
be repeated. The results of these tests will be reviewed. It is possible that after these tests are 
reviewed, you will not be able to take part in the study. If you are not able to take part in the 
study, your doctor will discuss with you the reasons why. 
 
• 
A medical history 
• 
Physical exam with vital signs 
• 
Bone marrow test to check your cancer (see Tests on the Bone Marrow, below) 
• 
Lumbar puncture to test the fluid in your spinal cord (see Lumbar Punctures, below) 
• 
Blood tests to check your organ (liver, kidneys) function 

TACL Protocol:  
T2012-002  
Original Version Date: 14-May-2016  
Activated: 
                 28-Jul-2016  
Amendment #1 Date: 16-Mar-2017 
 
 
Amendment #2 Date: 16-Jul-2018 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
T2012-002 Original Version Date: 14-May-2016   
CONFIDENTIAL 
Amendment #1 Date: 16-Mar-2017 
TACL Internal Distribution Only 
Amendment #2 Date: 16-Jul-2018  
83 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
• 
Tests to make sure you are not pregnant (if you are a female and old enough to 
become pregnant) or have certain types of infections 
• 
Echocardiogram (ECHO) which uses sound waves to test heart function 
• 
EKG a test to measure the electrical activity in your heart 
 
Tests on the Bone Marrow 
Examinations of the bone marrow will be performed routinely and may be done at the discretion 
of your study doctor. You have already had many tests of your bone marrow for your previous 
treatment of ALL. Many children receive some form of sedation or anesthesia during this 
procedure. A small area over your hipbone on the back will be cleaned and numbed with lidocaine 
and/or with an anesthetic cream. Approximately 2 teaspoons of bone marrow will be withdrawn 
through a needle inserted into the bone. The test is painful, especially when the bone marrow is 
withdrawn. There is also a small risk of bleeding or infection from this procedure. An optional 
research test to evaluate for the smallest amounts of leukemia detectable in the bone marrow 
(minimal residual disease) may be sent on your sample if you agree.  
 
Lumbar Punctures (“L.P.s”, “spinal taps”) 
You are familiar with spinal taps since they were done during your initial therapy for ALL. Whether 
you decide to participate or not on this study, additional spinal taps will need to be done to give 
medicines, which are necessary to prevent the leukemia from spreading to the spinal fluid. Many 
children receive some form of sedation or anesthesia during this procedure. Spinal taps are 
painful and may cause headaches. The skin at the site of needle insertion is usually numbed with 
an anesthetic cream or lidocaine before the procedure is performed. Approximately 1 teaspoon 
of spinal fluid will be withdrawn prior to injection of the medicine (methotrexate). 
 
 
Treatment 
 
There are three groups in which you may enroll and you and your doctor will discuss which regimen 
is best for you and your disease. 
 
Treatment cohort A of this study consists of approximately 4 weeks of re-induction chemotherapy. 
You will receive 4 weekly doses Marqibo®. The other standard chemotherapy will start on day 1 
and continue until day 19. The table below outlines the therapy you will receive. 
 
Treatment cohort B is the same as Cohort A except it is a milder regimen that does not use one of 
the drugs called anthracycline (e.g. mitoxantrone). 
 
Treatment cohort C is the mildest version of this regimen and consists of a cycle of 1 dose of Marqibo 
and a standard chemotherapy regimen of 2 weeks. This cycle may be repeated a second time if you 
and your doctor decide to do so. 
 
 

TACL Protocol:  
T2012-002  
Original Version Date: 14-May-2016  
Activated: 
                 28-Jul-2016  
Amendment #1 Date: 16-Mar-2017 
 
 
Amendment #2 Date: 16-Jul-2018 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
T2012-002 Original Version Date: 14-May-2016   
CONFIDENTIAL 
Amendment #1 Date: 16-Mar-2017 
TACL Internal Distribution Only 
Amendment #2 Date: 16-Jul-2018  
84 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
Cohort A: UK ALL R3/Marqibo 
 
 
Day  
1  
Day  
2  
Day  
3  
Day  
4  
Day  
5  
Day  
8  
Day  
15  
Day  
 16  
Day  
17  
Day  
18  
Day  
19  
Day  
22  
Day  
29  
Marqibo®  
  
  
  
  
  
    
  
  
  
  
  
 
Dexamethasone  
  
  
  
      
  
          
Mitoxantrone  
  
  
  
  
  
  
  
  
  
  
  
  
 
Pegaspargase  
  
  
  
  
  
  
  
  
    
  
  
IT Therapy  
  
  
  
  
  
    
  
  
  
  
  
# Erwina asparaginase or Rylaze ® may be substituted for pegaspargase if patient has a 
PEG allergy. 
 
Cohort B: UK ALL R3/Marqibo without anthracycline (e.g. mitoxantrone) 
 
 
 
 
 
 
 
 
 
 
 
Day 
1 
Day 
2 
Day 
3 
Day 
4 
Day 
5 
Day 
8 
Day 
15 
Day 
16 
Day 
17 
 
Day 
18 
Day 
19 
Day 
22 
Day 
29 
Marqibo® 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dexamethasone 
 
 
 
 
 
 
 
 
 

 
 
 
Pegaspargase 
 
 
 
 
 
 
 
 
 
 
 
 
 
IT Therapy 
 
 
 
 
 
 
 
 
 
 
 
 
 

TACL Protocol:  
T2012-002  
Original Version Date: 14-May-2016  
Activated: 
                 28-Jul-2016  
Amendment #1 Date: 16-Mar-2017 
 
 
Amendment #2 Date: 16-Jul-2018 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
T2012-002 Original Version Date: 14-May-2016   
CONFIDENTIAL 
Amendment #1 Date: 16-Mar-2017 
TACL Internal Distribution Only 
Amendment #2 Date: 16-Jul-2018  
85 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
Cohort C: Modified Maintenance with Marqibo® 
 
Cycle 1 
Day 
1 
Day 
2 
Day 
3 
Day 
4 
Day 
5 
Day 
8 
Daily 
through 
day 13 
Day 
14 
Marqibo® 
 
 
 
 
 
 
 
 
Dexamethasone 
 
 
 
 
 
 
 
Methotrexate 
(PO) 
 
 
 
 
 
 
 
Mercaptopurine 
(PO) 
  
        
 
IT Therapy as 
needed no more 
than 
once 
weekly  







 
 
Various methods will be used to give drugs:  
• 
PO – Drug is given by tablet or liquid swallowed through the mouth  
• 
IV – Drug is given using a needle or tubing inserted into a vein. It can be given by IV push 
over several minutes or by infusion over minutes to hours  
• 
IM – Drug is given using a needle injected into the muscle (IM shot)  
• 
IT – Drug used to treat the brain and spinal cord and given using a needle inserted into 
the spinal canal  
 
 
Medical Tests During Treatment  
  
Whether you are on this study or not the following medical tests will be done to monitor for 
response to treatment as well as side effects related to treatment. These include:  
• 
Physical exams with vital signs   
  
  
• 
Blood tests to check your organ function including  
o CBC to look at your blood cells  
o Chemistries to look at elements and minerals in your blood  
o Blood tests to look at your liver, pancreas and kidney function  
• 
Bone Marrow Tests  
• 
Lumbar Punctures  
• 
EKG a test to measure the electrical activity in your heart  
  
You will have regular medical appointments throughout treatment.  
  
Tests for research purposes:  

TACL Protocol:  
T2012-002  
Original Version Date: 14-May-2016  
Activated: 
                 28-Jul-2016  
Amendment #1 Date: 16-Mar-2017 
 
 
Amendment #2 Date: 16-Jul-2018 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
T2012-002 Original Version Date: 14-May-2016   
CONFIDENTIAL 
Amendment #1 Date: 16-Mar-2017 
TACL Internal Distribution Only 
Amendment #2 Date: 16-Jul-2018  
86 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
In addition to the routine tests listed above, we would like to do other tests while you are enrolled 
on the study.   
  
• 
Marqibo® Drug Levels (Pharmacokinetics)  
  
Mandatory: Pre-Dose 1, 2 and 3 samples for arm A and B. Arm C would only have pre-
dose 1 and day 8 trough levels during each cycle for patients that continue on to have a 
second cycle. These samples can be drawn from a central line, or the same line that is 
being used to give your chemotherapy.  
  
Optional: Dose 1 samples for Arm A and B. If you do not agree to have these samples 
taken, you can still receive treatment as part of this study. These samples must be 
obtained from a separate line that is not being used for infusion of Marqibo®. (e.g., 
peripheral IV)  
  
Doctors have developed tests to determine the levels of Marqibo® in the body. During 
therapy, researchers would like to draw an extra ½ teaspoon (2.5-3mL) of blood to 
measure the levels of Marqibo® in your body. Any leftover blood that is not used for this 
test will be destroyed. Samples will be drawn on the following schedule.   
  
Mandatory Arm A & B: (May 
be collected from same line as 
Marqibo® infusion line or a 
central line.)  
 
Optional for Arm A, B and C: 
(Must be collected from  
separate line than Marqibo® 
infusion line.) 
 
• 
30 minutes before start 
of infusion (SOI) prior to 
Dose #1 
 
• 
Pre Dose #21 
 
• 
Pre 
Dose 
#3 
(Not 
required for Arm C) 
 
 
• 
End of infusion (EOI) 
 
• 
3 hours (EOI + 2 hours) 
 
• 
25 hours (EOI + 24 
hours) 
Mandatory (Arm C): (May be 
collected from same line as 
Marqibo® infusion line or a 
central line.) 
 
• 
Pre-dose 1 
• 
Day 8 trough level 
 
• 
End of infusion (EOI) 
 
• 
3 hours (EOI + 2 hours) 
 
• 
25 hours (EOI + 24 
hours) 

TACL Protocol:  
T2012-002  
Original Version Date: 14-May-2016  
Activated: 
                 28-Jul-2016  
Amendment #1 Date: 16-Mar-2017 
 
 
Amendment #2 Date: 16-Jul-2018 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
T2012-002 Original Version Date: 14-May-2016   
CONFIDENTIAL 
Amendment #1 Date: 16-Mar-2017 
TACL Internal Distribution Only 
Amendment #2 Date: 16-Jul-2018  
87 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
1. For Arm C, each course will have only one dose of Marqibo, but on Day 8 there will be a trough 
level. 
 
Final Study Visit  
Within 30 days after you finish the last dose of study drugs, your doctor will need to check to see 
how you are doing. The doctor will ask you how you feel, if you have trouble doing your daily 
routine, and what drugs you are taking. You will also have the following tests done:   
• 
Physical exam, weight, and vital signs  
• 
CBC and chemistry blood tests  
• 
EKG a test to measure the electrical activity in your heart  
  
Follow-up Tests  
After completing the treatment on this study we would like to continue to collect some medical 
information about how you are doing for as long as you are willing to let us. We will collect 
information on how your ALL is doing, what kind of therapy you may be getting and if you have 
any long term side effects.   
  
What are my responsibilities?  
  
• 
During the study you will be asked to take all your chemotherapy drugs as prescribed. It is 
very important that you follow your doctor’s instructions regarding when and how to take your 
study medications. Be sure to ask your study doctor or nurse if you have any questions about 
taking your study medications.   
  
• 
If you experience any unusual side effects as explained by your study doctor, you should 
contact the study center immediately. You should also contact your study doctor if you are 
hospitalized for any reason during the study or within 30 days after completion of therapy.  
  
  
How long will I be in the study?   
  
You will be in the study for one course of therapy which will last approximately 1 month if you are 
in Cohort A or B. If you are in Cohort C, you will be in the study for 2 weeks if you receive 1 cycle 
and 1 month if you receive 2 cycles. After completing the study therapy, your doctor will discuss 
with you the options for additional treatment. These options will vary depending on whether or not 
your leukemia responded to the therapy. Additionally, after participating in the study, you will 
continue to be followed to evaluate for any late effects and overall outcomes. We will primarily 
obtain this information from your primary team, although the study committee may contact you in 
the future for any additional questions.   
Can I stop being in the study?  
  

TACL Protocol:  
T2012-002  
Original Version Date: 14-May-2016  
Activated: 
                 28-Jul-2016  
Amendment #1 Date: 16-Mar-2017 
 
 
Amendment #2 Date: 16-Jul-2018 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
T2012-002 Original Version Date: 14-May-2016   
CONFIDENTIAL 
Amendment #1 Date: 16-Mar-2017 
TACL Internal Distribution Only 
Amendment #2 Date: 16-Jul-2018  
88 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
Yes. You can decide to stop at any time. Your clinical care will not be affected by your decision to 
withdraw. Tell your doctor if you are thinking about stopping or decide to stop. He or she will tell 
you how to stop safely. You will be asked to visit the hospital or clinic for some follow-up tests to 
make sure all the side effects you may have experienced have gone away.  
  
It is important to tell your doctor if you are thinking about stopping so any risks from the study 
treatment and chemotherapy drugs can be evaluated by your doctor. Another reason to tell your 
doctor that you are thinking about stopping is to discuss what follow-up care and testing could be 
most helpful for you.  
  
Your doctor may stop you from taking part in this study at any time without your permission if 
he/she believes it is in your best interest; if you do not follow the study rules; if you become 
pregnant or begin to breast feed; or if the study is stopped.  
  
  
What side effects or risks can I expect from being in the study?   
  
All people who receive cancer treatment are at risk of having side effects. In addition to killing 
leukemia cells, chemotherapy drugs can damage normal tissues and produce side effects. Side 
effects are usually reversible when the medication is stopped, but occasionally can persist and 
cause serious complications or death. The therapy used in this clinical trial is made stronger so 
that it can kill cancer cells quickly before they can become resistant to treatment. Protocols used 
to treat relapsed leukemia are more intense than are those to treat newly diagnosed disease. It is 
not possible to predict whether the side effects listed below, or other rare side effects may occur. 
Side effects can be increased when chemotherapy drugs are combined. It is possible that this re-
induction therapy will prove better than past therapies for relapsed ALL, but it may be no better or 
worse than other treatments. Any or all of the agents used alone or in combination with other 
agents could lead to life-threatening complications and other side effects.   
 
 
 
Protocol Updates:  
As of 12/3/2021, a total of 23 subjects have been treated on study. 13 were treated on Cohort A, 
7 were treated on Cohort B and 3 were treated on Cohort C. At Dose Level 1 Cohort A, there were 
8 patients who were treated, and 2 patients developed infection with recovery from the infection. 
The most common side effects were low blood counts. At Dose Level 2 Cohort A, there were two 
patients with serious infections and delay in recovery of blood counts. In one patient, infection 
was the cause of death. Therefore, it was determined that Dose Level 2 was too high for Cohort 
A, which is the most intensive regimen. All future patients enrolled on Cohort A will be treated at 
Dose Level 1.  7 patients have been treated on Cohort B and 3 patients on Cohort  C at this time, 
and due to the lower intensity of this regimen, Cohorts B and C patients were treated at Dose 
Level 2 with a plan to decrease to Dose Level 1 if this level is found to be too high. Due to the 
development of toxicities, the last 5 patients in Cohort B were treated at Dose Level 1. As of 
Protocol Amendment #3, future patients on Cohort B will be treated at Dose level 1. On Cohort C, 

TACL Protocol:  
T2012-002  
Original Version Date: 14-May-2016  
Activated: 
                 28-Jul-2016  
Amendment #1 Date: 16-Mar-2017 
 
 
Amendment #2 Date: 16-Jul-2018 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
T2012-002 Original Version Date: 14-May-2016   
CONFIDENTIAL 
Amendment #1 Date: 16-Mar-2017 
TACL Internal Distribution Only 
Amendment #2 Date: 16-Jul-2018  
89 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
future patients will be treated at Dose Level 2. This may change depending on new information 
we get as more patients are treated on this study. 
 
Infection  
There is a serious risk of developing an infection while being treated on this research study. This 
could lead to life-threatening complications, including heart failure, severe infection or death. 
Because of the intensity of Cohort A, risks of infection may be higher.  
 
To reduce the risk of developing an infection, you will be required to take antifungal medication if you 
are enrolled onto Cohort A or B. You may need to be hospitalized for part of the treatment so that 
your doctors and nurses can monitor you very carefully for any signs or symptoms of infection.  
  
If you experience any of the following signs or symptoms while you are being treated on this 
research study, it is very important to call your doctor or nurse right away.  
• 
Fever  
• 
Pain (earache, sore throat, headache, pain with urination or with bowel movement)  
• 
Redness, swelling, pain, or pus at the site of your central catheter  
  
Common side effects include nausea, vomiting, hair loss and fatigue. The risks from having your 
blood taken are minimal, but can include an infection or a blood clot. There may be pain and or 
bruising at the site where the needle is inserted to draw your blood. Chemotherapy causes 
temporary bone marrow depression. Red blood cell and platelet transfusions may be required. 
Bone marrow depression means that your bone marrow may make:  
  
• 
Less red blood cells causing anemia;   
• 
Less platelet, causing bruising and an increased chance of bleeding;  
• 
Less white blood cells, causing a risk for serious infections.   
  
Each drug will have a unique set of side effects. Side effects related to drugs occur in people at 
different rates or frequencies.   
  
In a study of Marqibo in 21 children and adolescents with refractory malignant disease, at least 
one out of five children and adolescents reported the following adverse events:  
  
• 
Changes in blood test results of electrolytes (salts) and other chemistries including 
increases in liver enzymes, glucose, triglycerides, bilirubin, cholesterol, magnesium, and 
uric acid and decreases in potassium, calcium, magnesium, albumin, sodium, and 
phosphorus  
• 
Fatigue  
• 
Decreases in blood counts including red blood cells (anemia), white blood cells, platelet 
count, and neutrophil count  
• 
Abdominal pain  
• 
Fast heart rate  
• 
Diarrhea  

TACL Protocol:  
T2012-002  
Original Version Date: 14-May-2016  
Activated: 
                 28-Jul-2016  
Amendment #1 Date: 16-Mar-2017 
 
 
Amendment #2 Date: 16-Jul-2018 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
T2012-002 Original Version Date: 14-May-2016   
CONFIDENTIAL 
Amendment #1 Date: 16-Mar-2017 
TACL Internal Distribution Only 
Amendment #2 Date: 16-Jul-2018  
90 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
• 
Nausea, vomiting  
• 
Fever  
• 
Prolonged bleeding time  
• 
Bruising, nose bleeds  
• 
Reduced appetite  
• 
Constipation  
• 
Low blood pressure  
• 
Infections  
• 
Back pain, headache, pain, muscle pain  
• 
The sensation of numbness, tingling or burning on the skin   
• 
Itching  
• 
Rash  
  
In general, the safety profile of Marqibo has been similar to that of vincristine.  
  
Marqibo ®   
  
Likely (Happens to 21- 
100 children out of 100)  
Less Likely (Happens to 5-20 
children out of every 100)  
Rare (Happens to <5 children 
out of every 100)  
• 
Constipation  
• 
Hair loss  
• 
Reversible 
nerve 
problem that may affect 
the way you walk or the 
feelings in your fingers 
or toes  
• 
Loss of deep tendon 
reflexes (such as the 
“knee jerk”) noted only 
on physical exam  
• 
Insomnia  
• 
Headache  
• 
Nausea 
• 
Vomiting  
• 
Diarrhea 
• 
Anorexia 
 
 
  
• 
Jaw pain   
• 
Muscle weakness 
• 
Pain and bloating in your 
abdomen  
• 
Numbness and tingling  
• 
Wrist or foot drop  
• 
Abnormal 
walk 
with 
foot 
slapping  
• 
A drop in white blood cells, red 
blood cells and platelets in the 
blood  
• 
A low number of red blood cells 
can make you feel tired and 
weak.  
• 
A low number of white blood 
cells can make it easier to get 
infections.  
• 
A low number of platelets can 
make you bruise and bleed more 
easily. 
• 
Electrolyte (salt and mineral) 
abnormalities due to breakdown 
of tumor 
• 
High blood pressure 
• 
Complete stoppage of your 
intestinal activity which can 
result in intestinal blockage  
• 
If the drug leaks out of the 
vein 
when 
being 
administered it can cause 
damage to nearby tissue  
• 
Seizures  
• 
Vocal cord paralysis  
• 
Difficulty 
breathing 
and 
respiratory failure 
• 
Inability to walk  
• 
Decreased ability to hear 
clearly  
• 
Dizziness  
• 
Difficulty with urination or 
increase desire to urinate  
• 
Drooping eyelids  
• 
Double 
vision, 
difficulty 
seeing at night 
• 
Life-threatening 
infection 
which can lead to significant 
complications including death 
• 
Weight loss 

TACL Protocol:  
T2012-002  
Original Version Date: 14-May-2016  
Activated: 
                 28-Jul-2016  
Amendment #1 Date: 16-Mar-2017 
 
 
Amendment #2 Date: 16-Jul-2018 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
T2012-002 Original Version Date: 14-May-2016   
CONFIDENTIAL 
Amendment #1 Date: 16-Mar-2017 
TACL Internal Distribution Only 
Amendment #2 Date: 16-Jul-2018  
91 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
Likely (Happens to 21- 
100 children out of 100)  
Less Likely (Happens to 5-20 
children out of every 100)  
Rare (Happens to <5 children 
out of every 100)  
• 
Worsening of graft versus 
host disease 
  
  
 
 
 

TACL Protocol:  
T2012-002  
Original Version Date: 14-May-2016  
Activated: 
                 28-Jul-2016  
Amendment #1 Date: 16-Mar-2017 
 
 
Amendment #2 Date: 16-Jul-2018 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
T2012-002 Original Version Date: 14-May-2016   
CONFIDENTIAL 
Amendment #1 Date: 16-Mar-2017 
TACL Internal Distribution Only 
Amendment #2 Date: 16-Jul-2018  
92 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
Dexamethasone (given orally)  
  
Likely (Happens to 21- 
100 children out of 100) 
 
Less Likely (Happens to 5-20 
children out of every 100)  
Rare 
(Happens 
to 
<5 
children out of every 100)   
• 
Overeating  
• 
Difficulty sleeping 
or falling asleep  
• 
Decreased ability of 
the body to fight 
infection  
• 
Personality 
changes with mood 
swings  
• 
Changes 
in 
hormone  
• 
production 
that 
cause weight gain 
especially 
around 
the abdomen and 
shoulders, 
puffy 
cheeks, muscle  
• 
weakness 
and 
make 
your body 
less able to deal 
with stress  
• 
Pimples  
 
• 
Upset and irritated stomach 
with heartburn  
• 
High blood sugar which 
may  
• 
require treatment  
• 
Red face  
• 
Poor wound healing   
• 
Infections  
• 
Fluid retention  
• 
Stretch marks and easy 
bruising of the skin  
• 
Muscle weakness  
• 
Lessening of calcium in the 
bones making them more 
susceptible to fracture  
• 
Cataracts which are usually 
more reversible in children  
 
• 
Abnormal amounts of  
• 
uric acid in the blood  
• 
Inflammation of the 
pancreas  
• 
Increased pressure in 
the eyes High blood 
pressure  
• 
Serious changes in 
mood, 
personality 
and/or 
severe 
depression   
• 
Dizziness   
• 
Headache  
• 
Bone Fractures  
• 
Slowed growth   
• 
Stomach ulcers  
• 
Stomach 
and 
intestinal 
tract 
bleeding from ulcers  
Increased pressure in 
the brain which can 
lead 
to 
difficulty 
seeing, pressure in the 
eyes and headache  
• 
Damage to the joints 
which can result in 
pain 
and 
loss 
of 
motion 
usually 
involving the 
joints of the hip and 
knee  
  
  
  
 

TACL Protocol:  
T2012-002  
Original Version Date: 14-May-2016  
Activated: 
                 28-Jul-2016  
Amendment #1 Date: 16-Mar-2017 
 
 
Amendment #2 Date: 16-Jul-2018 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
T2012-002 Original Version Date: 14-May-2016   
CONFIDENTIAL 
Amendment #1 Date: 16-Mar-2017 
TACL Internal Distribution Only 
Amendment #2 Date: 16-Jul-2018  
93 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
Mercaptopurine  (given orally)  
 
 
Likely (Happens to 21-100 
children out of every 100) 
 
 
Less Likely (Happens to 5-20 
children out of every 100) 
 
Rare (Happens to <5 children 
out of every 100) 
• 
Condition where bone 
marrow 
activity 
is 
decreased so that there 
are fewer red blood 
cells, white blood cells, 
and cells involved in 
blood clotting (L) 
 
• 
Poor appetite  
• 
Nausea 
• 
Vomiting  
• 
Diarrhea  
• 
General feeling of being 
unwell 
• 
Red rash (L) 
• 
Low concentration of sperm 
 
• 
Hives 
• 
High level of molecule 
called uric acid in the blood 
• 
White layer of film in the 
mouth 
• 
Inflammation of the liver (L) 
• 
Increased liver enzymes  
• 
Increased darkening of the 
skin (L) 
• 
Inflammation 
of 
the 
pancreas   
• 
Fibrosis of the liver (L) 
• 
High levels of a molecule 
called bilirubin in the blood 
• 
Fibrosis of the lungs  
• 
Cancer caused by this 
therapy  
Birth defects caused by mercaptopurine have been noted in animals. Women receiving mercaptopurine 
in the first trimester of pregnancy have an increased chance of having an abortion. It is unknown whether 
the drug is excreted in breast milk.  
(L) Toxicity may also occur later.  
 
Methotrexate (orally) 
Likely (Happens to 21-100 
children out of 100) 
Less Likely (Happens to 5-20 
children out of every 100) 
Rare (Happens to <5 children 
out of every 100) 
• Elevation in the blood of 
certain enzymes found in the 
liver 
 
 
• Nausea 
• Vomiting 
• Decreased appetite 
• Low blood counts 
• Oral ulcers 
• Fatigue 
• Learning disability 
 
• Allergic reactions 
• Blurred vision 
• Severe skin reactions 
• Hair loss 
• Kidney damage 
• Neurologic 
toxicity 
(headache, blurred vision, 
difficulty moving, speaking 
or seeing) 

TACL Protocol:  
T2012-002  
Original Version Date: 14-May-2016  
Activated: 
                 28-Jul-2016  
Amendment #1 Date: 16-Mar-2017 
 
 
Amendment #2 Date: 16-Jul-2018 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
T2012-002 Original Version Date: 14-May-2016   
CONFIDENTIAL 
Amendment #1 Date: 16-Mar-2017 
TACL Internal Distribution Only 
Amendment #2 Date: 16-Jul-2018  
94 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
Likely (Happens to 21-100 
children out of 100) 
Less Likely (Happens to 5-20 
children out of every 100) 
Rare (Happens to <5 children 
out of every 100) 
• Diarrhea 
• Inflammation of the lungs 
and/or heart 
 
 
 
 
Mitoxantrone (given into the vein)  
 
Likely (Happens to 21-100 
children out of 100) 
Less Likely (Happens to 5-20 
children out of every 100) 
Rare (Happens to <5 children 
out of every 100) 
• 
Nausea 
• 
Vomiting 
• 
Diarrhea 
• 
Fever 
• 
Loss of Appetite 
• 
Blue or blue green color to 
urine and the white of the 
eye 
• 
Fewer white blood cells, red 
blood cells and platelets in 
the blood. 
• 
A low number of red 
blood cells can make 
you feel tired and weak 
• 
A low number of white 
blood cells can make it 
easier to get infections 
• 
A 
low 
number 
of 
platelets causes you to 
bruise and bleed more 
easily 
• 
Inflammation and/or sores 
in the mouth, throat and/or 
esophagus 
• 
Increase chance of infection 
• 
Temporary hair loss 
• 
Tiredness 
• 
Absence of or irregular 
menstrual cycles (periods)  
• Abdominal or back pain 
• Headache 
• Swelling of the veins 
• Constipation 
• Elevation in the blood of certain 
enzymes found in the liver 
• Rash and/or itching and dryness 
of the skin which can lead to 
flakey skin 
• Decrease in your hearts ability 
to pump blood 
• Damage to the heart muscle 
which may not be noticeable or 
may make you feel tired, weak, 
feel short of breath, and retain 
fluid 
 
 
• Severe allergic reaction 
which 
can 
be 
life 
threatening with shortness 
of 
breath, 
low 
blood 
pressure and a rapid heart 
rate  
• Increased fluid around the 
heart 
• An irregular heart beat 
which is usually slower 
than normal 
• Seizures 
• Damage to the skin if the 
medication leaks from a 
vein which can lead to 
pain and inflammation  
• The rapid death of large 
numbers of tumor cells 
which 
can 
cause 
the 
potassium and phosphate 
salts and the uric acid in 
the blood to rise quickly 
and this could lead to a life-
threatening irregular heart 
beat or damage to the 
kidneys. 
• Swelling and redness of 
the eyes 
• Ulceration or bleeding of 
the lower intestinal tract 

TACL Protocol:  
T2012-002  
Original Version Date: 14-May-2016  
Activated: 
                 28-Jul-2016  
Amendment #1 Date: 16-Mar-2017 
 
 
Amendment #2 Date: 16-Jul-2018 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
T2012-002 Original Version Date: 14-May-2016   
CONFIDENTIAL 
Amendment #1 Date: 16-Mar-2017 
TACL Internal Distribution Only 
Amendment #2 Date: 16-Jul-2018  
95 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
Likely (Happens to 21-100 
children out of 100) 
Less Likely (Happens to 5-20 
children out of every 100) 
Rare (Happens to <5 children 
out of every 100) 
• 
Temporary decrease in the 
number of sperm which 
may temporarily decrease 
the ability to have children  
 
 
• Damage or inflammation of 
lung tissue which may 
make you short of breath 
• Damage 
to 
the 
heart 
muscle which may make 
you tired, weak, feel short 
of breath, and retain fluid 
and may require treatment 
• Liver damage 
• A new cancer or leukemia 
resulting 
from 
this 
treatment. 
  
 
Methotrexate (given into the spinal fluid)  
  
Likely (Happens to 21-100 
children out of 100) 
Less Likely (Happens to 5-20 
children out of every 100) 
Rare (Happens to <5 children out 
of every 100) 
▪ 
Nausea 
▪ 
Headache 
▪ 
Abnormally high number of 
cells in the spinal fluid 
▪ 
Learning disability 
▪ 
Vomiting 
▪ 
Fever 
▪ 
Rash 
▪ 
Drowsiness 
▪ 
Stiff neck 
▪ 
Irritation of tissues in the 
brain/spinal cord 
▪ 
Unsteady walk 
▪ 
Seizures 
▪ 
Partial paralysis 
▪ 
Damage to brain tissue 
▪ 
Increasingly 
poor 
nervous 
system function 
▪ 
Fewer red and white blood 
cells and platelets in the blood 
• 
a low number of red 
blood cells can make 
you feel tired and 
weak 
• 
a low number of white 
blood cells can make it 
easier to get infections 
• 
a 
low 
number 
of 
platelets causes you 
to bruise and bleed 
more easily 
 
  
  
 
 

TACL Protocol:  
T2012-002  
Original Version Date: 14-May-2016  
Activated: 
                 28-Jul-2016  
Amendment #1 Date: 16-Mar-2017 
 
 
Amendment #2 Date: 16-Jul-2018 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
T2012-002 Original Version Date: 14-May-2016   
CONFIDENTIAL 
Amendment #1 Date: 16-Mar-2017 
TACL Internal Distribution Only 
Amendment #2 Date: 16-Jul-2018  
96 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
Pegaspargase (given into the muscle)  
Likely (Happens to 21-
100 children out of 100) 
Less Likely (Happens to 5-20 
children out of every 100) 
Rare but serious (Happens to <5 
children out of every 100) 
• An increase in the level 
of ammonia that is 
found in the blood 
• A decrease in levels of 
factors in the blood that 
help your blood to clot 
normally 
• A feeling of extreme 
tiredness not relieved 
by sleep 
• Weakness 
• Diarrhea 
 
• Rashes, hives, swelling of the 
lips 
• Feeling short of breath or 
shortness of breath 
• Some sort of allergic reaction 
such as a rash, hives or fever 
that may require pretreatment 
with antihistamines prior to the 
injection 
• Puffiness or swelling around 
the eyes 
• Fluid build-up in the tissues or 
Fluid retention 
• High levels of sugar in the 
blood 
that 
may 
require 
treatment 
• Elevation in the blood of certain 
enzymes or bilirubin found in 
the liver which may mean liver 
irritation or damage 
• High levels of uric acid in the 
blood which could damage the 
kidneys 
• Headache 
• Dizziness 
• Chest pain 
• A fast heartbeat which may 
cause pain in the chest 
• A decrease or an increase in 
blood pressure 
• Loss of desire to eat or appetite 
• Weight loss 
• Mild nausea and/or vomiting 
• Muscle and joint aches and 
pains 
• Numbness and tingling in the 
fingers and toes 
• Chills and fever 
• Changes in your mood such 
that 
you 
feel depressed, 
irritable, confused or have 
• Severe allergic reaction which 
can be life threatening with 
shortness of breath, low blood 
pressure, rapid heart rate 
chills and fever 
• Irritation of the small airways 
of your lungs that can make 
you cough and wheeze 
• Seizures 
• Coma 
• Sudden damage to the red 
blood cells (hemolytic anemia) 
which could cause a rapid 
decrease in the number of red 
blood cells such that you 
would be tired and weak and 
feel short of breath and may 
require a blood transfusion 
• Temporary decrease in blood 
to the brain which can lead to 
temporary 
loss 
of 
consciousness 
• A bleeding disorder that can 
lead to bleeding from many 
areas of the body or excessive 
clotting in 
blood vessels 
including those that lead to the 
brain 
• Damage to the bladder which 
can lead to large amounts of 
blood in the urine, pain and 
the urge to urinate frequently 
and also scarring of the 
bladder 
• High levels of nitrogen and/or 
a chemical (creatinine) in the 
blood which may indicate that 
the kidneys are not working as 
well as normal 
• Severe kidney damage 
• Severe damage to the liver 
which can lead to a fatty and 

TACL Protocol:  
T2012-002  
Original Version Date: 14-May-2016  
Activated: 
                 28-Jul-2016  
Amendment #1 Date: 16-Mar-2017 
 
 
Amendment #2 Date: 16-Jul-2018 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
T2012-002 Original Version Date: 14-May-2016   
CONFIDENTIAL 
Amendment #1 Date: 16-Mar-2017 
TACL Internal Distribution Only 
Amendment #2 Date: 16-Jul-2018  
97 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
Likely (Happens to 21-
100 children out of 100) 
Less Likely (Happens to 5-20 
children out of every 100) 
Rare but serious (Happens to <5 
children out of every 100) 
hallucinations (see or hear 
things that are not there) 
• An increase in the levels of 
lipids (fats) in your blood which 
if prolonged could lead to heart 
problems later in life 
• Shakiness or tremor which 
may cause jerky movements 
• Pain in the abdomen (belly) 
• Too much gas produced in the 
intestines 
• Inflammation of the pancreas 
(an organ in the abdomen 
which produces insulin and 
certain digestive chemicals) 
which may affect the function 
of the pancreas and which may 
cause pain in the abdomen 
(belly)which can be severe 
and may increase the blood 
sugar 
• Elevations of certain chemicals 
in the blood which may 
indicate 
damage 
to 
the 
pancreas 
• Fewer white blood cells, red 
blood cells and platelets in the 
blood  
o a low number of white 
blood cells can make it 
easier to get infections 
o a low number of red blood 
cells can make you feel 
tired and weak 
o a low number of platelets 
causes you to bruise and 
bleed more easily 
enlarged liver, inflammation 
and/or scarring which could 
lead to a yellow appearing 
skin, and fluid collection in the 
abdomen (belly) which makes 
it look larger 
• Reduced ability of the body to 
fight infection which can lead 
to infections including severe 
blood infections which will 
need to be treated and may be 
life threatening, infections of 
the valves in the heart, the 
bladder and other areas of the 
body 
 
 
Erwinia Asparaginase (given into the muscle)  
If you develop an allergic reaction to pegaspargase, you may be treated with  
Erwinia L-asparaginase (Erwinaze ® or Erwinase ®). This preparation has been given to hundreds 
of children over many years and many of the side effects are similar to those that occur with the 
other forms of asparaginase. Six injections of Erwinia L-asparaginase are required to substitute 

TACL Protocol:  
T2012-002  
Original Version Date: 14-May-2016  
Activated: 
                 28-Jul-2016  
Amendment #1 Date: 16-Mar-2017 
 
 
Amendment #2 Date: 16-Jul-2018 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
T2012-002 Original Version Date: 14-May-2016   
CONFIDENTIAL 
Amendment #1 Date: 16-Mar-2017 
TACL Internal Distribution Only 
Amendment #2 Date: 16-Jul-2018  
98 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
for each injection of pegaspargase and one injection of Erwinia L-asparaginase for each injection 
of asparaginase.  
 
Another alternative if you are not able to take Pegasparagase is Erwinia chrysanthemi (recombinant)-
rwyn (Rylaze ®) (given into the muscle). The side effects are the same as Erwinia asparaginase. 
 
Likely (Happens to 
21-100 children out 
of 100) 
Less Likely (Happens to 5-20 
children out of every 100) 
Rare But Serious (Happens to <5 
children out of every 100) 
 
 
• Allergic reaction by your body to 
the drug product that can occur 
immediately or may be delayed. 
The reaction may include hives, 
low blood pressure, wheezing, 
swelling of the throat, and 
difficulty breathing. 
• Allergic reaction which can be 
life-threatening and potentially 
fatal. This reaction requires 
immediate medical treatment. It 
may include fever, chills and 
skin rash. Less commonly 
wheezing, shortness of breath, 
swelling of the throat, drop in 
blood pressure, and rapid heart 
rate may occur. 
• Hives; red and sometimes itchy 
bumps on the skin. 
• Local 
allergic 
reactions 
including rashes and hives 
around the site of the injection 
 
• Inflammation of the pancreas 
(an organ in the abdomen which 
makes 
insulin 
and 
certain 
digestive 
chemicals) 
which 
causes severe pain in the 
abdomen (belly) and back and 
may increase the blood sugar  
• Formation of blood clots that 
plug blood vessels and can lead 
to pain and swelling in the area 
of the clot. Such clots may break 
loose and travel to another area. 
They can cause damage or be 
life-threatening depending on 
where they go. 
• Excessive 
or 
uncontrolled 
bleeding which can occur in the 
head, stools, the nose, urine 
and other parts of the body. 
• Sudden and temporary loss of 
blood flow and oxygen to the 
brain causing problems with 
vision, dizziness, weakness and 
numbness (especially in one 
side of the body), and trouble 
speaking. Also called 
mini 
stroke. 
• A bleeding disorder in which 
small 
blood 
clots 
develop 
throughout the 
bloodstream 
blocking small blood vessels 
and depleting platelets and 
clotting 
factors 
needed to 
control bleeding. This condition 
can lead to bleeding from many 
areas of the body and can be 
life-threatening. 

TACL Protocol:  
T2012-002  
Original Version Date: 14-May-2016  
Activated: 
                 28-Jul-2016  
Amendment #1 Date: 16-Mar-2017 
 
 
Amendment #2 Date: 16-Jul-2018 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
T2012-002 Original Version Date: 14-May-2016   
CONFIDENTIAL 
Amendment #1 Date: 16-Mar-2017 
TACL Internal Distribution Only 
Amendment #2 Date: 16-Jul-2018  
99 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
Likely (Happens to 
21-100 children out 
of 100) 
Less Likely (Happens to 5-20 
children out of every 100) 
Rare But Serious (Happens to <5 
children out of every 100) 
• Fever 
• Abnormal control of blood 
sugar level 
• Increase in the blood level of 
certain enzymes or bilirubin (a 
waste product that passes 
through the liver) which could 
indicate 
liver 
irritation 
or 
damage 
• High blood sugar which may 
require treatment with insulin 
• An increase in the level of 
ammonia that is found in the 
blood 
• Vomiting 
• Nausea  
• Belly pain 
• Headache 
• Diarrhea 
• Weight loss  
• 
Seizures; 
sudden, 
uncontrolled muscle spasm 
and loss of consciousness 
resulting from abnormal brain 
function. 
  
 
Reproductive risks   
Because the drugs in this study can affect an unborn baby, you should not become pregnant or 
father a baby while on this study. You should not nurse a baby while on this study. It is a condition 
of this study that adequate birth control methods be used by all participants and/or their sexual 
partners while enrolled in the study. Examples of these include total abstinence (no sex), oral 
contraceptives (“the pill”), an intrauterine device (IUD), Levonorgestrol implants (Norplant), or 
medroxyprogesterone acetate injections (Depo-provera shots). If one of these methods of birth 
control cannot be used, contraceptive foam with a condom is recommended. Ask your doctor 
about counseling and more information about preventing pregnancy.  
  
If you become pregnant/father a child during this study, contact your doctor immediately to discuss 
the requirements for pregnancy outcome follow-up. Female subjects will be given instructions for 
discontinuation of study medication.  
  

TACL Protocol:  
T2012-002  
Original Version Date: 14-May-2016  
Activated: 
                 28-Jul-2016  
Amendment #1 Date: 16-Mar-2017 
 
 
Amendment #2 Date: 16-Jul-2018 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
T2012-002 Original Version Date: 14-May-2016   
CONFIDENTIAL 
Amendment #1 Date: 16-Mar-2017 
TACL Internal Distribution Only 
Amendment #2 Date: 16-Jul-2018  
100 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
Confidential Information   
Because the sponsor of this study is outside of your medical center there is the potential small 
risk of accidental release of confidential information when sending out any research 
documentation. Please see the “Will my medical information be kept private?” section of this 
document for more details.  
Developing a Second Cancer  
It is possible that you may develop a second form of cancer as a result of this treatment. 
Experience so far suggests that the chance of this happening is very small. Not enough 
information has been gathered in children to be able to give an accurate prediction, although it 
may be in the range of one in every 50 to 800 children treated.   
  
Are there benefits to subjects taking part in the study?  
  
Participation on this study may or may not benefit you. Participating in this study will not cure your 
relapsed leukemia. Based on experience with the drugs used in the treatment plan, researchers 
believe this therapy may cause your leukemia to stop growing or go into remission for a period of 
time. Your cancer may not have any response to the therapy received while participating in this 
study.   
  
Are there benefits to society?  
  
It is hoped that the information learned from this study may help future children or young adults 
with relapsed ALL.   
  
  
What other choices do I have if I do not take part in this study?  
  
You do not have to participate in this study to receive treatment for recurrent leukemia. There is 
no “standard” therapy for recurrent leukemia. Most treatment plans have used drugs similar to 
those used in this protocol, although these drugs may be given in different combinations, and at 
different times. You can receive other combinations of chemotherapy without participating in this 
study.   
  
As an alternative to this study, you may decide you don’t want additional treatment for your 
relapsed leukemia. You will always receive medicines to help you feel more comfortable and deal 
with problems caused by your cancer or treatment whether you participate in this study or not.  
  
Talk to your doctor about your choices before you decide if you will take part in this study.  
  
Will my medical information be kept private?   
  

TACL Protocol:  
T2012-002  
Original Version Date: 14-May-2016  
Activated: 
                 28-Jul-2016  
Amendment #1 Date: 16-Mar-2017 
 
 
Amendment #2 Date: 16-Jul-2018 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
T2012-002 Original Version Date: 14-May-2016   
CONFIDENTIAL 
Amendment #1 Date: 16-Mar-2017 
TACL Internal Distribution Only 
Amendment #2 Date: 16-Jul-2018  
101 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
Members of the research team and, if appropriate, your primary care physicians and nurses will 
know that you are a research subject. All results will be kept confidential, but may be made 
available to you, and/or your physician if you wish. Because this study involves the treatment of 
a medical condition, a copy of this consent form will be placed in your medical record. This will 
allow the doctors that are caring for you to obtain information about what medications or 
procedures you are receiving in the study and treat you appropriately. You may read your medical 
record. The records are available to those caring for you at this hospital.  
  
Organizations that may inspect/or copy your research records for quality assurance and data 
analysis include:  
• 
Therapeutic Advances in Childhood Leukemia Consortium (TACL)  
• 
The United States Food and Drug Administration (FDA)  
• 
The United States Department of Health and Human Services (DHHS)  
• 
The Institutional Review Board (IRB) of Children’s Hospital Los Angeles (CHLA)  
• 
Acrotech Biopharma (the makers of Marqibo®)  
• 
DSMC (CHLA) 
 
As a result, these organizations may see your name; but they are bound by rules of confidentiality 
not to reveal your identity to others.   
  
Reasonable steps will be taken to protect your right to privacy. No information about you, or 
provided by you during the research, will be shared with others without your written permission, 
except as explained below:  
  
If necessary to protect your rights or welfare (for example, if you are injured and need emergency 
care); or  
if required by law (i.e., child abuse, reports of certain infectious diseases).  
  
The information collected will be used to meet the purpose of this clinical study. In addition, this 
information may be used to support applications to market the studied drug in the United States 
and in other countries. It may also be used in reports of the study or for scientific publications and 
presentations that will not identify study participants by name.   
  
A description of this clinical trial will be available on http://www.clinicaltrials.gov , as required by 
U.S. Law. This website will not include information that can identify you. At most, the website will 
include a summary of the results. You can search this website at anytime.  
  
What are the costs of taking part in this study?  
  
The health care costs during your participation in this study that are considered part of the 
standard treatment of your disease will be billed to your insurance or other third-party payer. This 
includes blood tests, hospitalizations, procedures that will be done and medications.   
  
You will not have to pay for the following tests that will be done for research purposes only.  

TACL Protocol:  
T2012-002  
Original Version Date: 14-May-2016  
Activated: 
                 28-Jul-2016  
Amendment #1 Date: 16-Mar-2017 
 
 
Amendment #2 Date: 16-Jul-2018 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
T2012-002 Original Version Date: 14-May-2016   
CONFIDENTIAL 
Amendment #1 Date: 16-Mar-2017 
TACL Internal Distribution Only 
Amendment #2 Date: 16-Jul-2018  
102 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
• 
Tests to measure Marqibo® levels  
  
Your family is responsible for other costs which may result from your participation in the study, 
such as, but not limited to, time off of work, car fare, baby sitter fees, food purchased while at the 
hospital, etc. You will not receive any type of payment for participating in this study. Taking part 
in this study may lead to added costs to your insurance company. Please ask about any expected 
added costs or insurance problems.  
  
For more information on clinical trials and insurance coverage, you can visit the National Cancer 
Institute’s Web site at http://cancer.gov/clinicaltrials/understanding/insurance-coverage . You can 
print a copy of the “Clinical Trials and Insurance Coverage” information from this Web site.  
  
Another way to get the information is to call 1-800-4-CANCER (1-800-422-6237) and ask them to 
send you a free copy.  
  
What happens if I am injured because I took part in this study?  
  
It is important that you tell your study doctor, __________________ [investigator’s name(s)], if 
you feel that you have been injured because of taking part in this study. You can tell the doctor in 
person or call him/her at __________________ [telephone number].  
  
You will get medical treatment if you are injured as a result of taking part in this study. You and/or 
your health plan will be charged for this treatment. The study will not pay for medical treatment.   
  
What are my rights if I take part in this study?  
  
Taking part in this study is voluntary. You may choose not to participate in this study. If you decide 
not to participate, you will not be penalized and you will still receive the standard treatment.  
  
If you choose to participate, you may discontinue your participation in the study at any time. If you 
discontinue participation in the study, physicians and hospital personnel will still take care of you.  
  
You also have the right to know about new information that may affect your health, welfare, or 
your willingness to participate in the study. You will be provided with this information as soon as 
it becomes available.  
  
Whether you participate or not, you will continue to get the best medical care this hospital can 
provide.  
  
Who can answer my questions about the study?  
  

TACL Protocol:  
T2012-002  
Original Version Date: 14-May-2016  
Activated: 
                 28-Jul-2016  
Amendment #1 Date: 16-Mar-2017 
 
 
Amendment #2 Date: 16-Jul-2018 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
T2012-002 Original Version Date: 14-May-2016   
CONFIDENTIAL 
Amendment #1 Date: 16-Mar-2017 
TACL Internal Distribution Only 
Amendment #2 Date: 16-Jul-2018  
103 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
You can talk to your study doctor about any questions or concerns you have about this study. 
Contact your study doctor __________________ [name(s)] at __________________ [telephone 
number].  
  
For 
questions about your 
rights 
while 
taking 
part 
in 
this 
study, 
call 
the 
________________________ [name of center] Institutional Review Board (a group of people 
who review the research to protect your rights) at __________________ [telephone number]. 
[Note to Local Investigator: Contact information for patient representatives or other individuals in 
a local institution who are not on the IRB or research team but take calls regarding clinical trial 
questions can be listed here.]   
  
Where can I get more information?  
  
Call the National Cancer Institute’s Cancer Information Service:  
1-800-4-CANCER (1-800-422-6237) OR 1-800-332-8615 (for the hearing impaired)  
  
• 
You will be given a copy of this consent form.  
• 
You will be given a copy of this treatment plan upon request.  
• 
The National Cancer Institute web site: www.cancer.gov. It contains peer-reviewed summaries 
on cancer treatment, screening, prevention, and supportive care; a registry of about 1,700 
open and 10,300 closed cancer clinical trials from around the world; and directories of 
physicians, genetic counselors, and organizations that provide cancer care.  
• 
ClinicalTrials.gov: https://clinicaltrials.gov/. ClinicalTrials.gov is a registry and results database 
of publicly and privately supported clinical studies of human participants conducted around 
the world.   
• 
Visit the TACL Consortium Website at https://tacl.chla.usc.edu    
  
CONSENT FOR OPTIONAL STUDIES FOR RESEARCH  
  
THESE TESTS ARE OPTIONAL. YOU MAY STILL PARTICIPATE IN THE STUDY EVEN IF YOU 
DO NOT AGREE TO THESE TESTS.   
  
Marqibo® Drug Levels (Pharmacokinetics)-Optional studies  
  
During therapy, researchers would like to draw an extra ½ teaspoon (2.5-3mL) of blood at each 
time point. Samples will be drawn on the following schedule. You will not get a copy of the results 
of this testing.   
• 
End of infusion (EOI) after dose #1 of Marqibo®  
• 
3 hours (EOI + 2 hours)  
• 
25 hours (EOI + 24 hours)  
 YES, I agree to have blood drawn for Marqibo® levels with the first dose of Marqibo®  
  

TACL Protocol:  
T2012-002  
Original Version Date: 14-May-2016  
Activated: 
                 28-Jul-2016  
Amendment #1 Date: 16-Mar-2017 
 
 
Amendment #2 Date: 16-Jul-2018 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
T2012-002 Original Version Date: 14-May-2016   
CONFIDENTIAL 
Amendment #1 Date: 16-Mar-2017 
TACL Internal Distribution Only 
Amendment #2 Date: 16-Jul-2018  
104 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
_______ initials of subject (if subject is 14 years or older)  
  
_______ initials of parent/legal guardian (if subject is a minor)  
  
_______ initials of parent/legal guardian (if subject is a minor)  
  
NO, I do not agree to have blood drawn for Marqibo® levels with the first dose of Marqibo® 
  
_______ initials of subject (if subject is 14 years or older) _______ initials of 
parent/legal guardian (if subject is a minor)  
  
_______ initials of parent/legal guardian (if subject is a minor)  
  
Pre-treatment bone marrow sample for minimal residual disease 
 
Before you start treatment, researchers may take some of the bone marrow that is normally taken for your 
medical care and send it to be tested to evaluate for the smallest amount of leukemia in the bone marrow 
(minimal residual disease). 
 
YES, I agree to have this sample sent 
_______ initials of subject (if subject is 14 years or older)  
  
_______ initials of parent/legal guardian (if subject is a minor)  
  
_______ initials of parent/legal guardian (if subject is a minor)  
 
NO, I do not agree to have this sample sent 
 
_______ initials of subject (if subject is 14 years or older)  
 
_______ initials of parent/legal guardian (if subject is a minor)  
  
_______ initials of parent/legal guardian (if subject is a minor)  
 
SIGNATURE PAGE  
Use your own institutional signature page.  
  
  
 

TACL Protocol:  
T2012-002  
Original Version Date: 14-May-2016  
Activated: 
                 28-Jul-2016  
Amendment #1 Date: 16-Mar-2017 
 
 
Amendment #2 Date: 16-Jul-2018 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
T2012-002 Original Version Date: 14-May-2016   
CONFIDENTIAL 
Amendment #1 Date: 16-Mar-2017 
TACL Internal Distribution Only 
Amendment #2 Date: 16-Jul-2018  
105 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
APPENDIX 1: PERFORMANCE STATUS SCALES/SCORES  
  
Performance Status Criteria  
Karnofsky and Lansky performance scores are intended to be multiples of 10  
ECOG (Zubrod)  
Karnofsky  
Lansky  
Score  Description  
Score  Description  
Score  Description  
0  
Fully active, able to carry 
on 
all 
pre-disease 
performance 
without 
restriction.  
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 restrictions in 
physically strenuous 
activity.  
1  
Restricted in physically 
strenuous activity but 
ambulatory and able to 
carry out work of a light 
or sedentary nature,  
e.g., light housework, 
office work.  
80  
Normal activity with 
effort; some signs or 
symptoms of disease.  
80  
Active, but tires 
more 
quickly  
70  
Cares for self, unable to 
carry on normal activity or 
do active work.  
70  
Both greater restriction of 
and less time spent in play 
activity.  
2  
Ambulatory and capable 
of all 
self-care but 
unable to carry out any 
work activities. Up and 
about more than 50% of 
waking hours  
60  
Required 
occasional 
assistance, but is able to 
care for most of his/her 
needs.  
60  
Up and around, but minimal 
active play; keeps busy with 
quieter activities.  
50  
Requires 
considerable 
assistance and frequent 
medical care.  
50  
Gets dressed, but lies 
around much of the day; no 
active 
play, 
able 
to 
participate in all quiet play 
and activities.  
3  
Capable of only limited 
self-care, confined to 
bed or chair more than 
50% of waking hours.   
40  
Disabled, 
requires 
special 
care 
and 
assistance.  
40  
Mostly in bed; participates 
in quiet activities.  
30  
Severely 
disabled, 
hospitalization indicated.  
Death not imminent.  
30  
In bed; needs assistance 
even for quiet play.  
4  
Completely 
disabled. 
Cannot carry on any 
20  
Very sick, hospitalization 
indicated. 
Death 
not 
imminent.  
20  
Often sleeping; play entirely 
limited to very passive 
activities.  

TACL Protocol:  
T2012-002  
Original Version Date: 14-May-2016  
Activated: 
                 28-Jul-2016  
Amendment #1 Date: 16-Mar-2017 
 
 
Amendment #2 Date: 16-Jul-2018 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
T2012-002 Original Version Date: 14-May-2016   
CONFIDENTIAL 
Amendment #1 Date: 16-Mar-2017 
TACL Internal Distribution Only 
Amendment #2 Date: 16-Jul-2018  
106 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
self-care. 
Totally 
confined to bed or chair.  
10  
Moribund, 
fatal 
processes 
progressing 
rapidly.  
10  
No play; does not get out of 
bed.  
 
 

TACL Protocol:  
T2012-002  
Original Version Date: 14-May-2016  
Activated: 
                 28-Jul-2016  
Amendment #1 Date: 16-Mar-2017 
 
 
Amendment #2 Date: 16-Jul-2018 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
T2012-002 Original Version Date: 14-May-2016   
CONFIDENTIAL 
Amendment #1 Date: 16-Mar-2017 
TACL Internal Distribution Only 
Amendment #2 Date: 16-Jul-2018  
107 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
APPENDIX 2: GUIDANCE FOR DETERMINING PREVIOUS CUMULATIVE ANTHRACYCLINE 
DOSE  
Total Anthracycline Calculation Worksheet 
Instructions: 
In order to calculate the total anthracycline received by a patient, you will need to review the patient’s previous 
treatment. You will need to document each dose of anthracycline chemotherapy prescribed and received by the 
patient. 
Step 1: Indicate which drug the patient received (Contact TACL Operations if drug not listed) 
Step 2: Enter the prescribed dose for that drug per the chemotherapy roadmap/orders. Be sure to list all doses. 
Step 3: Enter the corresponding conversion factor for the drug given. 
Step 4: Multiply the prescribed dose by the conversion factor and enter the result in the “Total Anthracycline” column. 
Step 5: After you have completed this worksheet for all doses, add all the total doses to obtain the Total 
Cumulative Dose. 
Drug 
Prescribed Dose 
The prescribed dose is the 
dose of 
chemotherapy written in the protocol. It will be 
listed as mg/m2. (It is not the actual dose 
received by the patient) 
Conversion Factor 
Doxorubicin = 1 
Daunorubicin = 1 
Idarubicin = 4 
Mitoxantrone = 4 
Total 
Anthracyclin
e 
 Doxorubicin 
 Daunorubicin 
 Idarubicin 
 Mitoxantrone 
EXAMPLE: 
 
10 mg/m2 
 
4 
 
40 mg/m2 
Doxorubicin 
 Daunorubicin 
 Idarubicin 
 Mitoxantrone 
 
 
 
 Doxorubicin 
 Daunorubicin 
 Idarubicin 
 Mitoxantrone 
 
 
 
 Doxorubicin 
 Daunorubicin 
 Idarubicin 
 Mitoxantrone 
 
 
 
 Doxorubicin 
 Daunorubicin 
 Idarubicin 
 Mitoxantrone 
 
 
 
 Doxorubicin 
 Daunorubicin 
 Idarubicin 
 Mitoxantrone 
 
 
 

TACL Protocol:  
T2012-002  
Original Version Date: 14-May-2016  
Activated: 
                 28-Jul-2016  
Amendment #1 Date: 16-Mar-2017 
 
 
Amendment #2 Date: 16-Jul-2018 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
T2012-002 Original Version Date: 14-May-2016   
CONFIDENTIAL 
Amendment #1 Date: 16-Mar-2017 
TACL Internal Distribution Only 
Amendment #2 Date: 16-Jul-2018  
108 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
  
 
 
 Doxorubicin 
 Daunorubicin 
 Idarubicin 
 Mitoxantrone 
 
 
 
Total Cumulative Dose 
 

TACL Protocol:  
T2012-002  
Original Version Date: 14-May-2016  
Activated: 
                 28-Jul-2016  
Amendment #1 Date: 16-Mar-2017 
 
 
Amendment #2 Date: 16-Jul-2018 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
T2012-002 Original Version Date: 14-May-2016   
CONFIDENTIAL 
Amendment #1 Date: 16-Mar-2017 
TACL Internal Distribution Only 
Amendment #2 Date: 16-Jul-2018  
109 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
APPENDIX 3: PARTIAL LIST OF CONCOMITANT MEDICATIONS KNOWN TO INTERACT WITH 
CYTOCHROME P450-3A4 ISOENZYMES AND/OR P-GLYCOPROTEIN (TO BE USED WITH 
CAUTION)  
 Please note that this is not a comprehensive listing and other medications should be reviewed with the 
PI. 
• 
Atazanavir 
• 
Atorvastin  
• 
Azithromycin  
• 
Carbamazepine 
• 
Chlorpheniramine  
• 
Cimetidine 
• 
Ciprofloxacin  
• 
Clarithromycin  
• 
Clotrimazole* 
• 
Cyclosporine 
• 
Dexamethasone^ 
• 
Digoxin  
• 
Diltiazem 
• 
Ergotamine 
• 
Erythromycin  
• 
Fluconazole* 
• 
Grapefruit Juice 
• 
Haloperidol 
• 
Indinavir 
• 
Itraconazole* 
• 
Ketoconazole* 
• 
Lidocaine 
• 
Lovastatin 
• 
Miconazole* 
• 
Nefazodone 
• 
Nelfinavir 
 
• 
Norfloxacin  
• 
Orphenadrine 
• 
Paroxetine  
• 
Phenobarbital 
• 
Phenytoin  
• 
Posaconazole* 
• 
Progesterone  
• 
Rapamycin 
• 
Rifabutin 
• 
Rifampin  
• 
Rifapentine 
• 
Ritonavir 
• 
Rosiglitazone  
• 
Saquinavir 
• 
Sertraline  
• 
Simvastatin 
• 
St. John’s Wort 
• 
Tacrolimus 
• 
Tamoxifen 
• 
Telithromycin 
• 
Toremfine 
• 
Trazadone 
• 
Verapamil 
• 
Voriconazole* 
• 
Zafirlukast 
 
* No azole-based antifungal therapy is permitted without PI approval. 
 
^ Dexamethasone has been used in combination with standard vincristine in the UK ALL R3 regimen 
(Parker et al. Lancet 2010) and in combination trials with Marqibo®in adults (Thomas et al. Cancer 
2009) with an acceptable toxicity profile. Dexamethasone will be used on this trial. 
 
 
 

TACL Protocol:  
T2012-002  
Original Version Date: 14-May-2016  
Activated: 
                 28-Jul-2016  
Amendment #1 Date: 16-Mar-2017 
 
 
Amendment #2 Date: 16-Jul-2018 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
T2012-002 Original Version Date: 14-May-2016   
CONFIDENTIAL 
Amendment #1 Date: 16-Mar-2017 
TACL Internal Distribution Only 
Amendment #2 Date: 16-Jul-2018  
110 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
APPENDIX 4: NEUROLOGICAL EXAM 
TACL Registration #: 
 
  TACL Protocol #: 
 
TACL Subject ID : 
 
   Enrollment Date: 
  
 
 
 
 
Assessment Date: 
 
 
 
 
 
If Pretreatment or Off 
Study 
Neurological 
Exam Section must be 
completed. 
 
Pretreatment 
 
Dose 3  
 
 
Dose 1 
 
Dose 4 
 
 
Dose  2 
 
Off Study 
Performance Status: 
Lansky:  
 
Karnofsky:  
 
 
 
 
 
 
Neurological Status : 
 
 
General: 
 
 
No neurological findings 
 
Stable 
 
 
 
Improved 
 
Worse 
 
Resolved 
 
 
 
Any Change from baseline: 
 
Yes 
 
No 
If Yes, go to Neuro  
exam; If no to both then 
assessment 
is 
complete.
Any Change from previous assessment: 
 
Yes 
 
No 
 
 
 
Neurological Exam:  
 
Mark Normal or Abnormal with an X. 
If abnormal, record a brief description of the current abnormality. 
Record ND for any examination not done. 
 
 
 
Normal 
Abnormal 
Description of abnormality 
Muscle Tone & Strength: (weakness) 
 
 
 
 
 
 
 
Reflexes: (Brachioradialis, biceps, 
knee, ankle) 
 
 
 
 
 
 
 
Gait: 
 
 
 
 
 
 
 
Postural Hypotension: 
 
 
 
 
 
 
 
Sensory: (Pain, jaw pain, numbness, 
paresthesias, constipation, vibration 
first toe) 
 
 
 
 
 
 
 
Stretch-extension of wrist: 
 
 
 
 
 
 
 
Stretch-dorsiflexion of foot: 
 
 
 
 
 
 
 

TACL Protocol:  
T2012-002  
Original Version Date: 14-May-2016  
Activated: 
                 28-Jul-2016  
Amendment #1 Date: 16-Mar-2017 
 
 
Amendment #2 Date: 16-Jul-2018 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
T2012-002 Original Version Date: 14-May-2016   
CONFIDENTIAL 
Amendment #1 Date: 16-Mar-2017 
TACL Internal Distribution Only 
Amendment #2 Date: 16-Jul-2018  
111 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
Comments: 
 
 
 
 
 
 
 
 
 
MD Signature  
 
 
 
Date 
 
 

TACL Protocol:  
T2012-002  
Original Version Date: 14-May-2016  
Activated: 
                 28-Jul-2016  
Amendment #1 Date: 16-Mar-2017 
 
 
Amendment #2 Date: 16-Jul-2018 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
T2012-002 Original Version Date: 14-May-2016   
CONFIDENTIAL 
Amendment #1 Date: 16-Mar-2017 
TACL Internal Distribution Only 
Amendment #2 Date: 16-Jul-2018  
112 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
APPENDIX 5: NEUROLOGIC TOXICITY GRADING   
Grade  Peripheral Motor Neuropathy 
(CTCAEv4.03)  
Peripheral Sensory   
Neuropathy  
(CTCAEv4.03)  
1  
Asymptomatic; 
clinical 
or 
diagnostic observations only; 
intervention not indicated  
Asymptomatic; loss of 
deep tendon reflexes or 
paresthesia  
2  
Moderate symptoms; limiting 
instrumental ADL  
Moderate 
symptoms; 
limiting instrumental  
ADL  
3  
Severe symptoms; limiting self 
care ADL; assistive device 
indicated  
Severe symptoms;  
limiting self care ADL;   
4  
Life-threatening consequences; 
urgent intervention indicated  
Life-threatening 
consequences; 
urgent 
intervention indicated  
5  
Death  
Death  
Peripheral motor neuropathy: A disorder characterized by inflammation or degeneration of the 
peripheral motor nerves.  
   
Peripheral sensory neuropathy: A disorder characterized by inflammation or degeneration of the 
peripheral sensory nerves.   
 
  

TACL Protocol:  
T2012-002  
Original Version Date: 14-May-2016  
Activated: 
                 28-Jul-2016  
Amendment #1 Date: 16-Mar-2017 
 
 
Amendment #2 Date: 16-Jul-2018 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
T2012-002 Original Version Date: 14-May-2016   
CONFIDENTIAL 
Amendment #1 Date: 16-Mar-2017 
TACL Internal Distribution Only 
Amendment #2 Date: 16-Jul-2018  
113 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
APPENDIX 6: BOWEL PROPHYLAXIS AND MANAGEMENT GUIDELINES  
• 
A diet high in bulk fiber, fruits and vegetables, and adequate fluid intake may help minimize 
constipation.  
• 
Bowel regimen may be held if diarrhea develops.   
  
Level I: Prophylaxis  
All subjects must receive a concomitant stool softener, or equivalent agents (e.g., Miralax®), 
during and for at least 7 days post discontinuation of Marqibo®. Stool softeners may be held if 
diarrhea develops.    
 
• 
Docusate; or   
• 
Lactulose; or  
• 
Docusate/sennosides A and B (US Peri-Colace®).  
  
Level II: Active Intervention  
To be initiated if a patient is constipated per definition below, with institution of one of the following 
options, or equivalent agents:  
• 
Substitution of Docusate/sennosides A and B (US Peri-Colace®) for one dose of docusate; or  
• 
Increase dose and/or frequency of lactulose or Docusate/sennosides A and B (US 
PeriColace®); or  
• 
Provide a dose of milk of magnesia at bedtime.  
  
Level III: Escalated Intervention  
To be initiated if the patient is still constipated per definition after 2 days with active intervention, 
with the addition of one of the following options, or equivalent agents:  
• 
Bisacodyl tablets; or   
• 
Mineral oil orally; or  
• 
Phosphate buffered solution orally.  
  
Level IV: Aggressive Intervention  
To be initiated if the patient is still constipated as per definition after 2 days of escalated 
intervention, with the addition of one of the following, or equivalent agents:  
• 
Magnesium citrate oral solution; or  
• 
Bisacodyl suppository (NOT with neutropenia); or    
• 
Phosphate enema (NOT with neutropenia); or   
 
• 
Mineral oil enema (NOT with neutropenia).  
  
Definition of Constipation: Change in the usual pattern of elimination including two or more of 
the following symptoms:  
• 
Decrease frequency of stool and/or < 3 times per week  
• 
Difficulty passing stool  
• 
Passage of hard stool  
  

TACL Protocol:  
T2012-002  
Original Version Date: 14-May-2016  
Activated: 
                 28-Jul-2016  
Amendment #1 Date: 16-Mar-2017 
 
 
Amendment #2 Date: 16-Jul-2018 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
T2012-002 Original Version Date: 14-May-2016   
CONFIDENTIAL 
Amendment #1 Date: 16-Mar-2017 
TACL Internal Distribution Only 
Amendment #2 Date: 16-Jul-2018  
114 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
  
Agent Schedules and Doses  
Docusate  
 
• 
Adults and children older than 12 years of age: 50 to 360 mg orally daily  
• 
Children 2 to 12 years of age: 50 to 150 mg orally daily  
• 
Children Younger than 2 years of age: 25 mg orally daily  
Alternatively, children 3 to 6 years of age may receive oral docusate sodium dosages of 20 to 60 mg 
daily and children younger than 3 years of age may receive 10 to 40 mg daily. Doses at the higher end 
of these dosage ranges may be required initially.  
  
Lactulose  
• 
Adults: initial dosage is 10 to 20 g orally daily; may be increased to 40 g daily if necessary.  
• 
Children: 5 to 7.5 g orally daily, usually given as a single dose after breakfast.  
  
Docusate/sennosides A and B (US Peri-Colace®).  
• 
Adults: 1 or 2 capsules orally at bedtime, or as indicated. In severe cases, dosage may be 
increased to 2 capsules twice daily, or 3 capsules at bedtime.  
• 
Children: 1 to 3 teaspoons of syrup orally at bedtime, or as indicated. Peri-Colace  syrup may 
be given in a 6 oz. to 8 oz. glass of milk or fruit juice or in infant’s formula to prevent throat 
irritation.  
  
Milk of Magnesia  
• 
Adults and children older than 12 years of age: 30 to 60 mL orally daily, given as a single 
dose or in divided doses.  
• 
Children 6 to 11 years of age: 15 to 30 mL orally daily, given as a single dose or in divided 
doses.  
• 
Children 2 to 5 years of age: 5 to 15 mL orally daily, given as a single dose or in divided 
doses.  
  
Bisacodyl   
 
• 
Adults and children 12 years of age and older: 5 to 15 mg orally daily as a single dose  
SOP Development 
- 
Update protocol deviation SOP 
  
Mineral Oil Orally  
• 
Adults and children 12 years of age and older: 15 to 45 mL orally daily, given as a single 
dose (minimum dose of 15 mL) or in divided doses.  
• 
Children 6 to 11 years of age: 5 to 15 mL orally daily, given as a single dose (minimum dose 
of 5 mL) or in divided doses.  
  
Phosphate Buffered Solution Oral  

TACL Protocol:  
T2012-002  
Original Version Date: 14-May-2016  
Activated: 
                 28-Jul-2016  
Amendment #1 Date: 16-Mar-2017 
 
 
Amendment #2 Date: 16-Jul-2018 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
T2012-002 Original Version Date: 14-May-2016   
CONFIDENTIAL 
Amendment #1 Date: 16-Mar-2017 
TACL Internal Distribution Only 
Amendment #2 Date: 16-Jul-2018  
115 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
• 
Adults and children 12 years of age and older: 20 to 45 mL orally (4 to 9 teaspoons).  
• 
Children 10 and 11 years of age: 10 to 20 mL orally (2 to 4 teaspoons).  
• 
Children 5 to 9 years of age: 5 to 10 mL orally (1 to 2 teaspoons).   
 
• 
Children under 5 years: Physician discretion  
**DO NOT TAKE MORE THAN THIS AMOUNT IN A 24 HOUR PERIOD  
  
Magnesium Citrate Oral Solution (1.745 gm/30mL)  
• 
Adults and children 12 years of age and older: 11 to 25 g orally daily, given as a single 
dose or in divided doses.  
• 
Children 6 to 11 years of age: 5.5 to 12.5 g orally daily, given as a single dose or in divided 
doses.  
• 
Children 2 to 5 years of age: 2.7 to 6.25 g orally daily, given as a single dose or in divided 
doses.  
  
Bisacodyl Suppository (**NOT WITH NEUTROPENIA)   
• 
Adults and children 12 years of age and older: 10 mg daily, given as a single dose   
• 
Children 2 to 11 years of age: 5 to 10 mg (one-half to one suppository) daily, given as a 
single dose   
• 
Children younger than 2 years of age: 5 mg (one-half suppository daily, given as a single 
dose   
  
Phosphate Enema (**NOT WITH NEUTROPENIA)   
• 
Adults and children 12 years of age and older: 118 mL (one bottle) daily as a single dose  
• 
Children 2 to 11 years of age: 59 mL (one bottle of Fleet enema for children) daily as a single 
dose  
  
Mineral Oil Enema (**NOT WITH NEUTROPENIA) 
• 
 Adults and children 12 years of age and older: 118 mL (one bottle) daily as a single dose  
• 
Children 2 to 11 years of age: 59 mL (one half bottle) daily as a single dose  
  
Dosing information from 2001 edition of the American Hospital Formulary Service’s Drug 
Information book or the 2001 edition of the Physician’s Desk Reference.  
  
  
  
  
  
  
  
  
  

TACL Protocol:  
T2012-002  
Original Version Date: 14-May-2016  
Activated: 
                 28-Jul-2016  
Amendment #1 Date: 16-Mar-2017 
 
 
Amendment #2 Date: 16-Jul-2018 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
T2012-002 Original Version Date: 14-May-2016   
CONFIDENTIAL 
Amendment #1 Date: 16-Mar-2017 
TACL Internal Distribution Only 
Amendment #2 Date: 16-Jul-2018  
116 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
  
  
  
  
  
  
  
  
 
APPENDIX 7: PHARMACOKINETIC WORKSHEET – T2012-002 MARQIBO® Study  
  
 
TACL Registration #: _______________  
  
BSA (m2): _______________  
  
 
Height (cm): _______________  
  
  
Assigned Dose (mg/m2): _______________  
  
 
Weight (kg): _______________  
  
  
Actual dose (mg): _______________  
  
  
Dose 1:   
  
Date of Administration  
  
  
Infusion Start Time  
  
  
Infusion End Time  
__________________  
  
Dose 2 (arm C will have a 
trough level but no dose 
administered1):   
  
  
_________________  
  ______________  
Date of Administration  
  
  
Infusion Start Time  
  
  
Infusion End Time  
__________________  
  
Dose 3  (Not required for 
Arm C) 
  
 
_________________  
  ______________  
Date of Administration  
  
  
Infusion Start Time  
  
  Infusion End Time  
__________________  
  
__________________  
  ________________  
  
 1.Complete a second form if there is a second cycle of Arm C 
  
Sample  
#  
Day  
Date  
Hour  
Target 
Time  
Time 
obtained  
Comments  

TACL Protocol:  
T2012-002  
Original Version Date: 14-May-2016  
Activated: 
                 28-Jul-2016  
Amendment #1 Date: 16-Mar-2017 
 
 
Amendment #2 Date: 16-Jul-2018 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
T2012-002 Original Version Date: 14-May-2016   
CONFIDENTIAL 
Amendment #1 Date: 16-Mar-2017 
TACL Internal Distribution Only 
Amendment #2 Date: 16-Jul-2018  
117 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
1  
1  
  
All: Pre-Dose  
  
  
  
2*  
1  
  
Arm A/B: 
End of 
Infusion (EOI)  
  
  
  
3*  
1  
  
Arm A/B: EOI + 2 
hours  
  
  
  
4*  
1  
  
Arm A/B:EOI + 24 
hours  
  
  
  
5  
8  
  
All: 
Pre dose #2 
(trough level for Arm 
C) 
  
  
  
6  
15  
  
Arm A/B: Pre dose #3   
  
  
EOI = End of infusion. * Obtain sample, if feasible, in consenting patients from a line separate 
than the one used to infuse Marqibo®  
  
Blood Sample Collection and Processing  
  
1. For non-mandatory samples, a peripheral or central access device may be used for 
collection of the PK samples. This must be a separate line from that used for Marqibo® 
infusion.  
  
2. Mandatory PK samples may be collected through the line used for Marqibo® infusion. 
  
3. If blood samples are taken via an indwelling central venous cannula, an appropriate 
amount of fluid should be removed from the cannula to clear the line before each blood 
sample is taken.    
4. Blood samples of 3 mL will be collected in lavender-top (EDTA) vacutainers at each of the 
time points indicated above.  Invert the lavender-top vacutainer 10 times to mix completely.  
  
5. Complete the labels using a waterproof pen and apply to the Vacutainer tubes. Complete 
information requested on this PK sheet for each sample.  Remember to record all sampling 
times (use the 24 hour clock; for example, 1:00 PM = 13:00).Add comments, as necessary. 
Place the samples on ice until centrifugation.    
6. Plasma: should be separated by centrifugation at 10°C (10 min at 1000 g or 2500 rpm) 
within four hours after collection. Separated plasma should be transferred to screw capped 
polyproplyene tubes (i.e. Nunc 3.6 ml #379189, 366524 or equivalent) and labeled with 
the TACL registration number, date and time of sampling, and sample number. Plasma 
samples should be stored in the dark at -70° C.    
 
7. Shipment: Participating sites should ship samples on dry ice using priority Federal Express 
(contact TACL Operations for a FedEx label to be used for sample shipments.) Samples 
should be shipped Monday, Tuesday or Wednesday only. Lab receives samples Tuesday 

TACL Protocol:  
T2012-002  
Original Version Date: 14-May-2016  
Activated: 
                 28-Jul-2016  
Amendment #1 Date: 16-Mar-2017 
 
 
Amendment #2 Date: 16-Jul-2018 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
T2012-002 Original Version Date: 14-May-2016   
CONFIDENTIAL 
Amendment #1 Date: 16-Mar-2017 
TACL Internal Distribution Only 
Amendment #2 Date: 16-Jul-2018  
118 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
through mid-Friday. Samples should not be sent on the day preceding a holiday. All 
samples 
should 
be 
batched 
per 
patient. 
Send 
a 
notification email 
to 
marqibo@mail.nih.gov when sending samples.   
  
 
Ship samples to:  
    
Figg Lab  
Clinical Pharmacology Program  
National Cancer Institute  
9000 Rockville Pike  
Building 10, Room 5A08 
Bethesda, MD 20892  
(O) 240-760-6180 
(F) 301-402-8606  
 
8. Please notify the PK team by e-mail (marqibo@mail.nih.gov) or phone (301-402-6642) 
with questions regarding sample handling and shipment.  
  
  
  
  
  
  
  
  
  
  
  
 
 
 
 
 
 
 
 
 
 
 
 

TACL Protocol:  
T2012-002  
Original Version Date: 14-May-2016  
Activated: 
                 28-Jul-2016  
Amendment #1 Date: 16-Mar-2017 
 
 
Amendment #2 Date: 16-Jul-2018 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
T2012-002 Original Version Date: 14-May-2016   
CONFIDENTIAL 
Amendment #1 Date: 16-Mar-2017 
TACL Internal Distribution Only 
Amendment #2 Date: 16-Jul-2018  
119 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
Appendix 8: Mercaptopurine Dosing Guidelines (As per Children’s Oncology Group AALL1131 
Trial 

TACL Protocol:  
T2012-002  
Original Version Date: 14-May-2016  
Activated: 
                 28-Jul-2016  
Amendment #1 Date: 16-Mar-2017 
 
 
Amendment #2 Date: 16-Jul-2018 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
T2012-002 Original Version Date: 14-May-2016   
CONFIDENTIAL 
Amendment #1 Date: 16-Mar-2017 
TACL Internal Distribution Only 
Amendment #2 Date: 16-Jul-2018  
120 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 

TACL Protocol:  
T2012-002  
Original Version Date: 14-May-2016  
Activated: 
                 28-Jul-2016  
Amendment #1 Date: 16-Mar-2017 
 
 
Amendment #2 Date: 16-Jul-2018 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021 
 
T2012-002 Original Version Date: 14-May-2016   
CONFIDENTIAL 
Amendment #1 Date: 16-Mar-2017 
TACL Internal Distribution Only 
Amendment #2 Date: 16-Jul-2018  
121 
Amendment #3 Date: 24-Apr-2020 
Amendment #4 Date: 8-Dec-2021