A Phase II Study Incorporating Panobinostat, Bortezomib and Liposomal Vincristine Into Re-Induction Therapy for Relapsed Pediatric T-Cell Acute Lymphoblastic Leukemia or Lymphoma
Phase: PHASE2
Conditions: Acute Lymphoblastic Leukemia, Lymphoma, Non-Hodgkin's, Leukemia, T-Cell, Leukemia, B-Cell
Sponsor: St. Jude Children's Research Hospital

TSALV 
 
Amendment 1.0, dated: 12-14-2015 
 
IRB Approval date: 02-01-2016 
Protocol document dated: 01-28-2016 
St. Jude 
TSALV ID NCT02518750 
Initial version, dated:  12-23-2014.  Resubmitted to CT-SRC 03-31-2015.  Resubmitted to IRB 
05-08-2015.  (IRB approved:  06-03-2015).   
Revision 0.1, dated:  05-14-2015 (IRB approved: 06-04-2015) 
Revision 0.2, dated: 07-15-2015 (IRB approved: 07-15-2015) 
Activation date: 12-09-2015 
Amendment 1.0, dated:  12-14-2015.  Resubmitted to IRB 01-28-2016 
 (IRB approved: 02-01-2016) 
Activation date: 03-30-2016 
 
 
A PHASE II STUDY INCORPORATING PANOBINOSTAT, BORTEZOMIB, AND 
LIPOSOMAL VINCRISTINE INTO RE-INDUCTION THERAPY FOR RELAPSED 
PEDIATRIC T-CELL ACUTE LYMPHOBLASTIC LEUKEMIA OR LYMPHOMA 
 
 
IND# 126,426 
 
Principal Investigator 
Sima Jeha, MD 
Department of Oncology 
Leukemia/Lymphoma Division 
 
Co-Investigators 
 
Hiroto Inaba, MD, PhD 
Kristine Crews, PharmD 
Jeffrey E. Rubnitz, MD, PhD 
Jun J. Yang, PhD 
Raul C. Ribeiro, MD 
Charles Gawad, MD 
Patrick Campbell, MD, PhD 
Tanja Gruber, MD, PhD 
Jennifer Pauley, PharmD 
Department of Pharmaceutical Sciences 
 
Charles G. Mullighan, MBBS(Hons), MSc, MD 
Monika Metzger, MD, MS 
John T. Sandlund, MD 
John K. Choi, MD, PhD 
Department of Pathology 
Department of Oncology 
 
Leukemia/Lymphoma Division 
 
Cheng Cheng, PhD 
Department of Biostatistics 
Brandon M. Triplett, MD 
Department of Bone Marrow Transplant & Cell Therapy 
 
Kirsten K. Ness, PT, PhD 
Department of Epidemiology and Cancer Control 
Hana Hakim, MD 
Department of Infectious Diseases 
 
Raja  B. Kahn, MD 
Zsila Sadighi, MD 
Department of Pediatric Medicine 
Division of Neurology 
 
 
St. Jude Children's Research Hospital 
262 Danny Thomas Place 
Memphis, Tennessee  38105-3678 
Telephone:  (901) 595-3300 
 

TSALV 
 
Amendment 1.0, dated: 12-14-2015 
 
IRB Approval date: 02-01-2016 
Protocol document dated: 01-28-2016 
Contents of this document may not be extracted without permission from the Principal Investigator 

TSALV 
 
Amendment 1.0, dated: 12-14-2015 
 
IRB Approval date: 02-01-2016 
Protocol document dated: 01-28-2016 
List of Collaborating Investigators/Institutions 
Contact Information  
 
 
Pending 
 
 
 

TSALV 
 
Amendment 1.0, dated: 12-14-2015 
 
IRB Approval date: 02-01-2016 
Protocol document dated: 01-28-2016 
PROTOCOL SUMMARY 
TSALV, A PHASE II STUDY INCORPORATING PANOBINOSTAT, BORTEZOMIB, AND 
LIPOSOMAL VINCRISTINE INTO RE-INDUCTION THERAPY FOR RELAPSED 
PEDIATRIC T-CELL ACUTE LYMPHOBLASTIC LEUKEMIA OR LYMPHOMA 
Principal Investigator: Sima Jeha, M.D. 
IND holder: St. Jude Children’s Research Hospital, IND# 126,426 
Brief overview: This is a phase-II study to evaluate the efficacy of a salvage regimen consisting of 
liposomal vincristine, mitoxantrone, Peg-asparaginase, ITMHA, dexamethasone, panobinostat, and 
bortezomib in children with relapsed T-cell ALL or lymphoma.  
Intervention: Systemic chemotherapy, intrathecal chemotherapy, panobinostat, bortezomib, and 
HSCT for children with relapsed T-cell ALL or lymphoma.  
Brief outline of treatment plan: Three Block Induction: 
 
Block A: approximately 5 weeks 
• Dexamethasone 10 mg/m2/day PO Days 1-8, 15-22 (Total 16 days) 
• Panobinostat 24 mg/m2/dose PO Day 2,4,6 
• Liposomal vincristine (VSLI)  2.25 mg/m2 no cap IV on Days 7, 14, 21, 28 
• Mitoxantrone 10 mg/m2 IV Day 7,14 (In the absence of peripheral blasts, Day 14 
Mitoxantrone will be given if WBC ≥1000 and ANC ≥300) 
• Peg-asparaginase 2500 units/m2 on Days 9,23 
• Bortezomib 1.3 mg/m2 IV Days 16, 19, 23, 26 
• ITMHA Days 1, 7, 14, 21, 28.  Additional ITs on Days 10 and 17 for patients with CNS 2, 3 or 
traumatic tap with blasts 
 
Block B: approximately 5 weeks 
• High-dose methotrexate 8 g/m2 IV over 24 hours (will not be given to patients with prior 
cranial irradiation) Day 1 
• 6-mercaptopurine 50 mg/m2 PO days 1-14 
• ITMHA Day 1 
• High-dose cytarabine 3 g/m2 IV Q12H Days 15 and 16 
 
Block C: approximately 3 weeks 
• Nelarabine 650 mg/m2/day IV Days 1-5  
(Clofarabine 40 mg/m2/day IV Days 1-5 will be given instead of nelarabine for patients with 
B-lymphoblastic leukemia and lymphoma in stratum II) 
• Cyclophosphamide 300 mg/m2 IV Days 1-5 
• Etoposide 100 mg/m2/day IV Days 1-5 
 
Response evaluation is performed after the end of each treatment block. All patients should proceed 
to HSCT after achieving negative MRD when a suitable donor is identified. Patients could continue 
on Block B and Block C if not ready for HSCT. If after completion of Block C MRD is persistently 
positive, the plan will be discussed with the PI/co PI and the transplant team. Enrollment on ongoing 
NK cell studies will be considered. For patients who require a second transplant, HAP3R may be an 
option. Donor will be selected according to institutional practices and transplant regimens will be 
used according to institutional HSCT protocols and guidelines.  

TSALV 
 
Amendment 1.0, dated: 12-14-2015 
 
IRB Approval date: 02-01-2016 
Protocol document dated: 01-28-2016 
TSALV, A PHASE II STUDY INCORPORATING PANOBINOSTAT, BORTEZOMIB, AND 
LIPOSOMAL VINCRISTINE INTO RE-INDUCTION THERAPY FOR RELAPSED 
PEDIATRIC T-CELL ACUTE LYMPHOBLASTIC LEUKEMIA OR LYMPHOMA 
Study design:  
Primary objective: To evaluate the complete remission (CR) rate for patients with T-cell 
lymphoblastic leukemia or lymphoma in first relapse: n=24. Point estimate and the Blyth-Casella 
exact 95% confidence interval of the CR rate will be computed. Secondarily a comparison to the 
historical CR rate (R16 and R17 combined) will be performed by Fisher’s exact test. 
 
Historical data: 
Outcome in R16 and R17 T-cell patients 
  
R16 (n = 9 ) 
R17 ( n= 7) 
Total 
CR 
7 (77.8%) 
5 (71.4%) 
12 (75.0%) 
No CR 
2 (22.2%) 
2 (28.6%) 
4 (25.0%) 
Total 
9 
7 
16 
  
Stratum II: Patients with B-cell or T-cell lymphoblastic leukemia or lymphoma in second or third 
relapse, or refractory to 2 or 3 induction or re-induction attempts; n=10 patients for descriptive 
analyses only (exploratory objectives). 
Sample size:   
T-cell lymphoblastic leukemia or lymphoma in first relapse: n=24 evaluable patients 
B-cell or T-cell lymphoblastic leukemia or lymphoma in second or greater relapse: n=10 evaluable 
patients.  Total enrollment:  n=40 
Data management:  Data management and statistical analysis will be provided locally by the 
Comprehensive Cancer Center Hematological Malignancies Program, and Biostatistics Department 
at St. Jude Children’s Research Hospital. 
Human subjects: The main risk to research participants will be the potential toxicities associated 
with the use of intensive salvage chemotherapy followed by HSCT. The research participants will be 
informed of the toxicities, which have been associated with the study drugs and potential side effects 
of procedures recommended in this study. Adverse events will be monitored, treated, and reported 
following institutional and federal guidelines and regulations. 

TSALV 
 
Amendment 1.0, dated: 12-14-2015 
 
IRB Approval date: 02-01-2016 
Protocol document dated: 01-28-2016 
Table of Contents 
 
1.0 
OBJECTIVES ......................................................................................................... 1 
1.1 
Primary Objective ........................................................................................................... 1 
1.2 
Secondary Objectives...................................................................................................... 1 
1.3 
Exploratory Objectives ................................................................................................... 1 
2.0  
BACKGROUND AND RATIONALE ................................................................... 2 
2.1 
Relapsed T-Cell ALL ...................................................................................................... 2 
2.2 
Vincristine Sulfate Liposome Injection (VSLI, Marqibo®) ............................................ 2 
2.3 
Panobinostat .................................................................................................................... 3 
2.4 
Bortezomib ...................................................................................................................... 6 
2.5 
Selection of Backbone Chemotherapy ............................................................................ 6 
2.6 
Background and Rationale for Secondary and Exploratory Objectives ......................... 7 
3.0  
ELIGIBILITY CRITERIA AND STUDY ENROLLMENT ............................... 12 
3.1 
Inclusion Criteria .......................................................................................................... 12 
3.2 
Exclusion Criteria ......................................................................................................... 13 
3.3 
Recruitment and Screening ........................................................................................... 15 
3.4 
Enrollment at St. Jude ................................................................................................... 15 
3.5 
Enrollment at Collaborating Sites ................................................................................. 15 
4.0 
TREATMENT PLAN ........................................................................................... 15 
4.1 
Intrathecal Chemotherapy ............................................................................................. 16 
4.2 
Block A: Approximately 5 Weeks ................................................................................ 16 
4.3  
Block B: Approximately 5 Weeks ................................................................................ 17 
4.4  
Block C: Approximately 3 Weeks ................................................................................ 20 
4.5  
Timing of Bone Marrow Aspirate and MRD Assessments .......................................... 20 
4.6  
Recommendations for Post-Protocol Therapy .............................................................. 20 
4.7 
CNS and Testicular Leukemia ...................................................................................... 21 
5.0 
DRUG/DEVICE/BIOLOGIC AGENT INFORMATION .................................... 21 
5.1 
Dexamethasone (Decadron®) ....................................................................................... 21 
5.2 
Panobinostat (LBH589) ................................................................................................ 22 
5.3 
vinCRIStine sulfate LIPOSOME injection (VSLI, Marqibo®) ................................... 22 
5.4 
Mitoxantrone (Novantrone) ....................................................................................... 23 
5.5 
Peg-L-Asparaginase (Pegaspargase, Oncaspar) ........................................................ 24 
5.6 
Erwinia L-Asparaginase (Erwinase) .......................................................................... 25 
5.7 
Bortezomib (Velcade, PS-341, MLN341, LDP-341) ................................................... 26 
5.8 
Methotrexate (IV) ......................................................................................................... 28 
5.9 
Mercaptopurine (6-MP) (Purinethol) ......................................................................... 29 
5.10 
Cytarabine (Ara-C) (Cytosar-U) ................................................................................ 30 
5.11 
Nelarabine (Arranon®, Compound 506U78) ............................................................... 31 
5.12 
Clofarabine (Clolar™, Clofarex) .................................................................................. 32 
5.13 
Cyclophosphamide (Cytoxan) ................................................................................... 33 
5.14 
Etoposide (VP-16) (Vepesid) .................................................................................... 34 
5.15 
Etoposide Phosphate (Etopophos®) ............................................................................. 34 
5.16 
Intrathecal Triples (ITMHA, methotrexate/hydrocortisone/cytarabine) ....................... 35 
5.17 
Drug Shortages and Unavailability ............................................................................... 35 
6.0 
TREATMENT MODIFICATIONS ...................................................................... 36 
6.1 
PEG-Asparaginase Allergies/Hypersensitivity ............................................................. 36 
6.2 
Participants with Renal Dysfunction ............................................................................ 36 

TSALV 
 
Amendment 1.0, dated: 12-14-2015 
 
IRB Approval date: 02-01-2016 
Protocol document dated: 01-28-2016 
6.3 
Participants with Hepatic Dysfunction ......................................................................... 36 
6.4 
Cardiotoxicity ............................................................................................................... 37 
6.5 
Peripheral Neuropathy .................................................................................................. 37 
7.0 
REQUIRED EVALUATIONS, TESTS, AND OBSERVATIONS ..................... 38 
7.1 
Pretreatment Evaluation ................................................................................................ 38 
7.2 
Evaluations during Therapy .......................................................................................... 39 
8.0 
CORRELATIVE RESEARCH STUDIES ........................................................... 40 
8.1 
Pharmacokinetic Studies ............................................................................................... 40 
8.2 
Pharmacodynamic, Genomic and MRD Studies .......................................................... 40 
8.3 
NK Cell Receptor Studies ............................................................................................. 42 
8.4 
Intestinal Microbiome Research ................................................................................... 42 
8.5 
Neuropathy and Function Assessments ........................................................................ 43 
9.0 
EVALUATION CRITERIA ................................................................................. 44 
9.1 
Response Criteria for Lymphoblastic Leukemia .......................................................... 44 
9.2 
Response Criteria for Lymphoblastic Lymphoma ........................................................ 45 
10.0 
CONCOMITANT THERAPY.............................................................................. 45 
11.0 
SUPPORTIVE CARE GUIDELINES .................................................................. 46 
11.1 
Management of Hyperleukocytosis .............................................................................. 46 
11.2 
Metabolic Derangements .............................................................................................. 46 
11.3 
Bacterial, Fungal and Viral Prophylaxis ....................................................................... 46 
11.4 
Management of Febrile Neutropenia ............................................................................ 47 
11.5 
Drug Interactions .......................................................................................................... 47 
11.6 
Growth Factors.............................................................................................................. 47 
11.7 
Etoposide Reactions ...................................................................................................... 47 
11.8 
Nelarabine-Related Neurotoxicity ................................................................................ 48 
11.9 
Bortezomib-Related Toxicities ..................................................................................... 49 
11.10 Special Considerations for Administration of Clofarabine ........................................... 50 
12.0 
OFF TREATMENT AND OFF STUDY CRITERIA .......................................... 50 
12.1 
Off Treatment Criteria .................................................................................................. 50 
12.2 
Off Study Criteria ......................................................................................................... 51 
13.0 
SAFETY AND ADVERSE EVENT REPORTING REQUIREMENTS ............. 51 
13.1 
Reporting Adverse Experiences and Deaths to St. Jude IRB ....................................... 51 
13.2 
Reporting to Novartis Pharmaceuticals and Spectrum Pharmaceuticals ...................... 53 
13.3 
Reporting to Regulatory Affairs Office and FDA ........................................................ 54 
13.4 
Recording Adverse Events and Serious Adverse Events .............................................. 55 
13.5 
Process for Reporting Adverse Events from and to Collaborating Sites ...................... 56 
14.0 
DATA COLLECTION, MONITORING AND CONFIDENTIALITY ............... 57 
14.1 
Data Collection ............................................................................................................. 57 
14.2 
Study Monitoring .......................................................................................................... 57 
14.3 
Confidentiality .............................................................................................................. 58 
15.0 
STATISTICAL CONSIDERATIONS.................................................................. 58 
15.1 
Analysis of Primary Objective ...................................................................................... 58 
15.2 
Analysis of Secondary Objectives ................................................................................ 60 
15.3 
Analysis of Exploratory Objectives .............................................................................. 60 
15.4 
Accrual and Study Duration.......................................................................................... 61 
16.0  OBTAINING INFORMED CONSENT ............................................................... 61 
16.1 
Consent Prior to Research Interventions....................................................................... 61 
16.2 
Consent at Enrollment................................................................................................... 61 
16.3 
Consent at Age of Majority........................................................................................... 62 

TSALV 
 
Amendment 1.0, dated: 12-14-2015 
 
IRB Approval date: 02-01-2016 
Protocol document dated: 01-28-2016 
16.4 
Consent When English is Not the Primary Language .................................................. 62 
17.0 
REFERENCES ..................................................................................................... 63 
 
APPENDICES 
 
Appendix I: 
Performance Status Scales/Scores 
Appendix II: Tests Performed for Good Clinical Care and for Research 
Appendix III: CYP3A4/5 Inhibitors and Inducers 
Appendix IV:  Neuropathy Function and Assessments Forms 
 
 
 
 

TSALV 
 
 
Amendment 1.0, dated: 12-14-2015 
 
IRB Approval date: 02-01-2016 
Protocol document dated: 01-28-2016 
Stratum I:  T-cell leukemia or lymphoma in 1st relapse 
 
 
 
 
 
 
 
 
 
 
 
 
MRD neg 
 
Response Evaluation 
 
  
HSCT 
 
 
MRD pos or donor not ready 
 
 
 
 
 
 
 
 
 
 
 
 
 
MRD neg 
 
Response Evaluation 
 
HSCT 
 
 
 
MRD pos+ or donor not ready 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MRD neg- 
 
Response Evaluation 
 
HSCT 
 
 
MRD pos+ 
 
 
 
 
 
 
 
 
 
 
 
Block B 
HDMTX/6MP/HDARAC 
Block A 
DEX/PANO/VSLI/MITO/PEG-ASP 
Block C 
NELARABINE/CYCLO/ETOP 
OFFTREATMENT 

TSALV 
 
 
Amendment 1.0, dated: 12-14-2015 
 
IRB Approval date: 02-01-2016 
Protocol document dated: 01-28-2016 
Stratum II:  B-cell or T-cell lymphoblastic leukemia or lymphoma in 
2ND or greater relapse 
 
 
 
 
 
 
 
 
 
 
 
 
MRD neg- 
 
Response Evaluation 
 
  
HSCT 
 
 
MRD pos+ or donor not ready 
 
 
 
      
 
 
 
 
 
 
 
 
 
MRD neg- 
 
Response Evaluation 
HSCT 
 
 
MRD pos+ or donor not ready 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Response Evaluation  
Response Evaluation 
 
 
 
 
MRD neg - 
MRD neg- 
 
 
HSCT 
 
HSCT
 
 
 
 
MRD pos+ 
 
 
MRD pos+ 
 
 
 
 
Block B 
HDMTX/6MP/HDARAC 
Block A 
DEX/PANO/VSLI/MITO/PEG-ASP 
Block C – B-cell malignancies 
CLOFARABINE/CYCLO/ETOP 
OFFTREATMENT 
Block C – T-cell malignancies 
NELARABINE/CYCLO/ETOP 
OFFTREATMENT 

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Amendment 1.0, dated: 12-14-2015 
 
IRB Approval date: 02-01-2016 
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1.0 
OBJECTIVES 
 
The overall objective of this study is to improve the cure rate of relapsed T-cell 
lymphoblastic leukemia and lymphoma. 
 
1.1 
Primary Objective 
 
To estimate the complete remission (CR) rate for patients with T-cell 
lymphoblastic leukemia and lymphoma in first relapse. 
 
1.2 
Secondary Objectives 
 
1.2.1 To evaluate minimal residual disease (MRD) levels at end of each block of 
therapy. 
 
1.2.2 To describe the toxicities of vincristine sulfate liposome injection (VSLI) 
when used in combination with chemotherapy and bortezomib. 
 
1.3   
Exploratory Objectives 
 
1.3.1 To identify molecular determinants and biomarkers of histone deacetylase 
(HDAC) inhibitor response. 
 
1.3.2 To study the pharmacokinetics of panobinostat. 
 
1.3.3 To establish xenografts of relapsed T-cell lymphoblastic leukemia for 
downstream studies of cytotoxicity and therapy resistance. 
 
1.3.4 To perform genomic studies of leukemic cells at relapse, diagnosis and 
MRD (where available) to investigate clonal evolution and identify targets 
for therapeutic intervention. 
 
1.3.5 To validate new markers and methods for MRD detection.  
 
1.3.6 To genotype natural killer (NK) cell receptors and measure their 
expressions at diagnosis and before Block C, and to associate these 
features with treatment outcome.  
 
1.3.7 To perform a comprehensive analysis of the intestinal microflora in 
patients with relapsed hematologic malignancies prior to and subsequent 
to each block of intensive salvage chemotherapy using next generation 
sequencing technologies as an exploratory approach. 
 
1.3.8 To describe the frequency and severity of gastrointestinal illnesses during 
3 blocks of intensive salvage chemotherapy in patients who did and those 
who did not have changes in intestinal microbiota.  
 
 

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2.0  
BACKGROUND AND RATIONALE 
 
2.1 
Relapsed T-Cell ALL  
 
Patients with newly diagnosed T-cell ALL treated on contemporary protocols have a 5-
year EFS rates approaching 80%1,2. However, patients who relapse have a dismal 
outcome and only 5% to 16% survive their recurrence (Table 1) despite intensive salvage 
chemotherapy and hematopoietic stem cell transplantation (HSCT). In comparison to B-
cell ALL, relapses in patients with T-cell ALL tend to occur early (within 3 years of 
initial diagnosis), and fewer patients achieve second remission and low levels MRD 
allowing them to proceed to HSCT. Thus, newer approaches to therapy are warranted. 
 
Table 1: Outcomes for patients with T-cell ALL in first relapse 
Study 
N 
CR2 rates     
EFS 
COG 19413 
17 
82% 
7% (3-year) 
COG AALL01P24 
7 
29% 
0% (1-year) 
*ALL REZ BFM 905 
73 
NR 
16.4% (10-year) 
SJ ALLR16/17 
16 
75% 
12.5% (3-year) 
Italian ALL R-876 
15 
60% 
5% (7-year) 
POG 83037 
27 
81% 
NR 
Nelarabine phase II8 
39 
46% 
NR 
*composite of all T-cell ALL subtypes 
NR= not reported 
 
2.2 
Vincristine Sulfate Liposome Injection (VSLI, Marqibo®) 
 
Vincristine is a very effective drug in hematologic malignancies and is an important 
component of therapeutic regimens in childhood ALL. However, to avoid toxicities (in 
particular neurological toxicities), the dose is capped at 2 mg which can compromise 
effectiveness especially in adolescents and adults. VSLI is a sphingomyelin and cholesterol 
based nanoparticle formulation of vincristine that was designed to improve on the 
pharmacokinetic properties of standard vincristine9.  It circulates for a longer time in the 
plasma, accumulates in tumor tissue and slowly releases vincristine in the tumor instead of 
the systemic circulation. It is tolerated at a higher dose intensity compared to standard 
vincristine without increased toxicity9,10. In a phase II study of 65 adult patients with 
multiple relapsed ALL, single agent VSLI was administered at a dose of 2.25 mg/m2 
weekly without a dose cap11. Complete response was achieved in 13 patients (20%). Of the 
10 patients with T-cell ALL treated in this study, 2 (20%) also achieved CR. Based on 
these results, the FDA granted accelerated approval for VSLI in August 2012 for the 
treatment of adults with Philadelphia chromosome-negative ALL in second or greater 
relapse. An ongoing phase III randomized study compares vincristine and VSLI on a 
standard chemotherapy backbone in adult patients with newly diagnosed ALL 
(NCT01439347). A pediatric phase I dose escalation study for this agent is nearing 
completion at the NCI (NCT1222780). At the current dose level (2.25 mg/m2 weekly), it 
appears to be safe, tolerable and demonstrates preliminary activity in patients with 
refractory ALL and solid tumors12.  In view of these encouraging findings and enhanced 
pharmacokinetic properties allowing dose intensification of vincristine without increased 
toxicity, we will incorporate VSLI weekly x 4 doses in Block A therapy of TSALV.  

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2.3 
Panobinostat  
 
2.3.1 Epigenetics and Cancer  
 
In recent years, the importance of epigenetic regulatory mechanisms in normal and 
malignant cell development have become increasingly evident. The two best described 
epigenetic gene regulatory mechanisms leading to targeted therapeutic approaches are 
DNA promoter methylation and histone modification13.  
 
Abnormal DNA hypermethylation in promoter CpG islands leads to gene silencing. DNA 
methyltransferase inhibitors (e.g. azacytidine and decitabine) reverse promoter 
hypermethylation in tumor cells, lead to re-expression of aberrant silenced genes and 
induce tumor cell death. Both azacytidine and decitabine have demonstrated efficacy in 
myelodysplastic syndromes leading to FDA approval.  
 
Histone proteins are responsible for the assembly of DNA in the nucleus and are 
modulated by post-translational modifications such as acetylation and/or 
phosphorylation. Acetylation of amino acid residues on the histone tails leads to an open 
configuration of DNA on the histones and increases accessibility of transcription factors 
to gene promoter regions14. Deacytelation has the opposite effect decreasing access of 
transcription factors to promoter regions. Histone acetylation is mediated by histone 
acetyl transferases (HATs) while acetyl groups are removed by histone deacetylases 
(HDACs). HDACs have a critical role in modulating balance between pro and anti-
apoptotic proteins. High levels of HDAC enzymes and histone hypoacetylation is a 
common finding in multiple cancers14. HDAC-mediated deacetylation alters the 
transcriptional activity of nuclear transcription factors including p53, E2F, c-Myc, NF-kB 
and HIF-1α15. Several HDAC inhibitors are in clinical development15,16. Vorinostat was 
approved by the FDA for cutaneous T-cell lymphoma in October 2006.  
 
2.3.2 HDAC Inhibitors in Hematologic Malignancies with a Focus on T-Cell ALL 
 
By using gene expression profiling and small interfering RNA, it was shown by Pearl et 
al in 2005 that HDAC inhibitor exposure to T-lymphoblastic cell lines led to regulation 
of the expression of several genes (cyclins/cyclin dependent kinases, Bcl-2, caspases 
etc.), which favored induction of apoptosis and decreased cellular proliferation17. 
Multiple additional studies demonstrate modulation of the extrinsic and intrinsic 
apoptotic pathways as well as induction of non-apoptotic death (autophagy) by HDAC 
inhibitors in hematopoietic malignancies14,18. 
 
Resequencing efforts of matched diagnosis and relapsed ALL samples at St Jude have 
identified deleterious mutations of CREBBP in 20% of relapsed cases19. CREBBP 
encodes the CREB-binding protein which is a transcriptional co-activator that mediated 
glucocorticoid response and also plays a role in histone acetylation. Experiments in 
glucocorticoid-resistant ALL cell lines (including T-cell ALL) demonstrated sensitivity 
to vorinostat. Though all the mechanisms of action of HDAC inhibitors in ALL are not 
known, there is evidence to suggest that they lead to re-expression of pro-apoptotic BIM 
and restore sensitivity to glucocorticoids in resistant xenografts20. This finding has been 
validated in T-cell ALL cell lines at St Jude (Jun Yang, unpublished). In another study of 

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matched diagnosis and relapse blasts from patients with childhood ALL, a relapse 
specific gene-expression signature was identified. Using the Connectivity Map database 
that links disease to corresponding patterns produced by candidate drugs, vorinostat was 
the top candidate to reverse the relapse-specific signature21. Subsequent validation studies 
using primary patient samples and ALL cell lines demonstrated that vorinostat increased 
chemosensitivity to commonly used drugs such as prednisone, doxorubicin, cytarabine 
and etoposide.  
 
Additional evidence of epigenetic deregulation in T-cell ALL is provided by a whole 
genome sequencing study of early T-cell precursor (ETP) ALL. Forty-five percent of 
cases were characterized by somatic alterations targeting histone modification (EZH2, 
EED, SUZ12 and EP300)22. Twelve percent of non-ETP T-cell ALL cases also harbored 
alterations in these genes. EZH2, EED and SUZ12 are components of the polycomb 
repressor complex and play a role in the methylation of histones while EP300 is a HAT. 
Loss of function mutations in EP300 alters the balance in favor of HDACs versus HATs 
suggesting that HDAC inhibitors may be beneficial. 
 
Panobinostat is pan HDAC inhibitor with promising activity in solid tumors and 
hematologic malignancies23. It is more potent than vorinostat with a longer half-life. In a 
xenograft model of T-cell ALL, survival of the mice was significantly increased by 
treatment with panobinostat when compared to mice treated with conventional 
chemotherapy (vincristine and dexamethasone)24. The therapeutic effect of panobinostat 
was enhanced in combination with vincristine and dexamethasone without increased 
toxicity. In vitro studies at St Jude have demonstrated that panobinostat is highly 
cytotoxic across T-cell ALL cell lines, including ETP ALL cells at nanomolar 
concentrations. In addition, combination with steroids was highly synergistic in all T- cell 
ALL cell lines tested (Jun Yang, unpublished data, Figures 1 and 2). Panobinostat has a 
favorable clinical activity in phase I and II studies in leukemias and lymphomas, 
including peripheral T-cell lymphomas16,25. The pediatric phase I study in hematologic 
malignancies in ongoing (NCT 01321346). In TSALV, we will administer panobinostat 
along with dexamethasone during the first 6 days of therapy (window) to study the effects 
of panobinostat on dexamethasone sensitivity as well as its cytotoxic effects, 
pharmacokinetics and pharmacodynamics.  

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Figure 1: Cell cytotoxicity assays (MTT) of HDAC inhibitors at various concentrations in 
Loucy cell line (early T-cell precursor ALL). Both panobinostat and vorinostat were 
cytotoxic, but panobinostat was more potent than vorinostat.  
 
 
Figure 2: Cell cytotoxicity assays of panobinostat at various concentrations in multiple 
ALL cell lines. Panobinostat is highly cytotoxic 
 
 

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2.4 
Bortezomib 
 
Bortezomib, the first proteasome inhibitor approved by the Food and Drug 
Administration for multiple myeloma and relapsed non-Hodgkin lymphoma, showed 
preclinical activity against ALL and demonstrated synergy with dexamethasone26. 
Bortezomib was combined with a standard 4-drug regimen (vincristine, doxorubicin, 
prednisone, PEG-asparaginase) in the TACL2005-003 study which enrolled 22 patients 
with relapsed ALL that had failed 2 or 3 prior regimens27. The overall response rate was 
73% and overall survival at 24 months was 41% ± 13%, which is a significant 
improvement from historical data28. 
 
2.5 
Selection of Backbone Chemotherapy 
 
2.5.1 Induction Block A 
 
Block A is based on the TACL 2005-003 regimen26 combining bortezomib and 4 drug 
induction with following modifications:  
 
• One to two doses of mitoxantrone will be substituted for one dose of doxorubicin 
based on the UK ALL R3 trial demonstrating that a re-induction regimen 
incorporating mitoxantrone improved survival (3-year progression-free survival 
64.6%) in patients with ALL in first relapse28. 
• Only 2 doses of PEG-asparaginase will be given, instead of 4. 
• Dexamethasone will be given on a different schedule (8 days on, 6 days off, 8 
days on, 6 days off) instead of on days 1-14. 
• IT therapy is a different schedule and MHA is always given (not just Ara-C on 
Day 1). 
• VSLI will be substituted for vincristine. 
• A 6-day window of panobinostat and dexamethasone will explore the activity of 
this regimen in this patient population. 
 
2.5.2 Induction Block B 
 
Block B will comprise of high-dose methotrexate and high-dose cytarabine, which are 
established active drugs in T-cell leukemias and lymphomas and have excellent 
penetration into sanctuary sites like the CNS. 
 
A 24-hour infusion of HDMTX was shown to have superior anti-leukemic effect than a 
4-hour infusion of HDMTX in T-cell ALL29. Doses > 8 g/m2 have been used in multiple 
protocols for short infusions; doses of ~ 8 g/m2/24 hours (targeted to achieve steady-state 
plasma concentrations (Cpss) of 90 uM) were used in children with ALL in St. Jude 
Protocol Total XIV, although the number of patients receiving this dose was small30. 
However, we have experience targeting doses of ~ 5 g/m2/24 hours to a Cpss of  65 uM 
in over 180 children enrolled on Total XV31. There are multiple studies to support use of 
a higher dose of HDMTX in T-cell ALL29,32-38. Thus, our plan is to use the 24 hour 
infusion and a higher dose of HDMTX, performing intra-infusion targeting of the dose of 
HDMTX to achieve a Cpss of 90 uM (average expected from 8 g/m2 over 24 hours).  

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2.5.3 Induction Block C 
 
Nelarabine is a purine analog with selective cytotoxicity for T-lineage hematologic 
malignancies. In the COG phase II study for relapsed T-cell ALL, the response rate at the 
dose of 650 mg/m2 was 55% (11 CR, 2 partial response [PR]) for patients in first relapse 
and was 27% (7CR, 1PR) for those in second or greater relapse8. In a series of 7 patients 
with relapsed or refractory T-cell malignancies, nelarabine in combination with etoposide 
and cyclophosphamide induced complete remission in 5 patients and partial remission in 
2 patients.39 Thus, we will use this promising regimen for induction Block C. In patients 
with non-T-cell disease clofarabine will be substituted for nelarabine.  
 
2.6 
Background and Rationale for Secondary and Exploratory Objectives 
 
2.6.1 Minimal Residual Disease (MRD)  
 
MRD is an excellent surrogate marker for response and survival in childhood ALL at 
initial diagnosis40. At first relapse, studies at St Jude and other institutions have also 
demonstrated the prognostic implication of positive MRD (≥ 0.01%) at the end of 4-6 
weeks of therapy. In St. Jude ALLR11 and ALLR15 studies, the cumulative incidence of 
second relapse was 70.2% for MRD positive patients (≥ 0.01%) versus 28% for MRD 
negative patients (p=0.008)41. In the COG AALL01P2 study, the 12 month EFS was 80% 
versus 48% in patients with positive versus negative MRD at the end of the first block of  
remission induction therapy4. The proportion of patients who are MRD positive at the end 
of re-induction therapy is relatively high: 68% in AALL01P2 and 71% in ALLR17. Thus, 
in TSALV, we will attempt to decrease the rate of MRD positivity by utilizing a novel 
induction regimen. 
 
2.6.2 Toxicities of VSLI in Combination with Chemotherapy 
 
Neurotoxicities (especially peripheral neuropathy) of VSLI in the adult single-agent study 
of patients with multiply relapsed ALL have been characterized and were not increased 
compared to those associated with standard vincristine despite increased dose intensity 
and prior exposure to standard vincristine10. The patient population in TSALV will be 
less heavily pre-treated (first relapse) with less baseline neurotoxicity. For detailed 
characterization of neuropathy, the pediatric-modified total neuropathy scale, balance, 
manual dexterity and gait testing will be done prior to the first dose of liposomal 
vincristine and repeated on day 15 (prior to initiation of bortezomib) and after completion 
of Induction Block A.  
 
2.6.3 Molecular Determinants and Biomarkers of HDAC Inhibitor Response 
 
Molecular analyses of the tumor tissue ideally would help discriminate which tumors will 
respond to HDAC inhibitor therapy. HR23B is a candidate cancer biomarker identified in 
a genome-wide loss-of-function screen which influences sensitivity to HDAC 
inhibitors42. High expression of HR23B in biopsies of cutaneous T-cell lymphoma 
(CTCL) was associated with response. HR23B plays a role in shuttling ubiquitinated 
proteins to the proteasome. Another retrospective analysis of pretreatment CTCL skin 
biopsies found that high nuclear STAT1 and phospho-STAT3 staining in lymphoma cells 

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correlated with lack of clinical response to vorinostat43. We will perform genomic 
profiling studies ex vivo (e.g., global gene expression analyses) of xenografted primary 
ALL samples before and after HDAC inhibitor treatment to identify additional 
biomarkers of HDAC inhibitor response. 
 
2.6.4 Histone Acetylation  
 
Pharmacodynamic (PD) studies are incorporated in clinical trials of molecularly targeted 
agents to determine the relationship between drug exposure and target inhibition in 
cancer cells. Hyperacetylation of histone H3and H4 has been associated with regulated 
gene expression and has been used for PD analysis in HDAC inhibitor clinical trials44-46. 
Changes in histone H3 and H4 acetylation in malignant and normal progenitor cells will 
be assessed pre- and post-treatment in bone marrow and/or blood samples by multi-
parameter flow cytometry using cell lineage- and leukemic blast-specific markers. 
 
Optional pharmacodynamic studies will be performed in bone marrow and peripheral 
blood.  Samples will be collected pretreatment and on day 7 (course 1 only) to assess for 
histone H3 acetylation. Using multi-parameter flow cytometry and lineage and leukemic 
cell specific markers, H3 acetylation will be assessed in B cells (anti-CD19), T cells 
(anti-CD3), progenitors (anti-CD34), and leukemic blasts. Flow cytometry will be 
performed in Dr. Paul Mead’s laboratory.  
 
2.6.5 Pharmacokinetics of HDAC Inhibitors 
 
Panobinostat will be administered in combination with dexamethasone, which has the 
potential to induce panobinostat clearance. Panobinostat pharmacokinetic (PK) studies 
will be performed on days 2 (first panobinostat dose) and 6 (third panobinostat dose) to 
characterize the PK profile and determine the effect of dexamethasone on panobinostat 
PK. The potential for drug-drug interactions will be explored by comparison of 
panobinostat PK data in the present study with historical PK data of single-agent 
panobinostat (TACL T2009-012 trial) and PK parameters on days 2 and 6 will be 
compared. Inter- and intra-patient variability in panobinostat systemic exposure will be 
characterized and correlated with pharmacodynamic effects. 
 
2.6.6 Xenograft Models of ALL 
 
Establishing xenografts of primary human ALL samples has proven to be a powerful tool 
to establish bio-repositories of human leukemic cells to examine the genetic and biologic 
basis of treatment failure, to examine clonal heterogeneity and to use as a platform for the 
testing of novel therapeutic agents ex vivo and in vivo. At St Jude, several investigators 
have established xenotransplants of multiple ALL subtypes, including CRLF2-
rearranged, MLL-rearranged, BCR-ABL1-positive, BCR-ABL1-like, hypodiploid, and ETP 
ALL, and have achieved up to 80% engraftment rates with remarkable reproducibility 
between the tempo of engraftment between replicate mice transplanted with the same 
tumor. Moreover, for CRLF2 rearranged and hypodiploid ALL downstream genomic 
assays demonstrated that the genomic alterations in the relapsed tumor recapitulate those 
present in the primary leukemia. 

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The use of xenograft models has also proven valuable in determining the genetic basis of 
the aggressiveness of disease, and the basis of relapse47-49. At St Jude, these studies have 
been performed with cryopreserved viable cells stored by the St Jude Biorepository. Cells 
harvested from patients in this study will be used for engraftment into murine models and 
will contribute to the ongoing efforts at St. Jude to establish a panel of xenografts of high 
risk acute leukemia samples to serve as a resource for a range of studies of the biologic 
basis of relapse in acute leukemia, as well as establishing a platform for the preclinical 
testing of novel therapeutics. Murine models will be used to test the effect of HDAC 
inhibition on dexamethasone sensitivity by ex vivo cytotoxicity assays of established and 
novel agents. 
 
2.6.7 Genomic Studies on Leukemic Cells 
 
Matched diagnosis and relapse leukemic samples from the same patient offer an excellent 
resource to study the mechanisms of relapse and to identify potential new therapeutic 
targets. Studies of DNA alterations, including DNA copy number alterations, loss-of-
heterozygosity and sequence mutations at St Jude have provided insights into the clonal 
evolution from diagnosis to relapse50 and have led to the identification of novel mutations 
including those in the CREBBP gene at relapse19. These studies had a limited number of 
samples from patients with T-cell ALL and thus it was not possible to investigate changes 
specific to this subtype at relapse and correlate to multiple clinical features and response. 
In one limited, low-resolution study of matched samples from patients with late relapsing 
T-cell ALL, TCR gene rearrangements and NOTCH mutations differed  from diagnosis to 
relapse in a third of patients suggesting a second leukemia51. These findings require larger 
numbers for validation.  
 
In this study, we will collect bone marrow samples at the time of relapse and retrieve cells 
from initial diagnosis from the St. Jude Biorepository (if available). MRD samples will 
also be studied where available. Genomic analyses will be performed on diagnosis and 
relapse samples, and where available, intermediated time points, including samples 
corrected at the time of measurement of MRD, samples obtained at remission, and 
samples collected during the course of therapy. Genomic analyses will be performed, 
where possible, on high blast purity samples, or samples flow sorted to at least 90% 
purity. If samples are limiting and/or flow sorting is not feasible, analyses will be 
performed in unsorted material. Assays will include SNP genotyping to asses DNA copy 
number alterations, and next generation sequencing including exome and/or mRNA-
sequencing. Samples may also be studied using whole genome sequencing. DNA and 
RNA will be extracted using standard methods established in the laboratory of Dr 
Mullighan (e.g. phenol-chloroform extraction of DNA, TRIzol extraction of RNA). 
Genomic profiling, data analysis and verification of genomic alterations will be performed 
using the Hartwell Center for Bioinformatics and Biotechnology and established data 
analysis pipelines. 
 
2.6.8  Clonal Evolution 
 
MRD studies using deep sequencing provide an opportunity to follow clonal evolution using 
either IgH or TCR rearrangement as a biomarker of specific clones. Genomic DNA will be 
isolated from matched diagnosis (when available) and relapsed leukemic samples from the 

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same patient and submitted for deep sequencing. The clonal heterogeneity base on deep 
sequencing will be compared to the whole genomic sequencing studies to determine if there 
are concordances between IgH or TCR rearrangement changes with accumulation of new 
genomic mutations that may drive relapse. In selective cases, samples between diagnosis 
and relapse will be also studied to determine the temporal concordance between 
accumulation of the genomic mutations and deep sequencing. A good concordance would 
suggest IgH or TCR deep sequencing could predict the accumulation of new leukemic 
clones, acquisition of additional driver mutations, and relapse. 
 
Recent genomic profiling studies from our group and others identified somatic mutation 
within the NT5C2 gene directly related to drug resistance in relapsed ALL (~15-20% in T 
and B-lineage ALL at relapse52,53. Patients with NT5C2 gain-of-function mutation are 
dramatically resistant to thiopurine therapy, and we expect a substantial proportion of 
patients in this trial would be NT5C2 mutant. Therefore, this protocol offers a unique 
opportunity to examine the dynamics of NT5C2 mutation during therapy (e.g., the change 
of % mutant cells at a function of time), especially as patients progress through various 
blocks of therapy. This can be combined with immunoglobulin or TCR-based clonal 
monitoring.  
 
2.6.9 NK Cell Receptor Study 
 
The normal physiological roles of NK cells are to control infection and prevent cancer. In 
fact, NK cells are the only immune cells that have been shown by prospective cohort 
study in healthy persons to have immunosurveillance capability against human cancer54. 
In a prospective study of more than 3000 healthy volunteers who were followed for 11 
years, the risk of cancer was associated with decreased NK cell cytotoxicity against K562 
leukemia cells, decreased expression of the NK receptor NKRP1, and decreased 
production of cytokines such as TNFα and IFNγ in NK cells. 
 
Three studies of adult leukemia have demonstrated a direct link between leukemia and 
NK cell. In one study of patients with acute myeloid leukemia, the majority (16 of 18) of 
blood samples showed defective expression and function of NK cell–triggering receptors 
(NCRs) (dull)55. The expression of NK cell surface receptors was low, and the cytolytic 
activity against autologous leukemia cells, autologous B lymphoblasts, and NK cell–
sensitive cell lines was weak. The abnormal NCR (dull) phenotype was confirmed in 
another study of 71 patients with acute myeloid leukemia and was found to be present in 
various morphologic and genotypic subtypes of leukemia56. In the third study of 25 AML 
and 14 ALL cases, the expression of HLA class I was frequently downregulated and that 
of the NK cell receptor ligands PVR and Nectin-2 were upregulated57. Together, these 
results suggest that NK receptor–ligand interaction may be crucial for the development of 
leukemia. 
 
The normalization of NK cell receptor expression may be of prognostic value as NK cells 
may be important for the control of leukemia relapse and infection. These roles of NK 
cells have been shown by killer cell inhibitory receptor (KIR)-mismatched allogeneic 
stem cell transplantation58. Longitudinal study of adult AML patients showed that the 
NCR (dull) phenotype acquired during leukemia development was reversible in patients 
achieving complete remission after induction chemotherapy56. Reversibility of the NCR 

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(dull) phenotype after complete remission suggested that leukemia cells might be 
involved in NCR down-regulation. Alternatively, the recovery of normal NCRs may 
allow the recovery of normal NK cell function that contributes to the acquisition of 
remission status. Interestingly, a correlation was found between the NCR (dull) 
phenotype and poor survival in AML patients after chemotherapy56, suggesting that NK-
deficient activation caused by NCR down-regulation could play a role in treatment 
outcome. Therefore, we will study NK cell receptor expression at diagnosis and before 
reinduction to elucidate the role of NK cell in the development and treatment response of 
childhood ALL. 
 
We are currently studying the prognostic significance of NK cell expression at diagnosis 
and following therapy in newly diagnosed ALL patients. This study will allow us to study 
the potential role of NK cells in first T-cell relapse. 
 
2.6.10 Background and Rationale for Intestinal Microbiome Objectives  
 
Increased susceptibility to a number of pathogens in children with hematologic 
malignancies can result in significant morbidity and treatment delays, thus compromising 
outcome59. Acute gastroenteritis is one of the most common diseases affecting children 
worldwide. Viruses are recognized as a major cause of this disease, particularly in 
children. Little is known about the prevalence of enteric viruses in immunocompromised 
children. Several studies from the 1980’s have shown that children with HIV or T-cell 
deficiencies can develop chronic infections with several enteric viruses leading to 
persistent diarrhea, which can cause considerable problems of management. By 
evaluating the population dynamics of these enteric viruses prior to and after 
chemotherapy, we will obtain a greater understanding of the prevalence of these viruses 
in this patient population with the eventual goal of improved diagnostics and predictions 
of clinical complications. 
 
The intestinal microbiome consists of all the intestinal micro-organisms and their 
associated genetic elements. Several lines of evidence suggest that the interactions 
between the host's enteric microbiota and the innate immune system are important in 
modulating the intestinal response to cancer therapy60. Alterations in the host microbiota 
can translate into alterations in the susceptibility of the host to infection61. Clostridium 
difficile is a common cause of antibiotic-associated diarrhea in this patient population. As 
perturbations of the normal gut microflora are thought to predispose patients to infections 
caused by C. difficile, these investigations will also address what alterations in the 
microflora correlate with the predominance of C. difficile in the gastrointestinal tract. The 
gut microbiota plays a crucial role in the development of an effective immune response. 
Alterations in the gut microbiota can have profound consequences not only for intestinal 
diseases but also for mounting an effective immune response against invading pathogens 
at various sites in the human body62. Recent studies have shown that certain bacterial 
species in the gut can be utilized to estimate the risk of antibiotic-associated diarrhea with 
an error rate of 2%, emphasizing the relevant application of these data for improved 
prediction of clinical outcomes63. We will study the impact of intensive salvage therapy 
on the intestinal microbiome, and the relationship between the intestinal microbiome and 
the increased susceptibility of children with relapsed hematologic malignancies to 
infections, including gastroenteritis. 

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In summary, existing literature suggests that the human microbiome plays a variety of 
important roles in immunology and infectious diseases. Alterations in the host microbiota 
can have profound effects on the type and magnitude of the immune response against 
invading pathogens and thus on the infectious complications. We are currently 
conducting an investigation on the effect of frontline chemotherapeutic regimens for 
pediatric ALL on the gut microbiome. The current study allows us to also assess the 
alterations of the microbiome in relapsed hematologic malignancies and the subsequent 
effects on infection-related clinical outcomes. 
 
3.0  
ELIGIBILITY CRITERIA AND STUDY ENROLLMENT  
 
According to institutional and NIH policy, the study will accession research participants 
regardless of gender and ethnic background. Institutional experience confirms broad 
representation in this regard. 
 
3.1 
Inclusion Criteria 
 
3.1.1 Participants must have relapsed or refractory acute lymphoblastic leukemia or 
lymphoma: 
 
a. Stratum I: T-cell lymphoblastic leukemia or lymphoma in first relapse or 
refractory to one or two courses of frontline induction therapy. 
 
b. Stratum II: B-cell or T-cell lymphoblastic leukemia or lymphoma in second or 
third relapse or refractory to 2 or 3 induction or re-induction attempts. Patients 
with Ph+ ALL must be refractory or relapsed after treatment with a regimen 
that included a tyrosine kinase inhibitor (TKI). 
 
Relapse in ALL is defined as the reappearance (in a patient who has previously 
achieved remission) of leukemic blasts in the bone marrow.  
 
o Should flow cytometric analyses suggest relapse (by the reappearance of a 
similar immunophenotype to the original leukemia) in the presence of 
<5% blasts morphologically, a repeat bone marrow test is recommended to 
confirm relapse. 
 
o Molecular or genetic relapse is characterized by the reappearance of a 
cytogenetic or molecular abnormality. 
 
3.1.2 Age is < 21 years (participant has not yet reached 22nd birthday). 
 
3.1.3 Able to swallow capsules. 
 
3.1.4 Karnofsky or Lansky performance score is > 60%. The Lansky performance score 
should be used for participants < 16 years and the Karnofsky performance score 
for participants ≥ 16 years (see Appendix I). 
 
 

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3.1.5 Prior therapy: 
 
a. There is no waiting period for participants who relapse while receiving 
therapy if they are free from side effects attributable to such therapy. 
 
b. Emergent radiation therapy, one dose of intrathecal chemotherapy and up to 7 
days of steroids or hydroxyurea are permitted before start of treatment in 
participants who relapse after completion of frontline therapy. Other 
circumstances must be cleared by PI or medical designee.   
 
c. At least 90 days have elapsed since bone marrow transplant and participant is 
off immune suppression for > 2 weeks, if applicable. 
 
3.1.6 Adequate renal function defined as glomerular filtration rate > 60 cc/min/1.73m2 
or serum creatinine based on age as follows: 
 
Age (years)  
Maximum serum creatinine (mg/dL) 
 
 
 
Male Female 
1 to 2 years 
 
0.6 
0.6 
2 to 6 years 
 
0.8 
0.8 
6 to 10 years  
1 
1 
10 to <13 years 
1.2 
1.2 
13 to 16 years  
1.5 
1.4 
> 16 years 
 
1.7 
1.4 
 
3.1.7  Adequate hepatic function defined as:  
a. Direct bilirubin ≤ 1.4 mg/dL (if total bilirubin > 1.4 mg/dL) and 
b. AST and ALT < 5 x ULN for age. 
 
3.1.8 Adequate cardiac function defined as shortening fraction of > 27% or ejection 
fraction > 45%. 
 
3.1.9 Lymphoma participants without bone marrow involvement must have:  
a. Absolute neutrophil count (ANC) >1,000/mm3, and 
b. Platelet count >50,000/mm3 (without transfusion support) 
 
Note: these criteria are waived for participants with leukemia or lymphoma 
participants with bone marrow involvement. 
 
3.1.10 Written, informed consent and assent following Institutional Review Board, NCI, 
FDA and OHRP guidelines. 
 
3.2 
Exclusion Criteria 
 
3.2.1 Prior HDAC, DAC, HSP90 inhibitors or valproic acid for treatment of cancer. 
 

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3.2.2 Patients who will need valproic acid for any medical condition during the study or 
within 5 days prior to first panobinostat treatment. 
 
3.2.3 Impaired cardiac function or clinically significant cardiac diseases, history of 
arrhythmia (including ventricular fibrillation or torsade de pointes), bradycardia 
<50 bpm, screening ECG with prolonged QTc or uncontrolled hypertension. 
 
3.2.4 Impairment of GI function or GI disease that may significantly alter the 
absorption of panobinostat. 
 
3.2.5 Patients with diarrhea > CTCAE grade 2. 
 
3.2.6 Other concurrent severe and/or uncontrolled medical conditions (e.g., 
uncontrolled diabetes or active or uncontrolled infection) including abnormal 
laboratory values, that could cause unacceptable safety risks or compromise 
compliance with the protocol. 
 
3.2.7 Patients using medications that have a relative risk of prolonging the QT interval 
or inducing torsade de pointes if treatment cannot be discontinued or switched to 
a different medication prior to starting treatment. 
 
3.2.8 Patients who have received targeted agents within 2 weeks or within 5 half-lives 
of the agent and active metabolites (whichever is longer) and who have not 
recovered from side effects of those therapies. 
 
3.2.9 Patients who have undergone major surgery ≤ 4 weeks prior to starting treatment 
or who have not recovered from side effects of such therapy. 
 
3.2.10 Patients with known positivity for human immunodeficiency virus (HIV) or 
hepatitis B/C. 
 
3.2.11 Inability to swallow capsules. 
 
3.2.12 Active, uncontrolled infection or severe concurrent medical disease, including but 
not limited to congestive heart failure, cardiac arrhythmias, or psychiatric illness. 
 
3.2.13 Isolated extramedullary relapse (leukemia) or isolated CNS lymphoma. 
 
3.2.14 Pregnant or lactating (female participant of childbearing potential  must have 
negative serum or urine pregnancy test required within 7 days prior to start of 
treatment). Male or female of reproductive potential has agreed to use effective 
contraception method for duration of study treatment. 
 
3.2.15 Down syndrome. 
 
3.2.16 Inability or unwillingness or research participant or legal guardian/representative 
to give written informed consent. 
 

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3.3 
Recruitment and Screening 
 
Participants will be recruited by study investigators through their clinical practice. 
 
3.4 
Enrollment at St. Jude 
 
A member of the study team will confirm potential participant eligibility as defined in 
Section 3.1-3.2, complete and sign the ‘Participant Eligibility Checklist’. The study team 
will enter the eligibility checklist information into the Patient Protocol Manager (PPM) 
system. Eligibility will be reviewed, and a research participant-specific consent form and 
assent document (where applicable) will be generated. The complete signed consent / 
assent form(s) must be faxed or emailed to the CPDMO 
 to complete the 
enrollment process. 
 
The CPDMO is staffed 7:30 am-5:00 pm CST, Monday through Friday. A staff member 
is on call Saturday, Sunday, and holidays from 8:00 am to 5:00 pm. Enrollments may be 
requested during weekends or holidays by calling the CPDMO “On Call” cell phone 
 or referencing the “On Call Schedule” on the intranet. 
 
3.5 
Enrollment at Collaborating Sites 
 
Collaborating Site research participants should be registered at St. Jude within 24 hours 
of enrollment at the site. The completed Eligibility Checklist and entire signed Informed 
Consent should be faxed 
. Please call 
 if confirmation of 
the enrollment information is needed. The Protocol Eligibility Coordinator will then 
register the research participant in the Patient Protocol Manager (PPM) system. 
 
4.0 
TREATMENT PLAN 
 
This is a study of re-induction therapy that will comprise of three blocks of multi-agent 
chemotherapy. CR will be evaluated following each block of therapy. All patients will be 
candidates for HSCT once they achieve negative MRD. If patients cannot proceed to 
HSCT following Block A, they will continue therapy on Block B and Block C until ready 
for HSCT.  
 
No dose modifications will be made for hematologic toxicity once a therapeutic block has 
been initiated with the exception of Block B where mercaptopurine dose can be adjusted 
and high-dose cytarabine can be delayed for WBC < 1000/mm3, ANC < 300/mm3 and 
platelet count < 50,000/mm3). Dose calculations should be based on actual BSA. 
 

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4.1 
Intrathecal Chemotherapy  
 
age (months) 
methotrexate (mg) 
hydrocortisone (mg) 
cytarabine (mg) 
volume (ml) 
< 12 
6 
12 
18 
6 
12-23 
8 
16 
24 
8 
24-35 
10 
20 
30 
10 
> 36 
12 
24 
36 
12 
 
Leucovorin rescue (5 mg/m2/dose, max 5 mg) PO will be given at 24 and 30 hours after 
each triple intrathecal treatment.  Follow plasma methotrexate levels (starting 24 hours 
after intrathecal therapy and until level becomes undetectable) in patients with renal 
dysfunction or extra fluid in third space, and rescue with leucovorin according to PharmD 
recommendation. 
 
4.2 
Block A: Approximately 5 Weeks 
 
Day 1 
DEX  
ITMHA 
Day 2 
DEX 
PANO 
Day 3 
DEX 
Day 4 
DEX 
PANO 
Day 5 
DEX 
Day 6 
DEX 
PANO 
Day 7 
DEX 
VSLI 
MITOX 
ITMHA 
Day 8 
DEX  
Day 9 
PEG-Asp 
Day 10 
 (ITMHA) 
Day 11 
Day 12 
Day 13 
Day 14 
VSLI 
MITOX 
ITMHA 
Day 15 
DEX 
Day 16 
DEX 
BORTEZ 
Day 17 
DEX 
(ITMHA) 
Day 18 
DEX 
Day 19 
DEX 
BORTEZ 
Day 20 
DEX 
Day 21 
DEX 
VSLI 
ITMHA 
Day 22 
DEX 
Day 23 
PEG-Asp 
BORTEZ 
Day 24 
Day 25 
Day 26 
BORTEZ 
Day 27 
  
Day 28 
VSLI 
ITMHA 
• Dexamethasone (DEX) 10 mg/m2/day PO (may also give IV) divided TID, Days 1-8, 15-22 (total of 
16 days) 
• Panobinostat (PANO) 24 mg/m2/dose PO Day 2, 4, 6 (3 doses). Round dose up to next 5 mg increment  
• Liposomal vincristine (VSLI)  2.25 mg/m2 no cap IV on Days 7, 14, 21, 28 (4 doses) 
• Mitoxantrone (MITOX) 10 mg/m2 IV over 1 hour on Days 7 and 14 (2 doses).  (Day 14 
Mitoxantrone can be held in absence of peripheral blasts if WBC < 1000 and ANC < 300) 
• Peg-asparaginase (PEG-Asp) 2500 units/m2 IV over 1 hour on Days 9 and 23 (2 doses) 
• Bortezomib (BORTEZ) 1.3 mg/m2 IV Days 16, 19, 23, 26 (4 doses) 
• ITMHA Days 1, 7, 14, 21, 28.  Additional ITs on Days 10 and 17 for patients with CNS 2, 3 or 
traumatic tap with blasts  

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4.2.1 Bone marrow aspirate and MRD will be performed on Day 7 (optional, see Section 
8.2) and at completion of Block A after count recovery: 
 
• WBC ≥1500/mm3 and 
• ANC ≥300/mm3 and 
• Platelet count ≥50,000/mm3 
 
In the absence of count recovery, a bone marrow aspiration should be performed to 
evaluate for persistent leukemia within 4-6 week period from initiation of Block 
depending on counts and clinical status. 
 
4.2.2 Panobinostat administration:  patients should be instructed to take their once-a-
day oral dose of panobinostat at the same time each morning. Each dose of panobinostat 
should be taken with an 8 ounce/240 ml glass of water. Patients should be instructed to 
swallow the capsules whole and not chew them. 
 
Patients must avoid grapefruit or grapefruit juice and Seville (sour) oranges during the 
entire study. 
 
4.3  
Block B: Approximately 5 Weeks 
 
Block B will begin after count recovery from Block A (i.e., WBC ≥ 1500/mm3, ANC 
≥300/mm3 and platelet count ≥50,000/mm3)  
 
Day 1 
HDMTX 
ITMHA 
6MP 
Day 2 
6MP 
Day 3 
6MP 
Day 4 
6MP 
Day 5 
6MP 
Day 6 
6MP 
Day 7 
 6MP 
Day 8 
6MP 
Day 9 
6MP 
Day 10 
 6MP 
Day 11 
6MP 
Day 12 
6MP 
Day 13 
6MP 
Day 14 
6MP 
 
 
Day 15 
HDAC 
HDAC 
Day 16 
HDAC 
HDAC 
Day 17 
Day 18 
Day 19 
Day 20 
Day 21 
 
• High-dose methotrexate (HDMTX) 8 g/m2 IV over 24 hours (in patients with 
prior cranial irradiation HDMTX will be substituted with 2 doses of 
methotrexate 40 mg IV on Day 1 and Day 8) 
• 6-mercaptopurine (6MP) 50 mg/m2 PO days 1-14 (14 doses) 
• ITMHA Day 1  
• High-dose cytarabine (HDAC) 3 g/m2 IV over 2 hours Q12H Days 15 and 16 
(4 doses) 
 

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4.3.1 Bone marrow aspirate and MRD will be performed at end of Block B after count 
recovery: 
• WBC ≥ 1500/mm3, ANC ≥ 300/mm3 and  
• Platelet count ≥ 50,000/mm3  
 
In the absence of count recovery, a bone marrow aspiration should be performed to 
evaluate for persistent leukemia within 4-6 week period from initiation of Block B 
depending on counts and clinical status. 
 
4.3.2 Mercaptopurine Administration 
 
Mercaptopurine should be given daily at a consistent time that maximizes adherence with 
the prescribed treatment. Mercaptopurine may be held in the presence of ANC <300/mm3, 
WBC < 1,000/mm3, platelet count < 50,000/mm3 or grade 3 or 4 mucositis.  
 
4.3.3 High-Dose Methotrexate (HDMTX) Administration 
 
The dosage of high dose methotrexate will be adjusted to achieve a targeted steady-state 
plasma concentration at the end of a 24 hour infusion of 90 uM, which is approximately 
the level expected from a dose of 8 g/m2/24 hours, and one with which we have some 
experience.30 Ten percent of the estimated total dose is administered as a loading dose 
over 1 hour and the remainder over 23 hours. 
 
Clearance is estimated from the plasma concentrations up through 48 hours from 
methotrexate infusion using nonlinear curve fitting and a Bayesian estimation strategy.31 
 
4.3.3.1 Pre-hydration 
 
At least two hours before high dose methotrexate, pre-hydration IV fluid (D5W + 40 
mEq NaHCO3/L + 20 mEq KCl/L) will be administered at the rate of 200 ml/m2/hr. At 
start of pre-hydration, one IV dose of NaHCO3 (unless otherwise clinically indicated) 25 
mEq/m2 diluted in 50 ml D5W will be given over 15 minutes. Pre-hydration fluid may 
also be given overnight at a rate of at least 150 ml/m2/hr. High dose methotrexate 
treatment will follow, provided that urinary pH is >6.5; exceptions must be cleared with 
the pharmacokinetics service and the attending physician. 
 
4.3.3.2 High dose methotrexate infusion 
 
Methotrexate loading dose (generally 800 mg/m2) will be given over 1 hour, followed 
immediately by a maintenance infusion over 23 hours. The maintenance infusion will 
begin at 7200 mg/m2/23 hours; plasma methotrexate will be measured at least 2 time 
points within the first 6 hours of the infusion (e.g. at 1 and 3 hours), and the maintenance 
infusion will be adjusted to achieve a Cpss of 90 uM. During the methotrexate infusion, 
patients should receive hydration fluid with D5W + 40 mEq/L NaHCO3 + 20 mEq KCl/L 
at 125-150 ml/m2/hr. Urine pH will be monitored with each void during infusion. An IV 
bolus of 12 mEq/m2 NaHCO3 will be given if urine pH is 6.0; and 25 mEq/m2 will be 
given if urine pH is <6.0. Acetazolamide 500 mg/m2 orally every 6 to 8 hours may be 

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used if systemic alkalosis limits the administration of bicarbonate for urinary 
alkalinization. Patients with evidence of renal dysfunction or delayed clearance during 
the methotrexate infusion may receive less than a 24 hour methotrexate infusion. 
 
Blood samples for methotrexate pharmacokinetics will be drawn; 2-3 ml of blood will be 
obtained in EDTA tubes (purple top) pre-dose, at the end of the loading dose (1 hour), 
and at 3 hours from start of loading dose (timing of samples is not critical, but at least 
samples should be available between 0.5 and 6 hour). Samples will also be drawn at 23 
hours and 42 hours from the start of the infusion. Additional samples will be obtained in 
patients in whom there is clinical suspicion of poor clearance, or in those who have high 
plasma MTX concentration (e.g., >0.5 uM at 42 hours), to adjust leucovorin rescue.  
 
4.3.3.3 Leucovorin rescue  
 
Leucovorin, 15 mg/m2 (IV or PO) will be started at 42 hours after the start of 
methotrexate and repeated every 6 hours for a total of three doses. The dosage of 
leucovorin will be increased in patients with high plasma methotrexate concentrations 
(>1.0 uM at 42 hours) and continued until the methotrexate concentration is less than 
0.10 uM.  Additional measures, such as hydration, hemoperfusion, or carboxypeptidase 
will be considered in patients with 42-hour methotrexate levels > 10 uM. Patients with a 
history of gastrointestinal toxicity or a history of typhlitis with any chemotherapy should 
have leucovorin continue for 5, rather than 3 doses.    
 
4.3.4 Intrathecal Chemotherapy  
 
All patients will receive triple intrathecal therapy on the same day of the high dose 
methotrexate administration. Consult the PI or Pharmacokinetics if the IT and high dose 
methotrexate become separated by more than 12 hours. 
 
4.3.5 Conjunctivitis Prophylaxis 
 
Dexamethasone ophthalmic solution (0.1%), 2 drops to both eyes four times per day, or 
artificial tears (e.g., hydroxymethylcellulose, hypromellose, polyvinyl alcohol), 2 drops 
to both eyes every 2-6 hours, may be used during HDAC administration and for 24 hours 
after completion to prevent conjunctival irritation. 
 

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4.4  
Block C: Approximately 3 Weeks 
 
Block C will begin after count recovery from Block B (i.e., WBC ≥ 1500/mm3, ANC 
≥300/mm3 and platelet count ≥ 50,000/mm3)  
 
Day 1 
 
NELAR 
(Clofar)* 
CYCLO 
ETOP 
Day 2 
NELAR 
(Clofar)* 
CYCLO 
ETOP 
Day 3 
NELAR 
(Clofar)* 
CYCLO 
ETOP 
Day 4 
NELAR 
(Clofar)* 
CYCLO 
ETOP 
Day 5 
NELAR 
(Clofar)* 
CYCLO 
ETOP 
 
• Nelarabine (NELAR) 650 mg/m2/day IV Days 1-5  
*[or clofarabine (CLOFAR) 40 mg/m2/day IV Days 1-5 will be given instead of 
nelarabine for patients with B-lymphoblastic leukemia and lymphoma in stratum II] 
• Cyclophosphamide (CYCLO) IV 300 mg/m2 Days 1-5 
• Etoposide (ETOP) 100 mg/m2/day IV Days 1-5 
 
4.4.1 Bone marrow aspirate and MRD will be performed after count recovery:  
(WBC ≥ 1500/mm3, ANC ≥ 300/mm3 and platelet count ≥ 50,000/mm3). 
 
In the absence of count recovery, a bone marrow aspiration should be performed to 
evaluate for persistent leukemia within 4-6 week period from initiation of Block C 
depending on counts and clinical status. 
 
4.5  
Timing of Bone Marrow Aspirate and MRD Assessments 
 
• Baseline, prior to initiation of Block A therapy 
• Optional Day 7 Block A (pre VSLI and MITO; see Section 8.2) 
• After count recovery from Block A 
• After count recovery from Block B 
• After count recovery from Block C 
 
4.6  
Recommendations for Post-Protocol Therapy  
 
4.6.1  Hematopoietic Stem Cell Transplantation (HSCT) 
 
All patients should proceed to HSCT after completion of Block C if a suitable donor has 
been found and the patient achieves negative MRD (<0.01%). If MRD is persistently 
positive, the plan will be discussed with the PI or co-PI and the transplant team. The donor 
will be selected according to institutional practices and transplant regimens will be used 
according to institutional HSCT protocols and guidelines.  
 

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4.7 
CNS and Testicular Leukemia 
 
4.7.1  Craniospinal Irradiation 
 
Craniospinal irradiation is recommended for participants with CNS3 disease at relapse 
and whose first CR was less than 18 months; cranial irradiation only will be given for 
those whose CR was more than 18 months. The doses are 18 Gy cranial and 12 Gy 
spinal. Not all participants with CNS2 disease will require irradiation. These cases will be 
discussed individually with the radiation oncologist and PI/co-PI. Participants who will 
receive total body irradiation (TBI) for pre-transplant conditioning can receive a cranial 
irradiation boost (to a cumulative dose approximating 18 Gy in temporal proximity 
(typically prior) to TBI. Participants who will not receive TBI conditioning can receive 
cranial or craniospinal irradiation as above just prior to HSCT conditioning. 
 
4.7.2  Treatment of Testicular Involvement 
 
The plan for testicular irradiation for participants with testicular involvement will be 
discussed with the radiation oncologist and PI or co-PI at the time of diagnosis of relapse 
and at the end of induction therapy. The need for testicular radiation will be determined 
for individual participants based on response to therapy, ultrasound findings and possibly 
testicular biopsy. 
 
5.0 
DRUG/DEVICE/BIOLOGIC AGENT INFORMATION  
 
5.1 
Dexamethasone (Decadron®) 
 
Source and pharmacology: Dexamethasone is a synthetic congener of the natural adrenal 
hormone hydrocortisone. Dexamethasone is a white or yellowish crystalline powder.  It 
binds with steroid receptors on nuclear membranes to impair cellular mitosis and inhibit 
protein synthesis. Dexamethasone also has potent anti-inflammatory effects and 
suppresses the immune system. Dexamethasone is absorbed well orally. It is metabolized 
in the liver, and the metabolites are excreted mainly in the urine.   
 
Formulation and stability: Dexamethasone is available as tablets of various strengths and 
as an elixir. It is also available as a solution for parenteral use. All formulations of the 
drug can be stored at room temperature. The injectable form may be further diluted in 5% 
dextrose or 0.9% NaCl-containing solutions and is stable for at least 24 hours at room 
temperature. 
 
Supplier: The drug is commercially available. 
 
Toxicity: The side effects of dexamethasone vary depending on the duration of its use.  
Side effects that can occur with short-term use include peptic ulcers with possible 
perforation and hemorrhage, increased susceptibility to infections, emotional instability, 
insomnia, increased appetite, weight gain, acne, and hyperglycemia. Side effects more 
commonly associated with prolonged use include cataracts, increased intraocular pressure 
and associated glaucoma, development of a “cushingoid” state, compression fractures, 
menstrual irregularities, suppression of growth in children, secondary adrenocortical and 

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pituitary unresponsiveness particularly in times of stress as in trauma, surgery or illness, 
osteoporosis and muscle wasting. 
 
Dosage and route of administration: 10 mg/m2/day PO divided TID Days 1-8 and 15-22 
(total of 16 days) of Block A see Section 4.2. 
 
5.2 
Panobinostat (LBH589) 
 
Source and pharmacology: The oral formulation of panobinostat is 2-hydroxypropaonic 
acid compound with 2(E)-N-Hydroxy-3-(4-[[2-(2-methyl-1H-indol-3-yl)-ethylamino]-
methyl]-phenyl)-2-propenamide, a histone deacetylase inhibitor being developed for the 
treatment of patients with leukemias and lymphomas. Panobinostat has also been shown to 
block tumor cell growth and to activate the p21 promoter. Tumor cells undergo apoptosis in 
the presence of low nanomolar concentrations of panobinostat for at least 16 hours. 
However, normal healthy cells do not experience cell death when exposed to the same 
concentrations of panobinostat for 72 hours. Furthermore, increased levels of acetylated 
histones were observed in tumor cell cultures from xenograft mice models treated with 
panobinostat, proving that the drug functions as a histone deacetylase inhibitor. 
 
Formulation and stability: The oral formulation of panobinostat is an immediate-release 
solid hard gelatin capsule. Panobinostat lactate salt is the active ingredient in the capsule, 
provided in dosage strengths of 5 mg and 20 mg. The inactive ingredients of the capsule 
consist of mannitol, microcrystalline cellulose, starch, and magnesium stearate. The 
capsule formulation is created by an aqueous granulation and blending process. 
 
Supplier: Supplied by Novartis Pharmaceuticals. 
 
Toxicity: The most common adverse event from oral panobinostat is reversible 
thrombocytopenia; the degree of thrombocytopenia is dose-dependent. Other side effects 
include fatigue (dose-dependent), nausea, vomiting, and diarrhea, which can be 
controlled with loperamide. For orally administered panobinostat, no grade 4 QTc has 
been reported with “interrupted” dosing schedules. For oral dose of 20 mg or 60 mg 
given three times weekly, the incidence of grade 3 QTc prolongation ranges from <1% to 
6%. The largest QTc change is seen approximately five days after the drug is given and 
does not correlate with drug serum levels. See Investigator’s Brochure for further details. 
 
Dosage and route of administration: The oral panobinostat capsules will be provided in 
HDPE bottles with an induction seal and plastic (CR) closure.  24 mg/m2/dose PO Days 
2, 4, and 6 of Block A, see Section 4.2. 
 
5.3 
vinCRIStine sulfate LIPOSOME injection (VSLI, Marqibo®) 
 
Source and pharmacology: Marqibo is vincristine encapsulated in 
sphingomyelin/cholesterol liposomes for intravenous injection. The active ingredient in 
Marqibo is vincristine sulfate. Vincristine sulfate is a vinca alkaloid isolated as a 1:1 sulfate 
salt from the periwinkle plan (Catharanthus roseus). 
 

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Formulation and stability: Marqibo is prepared on site from the components in the 
Marqibo Kit (see package insert for preparation instructions for pharmacy). Following the 
preparation procedure, each single-dose vial of Marqibo (vinCRIStine sulfate 
LIPOSOME injection) contains 5 mg/31 mL (0.16 mg/mL) vincristine sulfate. 
 
Supplier: Supplied by Spectrum Pharmaceuticals. 
 
Toxicity: The most commonly reported adverse reactions (incidence ≥ 30%) in clinical 
studies include constipation, nausea, pyrexia, fatigue, peripheral neuropathy, febrile 
neutropenia, diarrhea, anemia, decreased appetite, and insomnia.  
 
Warnings:   
• Intrathecal administration is fatal  
• Extravasation causes tissue injury  
• Neurologic toxicity: Monitor patients for peripheral motor and sensory, central 
and autonomic neuropathy, and reduce, interrupt, or discontinue dosing. Patients 
with preexisting severe neuropathy should be treated with Marqibo only after 
careful risk-benefit assessment  
• Myelosuppression: Monitor blood counts prior to each dose of Marqibo. 
Neutropenia, thrombocytopenia, or anemia may occur; consider Marqibo dose 
reduction or interruption and supportive care measures  
• Tumor lysis syndrome: Anticipate, monitor for, and manage  
• Constipation, bowel obstruction, and/or paralytic ileus: Institute a prophylactic 
bowel regimen to prevent potential constipation, bowel obstruction, and/or 
paralytic ileus  
• Fatigue:  Severe fatigue can occur  
• Hepatic toxicity: Monitor liver function and modify or interrupt dosing (Section 6.3)  
• Embryo-fetal toxicity: Can cause fetal harm. Advise women of potential harm to 
the fetus. 
 
See package insert for additional information. 
 
Dosage and route of administration: FOR INTRAVENOUS USE ONLY. 2.25 mg/m2 (no 
cap) IV on Days 7, 14, 21, and 28 of Block A, see Section 4.2. 
 
5.4 
Mitoxantrone (Novantrone) 
 
Source and pharmacology:  Mitoxantrone is an anthracenedione that is structurally 
similar to the anthracyclines.  It is thought to act by intercalating into DNA, causing 
template disorder, steric obstruction and inhibition of DNA and RNA synthesis. In 
addition, mitoxantrone inhibits the action of topoisomerase II.  Mitoxantrone is active 
throughout the cell cycle.  Mitoxantrone is about 78% protein bound and does cross the 
blood brain barrier.  Mitoxantrone is metabolized in the liver to inactive metabolites.  The 
parent drug and metabolites are excreted primarily via hepatobiliary excretion with small 
amounts excreted in the urine.  Dosage adjustment is recommended for patients with 
severe hepatic dysfunction (total bilirubin > 3.4 mg/dl).   
 

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Formulation and stability: Mitoxantrone is available in multi-dose vials containing 20 
mg, 25 mg or 30 mg of mitoxantrone as a dark blue, aqueous solution at a concentration 
of 2 mg/ml. The intact vials should be stored at room temperature. Refrigeration may 
result in precipitation of mitoxantrone which will re-dissolve upon warming to room 
temperature. The drug should be further diluted to at least 50 ml in 5% dextrose or 0.9% 
NaCl prior to administration. These solutions are chemically stable for at least 7 days 
when stored at room temperature. 
 
Supplier: commercially available. 
 
Toxicity: The major dose-limiting toxicity of mitoxantrone is leukopenia with 
thrombocytopenia and anemia occurring much less frequently. Nausea and vomiting are 
usually moderate in severity. Other side effects reported commonly include alopecia, 
diarrhea, headache, fever and stomatitis. Blue to green discoloration of urine and other 
body fluids occur. Other side effects reported less commonly include elevated liver 
function tests, allergic reactions, seizures, jaundice and renal failure. Congestive heart 
failure has been reported, but is much less common than with doxorubicin. CHF has been 
reported primarily in patients receiving prior therapy with anthracyclines. Patients with 
an increased risk of cardiotoxicity include those having received prior therapy with 
anthracyclines, those with previous mediastinal radiotherapy and those with pre-existing 
cardiac conditions. 
 
Guidelines for administration: 10 mg/m2/day IV on days 7 and 14 of Block A, see 
Section 4.2. 
 
5.5 
Peg-L-Asparaginase (Pegaspargase, Oncaspar) 
 
Source and pharmacology: PEG-asparaginase is a modified version of the enzyme, L-
asparaginase. L-asparaginase is modified by covalently conjugating units of polyethylene 
glycol (PEG) to the enzyme. The asparaginase used in the manufacturing of PEG-
asparaginase is derived from Escherichia coli. Asparaginase hydrolyzes serum asparagine 
(an amino acid required to synthesize proteins and DNA) to aspartic acid and ammonia, 
and is therefore lethal to cells that cannot synthesize asparagine. Asparaginase is active 
during all phases of the cell cycle. Asparaginase is not absorbed from the GI tract and 
must be given parenterally. PEG-asparaginase has a plasma half-life of approximately 6 
days, but is measurable for at least 15 days following the initial treatment. It cannot be 
detected in the urine. 
 
Formulation and stability: PEG-asparaginase is available in single-use vials containing 5 
ml of PEG-asparaginase as a clear solution. Each vial contains 3750 units of drug at a 
concentration of 750 units/ml. The intact vials should be stored under refrigeration.  
Freezing destroys its activity, which cannot be detected visually. It should not be used if 
it is cloudy or a precipitate is present.   
 
Supplier:  commercially available. 
 

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Toxicity: Acute toxicity includes anaphylactic reactions which occur most commonly 
when the drug is given IV. These can be characterized by laryngeal constriction, 
hypotension, diaphoresis, fever, chills, edema and loss of consciousness. Allergic 
reactions at the site of IM injection include pain, swelling and erythema. The incidence of 
hypersensitivity reactions to PEG-asparaginase may be less than with conventional E. 
coli derived asparaginase although cross-sensitivity can occur. Other adverse effects 
include neutropenia and associated immunosuppression, mild nausea and vomiting, 
malaise, anorexia, elevated LFT’s, pancreatitis and hyperglycemia. A decrease in protein 
synthesis including albumin, fibrinogen and other coagulation factors may occur that can 
result in thrombosis or pulmonary embolism. Less common side effects include renal 
dysfunction and CNS complications, including somnolence, weakness, lethargy, coma 
and seizures.  
 
Guidelines for administration: 2500 U/m2 IV or IM on Days 9 and 23 of Block A, see 
Section 4.2. 
 
5.6 
Erwinia L-Asparaginase (Erwinase) 
 
To be used in case of allergy or intolerance to PEG-Asparaginase. 
 
Source and pharmacology: Erwinia asparaginase is an enzyme. It is derived from Erwinia 
chrysanthemi and may be useful in patients with an allergy to the E. coli derived product.  
Asparaginase hydrolyzes serum asparagine (an amino acid required to synthesize 
proteins) to aspartic acid and ammonia, and is therefore lethal to cells that cannot 
synthesize asparagine. Asparaginase is active during all phases of the cell cycle. 
Asparaginase is not absorbed from the GI tract and must be given parenterally. 
Asparaginase does not cross into the CSF. The plasma half-life of Erwinia asparaginase 
when given IM is approximately 16 hours. Only minimal urinary and biliary excretion 
occurs. Clearance is unaffected by age, renal function or hepatic function. 
 
Formulation and stability: Erwinia asparaginase is available in vials containing 10,000 
units of lyophilized drug.  Unused vials should be refrigerated. The contents of each vial 
should be diluted with 1 ml of preservative-free normal saline, giving a resultant solution 
of 10,000 units/ml. Once in solution, it is recommended that it be used within 8 hours as 
no preservative is added. Occasionally a small number of gelatinous-like fibers may 
develop upon standing. If this occurs, the solution can be filtered through a 5 micron 
filter to remove the particles with no change in potency. 
 
Supplier: Commercially available. 
 
Toxicity: Acute toxicity includes anaphylactic reactions that occur most commonly when 
the drug is given IV. These can be characterized by laryngeal constriction, hypotension, 
diaphoresis, fever, chills, edema and loss of consciousness. Allergic reactions at the site 
of IM injection include pain, swelling and erythema. Other adverse effects include 
neutropenia and associated immunosuppression, mild nausea and vomiting, malaise, 
anorexia, elevated LFTs, pancreatitis and hyperglycemia. A decrease in protein synthesis 
including albumin, fibrinogen and other coagulation factors may occur, which can result 

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in hemorrhage. Thrombosis and/or pulmonary embolism can also occur. Less common 
side effects include renal dysfunction and CNS complications including somnolence, 
weakness, lethargy, coma and seizures. 
 
Guidelines for administration: Intravenous or intramuscular injection. For additional 
information about this drug, please see package insert. 
 
5.7 
Bortezomib (Velcade, PS-341, MLN341, LDP-341) 
 
Source and pharmacology: Bortezomib (PS-341) is a reversible inhibitor of the 
chymotrypsin-like activity of the 26S proteasome (a multi-catalytic protease present in all 
eukaryotic cells). The 26S proteasome is a large protein complex that degrades proteins 
that have been conjugated to ubiquitin. The ubiquitin-proteasome pathway plays an 
essential role in regulating the intracellular concentration of specific proteins, and 
constitutes the major mechanism for intracellular protein degradation (80%). Those 
intracellular proteins that maintain homeostasis within cells include numerous regulatory 
proteins involved in cellular integrity, such as cell cycle control, cellular apoptosis, 
transcription factor activation, and tumor growth via ATP-dependent processes. 
Inhibition of the 26S proteasome prevents this targeted proteolysis, which can affect 
multiple signaling cascades within the cell. This disruption of normal homeostatic 
mechanisms can lead to cell death. The binding of bortezomib to human plasma proteins 
averages 83% over a concentration range of 100 to 1000 ng/mL. The mean elimination 
half-life of bortezomib after multiple dosing ranged from 40 to 193 hours after the 1 
mg/m2 dose and 76 to 108 hours after the 1.3 mg/m2 dose. In vitro studies with human 
liver microsomes and human cDNA-expressed cytochrome P450 isozymes indicate that 
bortezomib is primarily oxidatively metabolized via cytochrome P450 enzymes 3A4, 
2C19, and 1A2. Bortezomib metabolism by CYP 2D6 and 2C9 enzymes is minor. The 
major metabolic pathway is deboronation to form 2 deboronated metabolites that 
subsequently undergo hydroxylation to several metabolites. Deboronated bortezomib 
metabolites are inactive as 26S proteasome inhibitors. 
 
In vitro and in vivo studies showed that green tea compounds, ascorbic acid (vitamin C) 
and other antioxidants, have the potential to significantly inhibit the activity of 
bortezomib. Green tea constituents, in particular epigallocatechin gallate (EGCG) and 
other polyphenols with 1,2-benzenediol moieties, effectively prevented tumor cell death 
induced by bortezomib both in vitro and in vivo. In multiple myeloma cell lines or mouse 
xenografts, EGCG directly reacted with bortezomib and blocked its proteasome 
inhibitory function. As a result, bortezomib could not trigger endoplasmic reticulum 
stress or caspase-7 activation and could not induce tumor cell death. A more recent study 
investigated whether clinically relevant levels of EGCG or ascorbic acid could inhibit the 
antitumor activity of bortezomib in murine xenograft tumors. The addition of EGCG to 
bortezomib demonstrated no effect on tumor growth inhibition at lower concentrations of 
EGCG that the investigators compare to human dietary intake. Similar results were found 
for ascorbic acid at normal daily doses.  When bortezomib was given concurrently with 
much higher concentrations of EGCG, the investigators found that all antitumor activity 
was eliminated. The authors concluded that there is no interaction between EGCG and 
ascorbic acid when plasma concentrations are commensurate with dietary oral intake. 

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Vitamin C, at concentrations achieved during vitamin supplementation, has also been 
shown to inhibit the activity of bortezomib both in vitro and in vivo. Direct binding 
between the hydroxyl group of vitamin C and the boronic acid of bortezomib reduced the 
affinity of the proteasome inhibitor for the chymotrypsin like subunit of the proteasome. 
In addition, it was noted that besides vitamin C, other natural agents carrying a hydroxyl 
group, such as flavonoid compounds (quercetin among others), bind and inhibit the 
activity of bortezomib in vitro. To avoid the risk of any possible interaction it is 
recommended that green tea containing products and any supplemental products 
containing vitamin C, flavonoids or other antioxidants (e.g., vitamins, herbal 
supplements) be discontinued from at least 24 hours prior to the initiation of bortezomib 
through 72 hours after the last bortezomib dose. In addition, it is recommended that the 
total dietary intake of vitamin C not exceed the RDA for age (i.e., normally balanced 
diets are acceptable). 
 
Formulation and stability: Bortezomib is supplied as a lyophilized powder in sterile vials 
containing 3.5 mg and 35 mg mannitol, USP. Unopened vials may be stored at controlled 
room temperature 25ºC (77ºF); excursions permitted from 15ºC to 30ºC (59ºF to 86ºF).  
Retain in original package to protect from light. Reconstitute bortezomib with 3.5 mL 
normal saline, USP. Each milliliter of solution will contain 1 mg of bortezomib at a pH of 
approximately 5 to 6. The drug solution is clear and colorless. Bortezomib contains no 
antimicrobial preservative. When reconstituted as directed, bortezomib may be stored at 
25°C (77°F). Reconstituted bortezomib should be administered within 8 hours of 
preparation. The reconstituted material may be stored in the original vial and/or the 
syringe prior to administration. The product may be stored for up to 8 hours in a syringe; 
however, total storage time for the reconstituted material must not exceed 8 hours when 
exposed to normal indoor lighting. 
 
Supplier: Commercially available. 
 
Toxicity: The most commonly reported adverse reactions (incidence ≥ 20%) in clinical 
studies include nausea, diarrhea, thrombocytopenia, neutropenia, peripheral neuropathy, 
fatigue, neuralgia, anemia, leukopenia, constipation, vomiting, lymphopenia, rash, 
pyrexia, and anorexia. 
 
Warnings: 
• Peripheral neuropathy: Manage with dose modification or discontinuation. 
Patients with pre-existing severe neuropathy should be treated with VELCADE 
only after careful risk-benefit assessment. 
• Hypotension: Use caution when treating patients taking anti-hypertensives, with a 
history of syncope, or with dehydration. 
• Cardiac toxicity: Worsening of and development of cardiac failure has occurred. 
Closely monitor patients with existing heart disease or risk factors for heart disease. 
• Pulmonary toxicity: Acute respiratory syndromes have occurred.  Monitor closely 
for new or worsening symptoms. 
• Posterior reversible encephalopathy syndrome: Consider MRI imaging for onset 
of visual or neurological symptoms; discontinue VELCADE if suspected. 

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• Gastrointestinal toxicity: Nausea, diarrhea, constipation, and vomiting may 
require use of antiemetic and antidiarrheal medications or fluid replacement. 
• Thrombocytopenia or neutropenia: Monitor complete blood counts regularly 
throughout treatment. 
• Tumor lysis syndrome: Closely monitor patients with high tumor burden. 
• Hepatic toxicity: Monitor hepatic enzymes during treatment. 
• Embryo-fetal risk: Women should avoid becoming pregnant while being treated 
with VELCADE. Advise pregnant women of potential embryo-fetal harm. 
 
See package insert for further details. 
 
Dosage and route of administration: Bortezomib is to be given without further dilution as 
an IV push over 3 to 5 seconds. Consecutive doses must be separated by at least 72 hours. 
Grapefruit and its juice should be avoided for the duration of treatment with bortezomib. 
Special precautions: FOR INTRAVENOUS USE ONLY. The syringe containing 
bortezomib should be clearly labeled for intravenous use only. Three fatalities have been 
reported following accidental intrathecal administration of bortezomib. Special 
precautions should be employed to ensure that intravenous bortezomib and intrathecal 
medications are not inadvertently interchanged. 
 
Dose 1.3 mg/m2 IV Days 16, 19, 23 and 26 of Block A, see Section 4.2. 
 
5.8 
Methotrexate (IV) 
 
Source and pharmacology: Methotrexate is a folate analogue that acts by inhibiting 
dihydrofolate reductase. Dihydrofolate reductase is an enzyme important in the 
conversion of folic acid to tetrahydrofolic acid, which is necessary in the synthesis of 
purine nucleotides and thymidylate. By inhibiting the production of tetrahydrofolic acid, 
methotrexate interferes with DNA, RNA and protein synthesis. Methotrexate is poorly 
and variably absorbed orally, with an average of ≈ 40% for doses of < 30 mg/m2. At 
higher dosages, the extent of absorption decreases. Methotrexate is approximately 50% 
protein bound. It distributes widely into body tissues and fluids with sustained 
concentrations in the kidney and the liver. Methotrexate undergoes metabolism by 
cytosolic aldehyde oxidase to hydroxy methotrexate. It is excreted mainly in the urine as 
unchanged drug with small amounts being excreted in the bile and feces. The percent 
recovered as unchanged drug in the urine is higher with short infusions than with 
prolonged infusions. Methotrexate has biphasic elimination with an initial half-life of ≈ 
2-3 hours and a terminal half-life of 10-12 hours. Methotrexate may be “sequestered” in 
body fluid collections and eliminated slowly from these areas. Patients with effusions or 
GI obstruction should have plasma levels monitored closely for delayed excretion 
following high-dose methotrexate. 
 
Formulation and stability: Methotrexate is supplied in single-dose vials containing 50mg, 
100mg, 200mg, and 250 mg of methotrexate as a 25 mg/ml preservative-free solution and 
in vials containing 20mg, 50 mg, 100mg, 250 mg and 1000mg of lyophilized drug. It is 
also available in 2.5 mg tablets. Methotrexate preservative-free solution and lyophilized 
drug should be stored at room temperature and protected from light. Methotrexate tablets 

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can also be stored at room temperature. The vials containing 20, 50, 100 and 250 mg of 
lyophilized product can be reconstituted by adding sterile water, 0.9% NaCl or D5W to a 
final concentration not exceeding 25 mg/ml. The 1000mg vials containing lyophilized 
product are reconstituted to a final concentration of 50mg/ml. 
 
Supplier:  commercially available 
 
Toxicity:  The dose limiting toxicities of methotrexate are generally bone marrow 
suppression, ulcerative stomatitis, severe diarrhea or acute nephrotoxicity. Toxicities 
reported frequently include nausea and vomiting, diarrhea, anorexia, alopecia, hepatic 
toxicity and alopecia. Less common side effects include blurred vision, photosensitivity, 
anaphylaxis, headache, pneumonitis, skin depigmentation or hyperpigmentation, rash, 
vasculitis and encephalopathy. During high-dose methotrexate therapy, most patients 
experience a transient decrease in GFR, but renal failure can occur, particularly if the 
patient does not receive urinary alkalinization and aggressive hydration before, during 
and after receiving high dose methotrexate. Leucovorin rescue should be initiated within 
48 hours of starting high-dose methotrexate and adjusted based on MTX levels to prevent 
bone marrow toxicity and mucositis. Leucovorin may also be necessary after IT 
administration, especially if IT methotrexate therapy is given to patients with renal 
dysfunction. Patients with Down syndrome have a tendency to have delayed methotrexate 
clearance and a greater risk of toxicity, despite increased leucovorin rescue. 
 
Guidelines for administration: Intrathecal and intravenous. High dose methotrexate 8 
g/m2 IV over 24 hours Day 1 of Block B; see Section 4.2.  Also given IT with ITMHA 
during Blocks A and B, see Sections 4.1 and 4.2. 
 
5.9 
Mercaptopurine (6-MP) (Purinethol) 
 
Source and pharmacology: Mercaptopurine is a purine antimetabolite. It must be 
converted intracellularly to 6-thioguanine nucleotides (6-TGNs), the active forms of the 
drug. The 6-TGNs are then incorporated into DNA and RNA and cause inhibition of 
DNA and RNA synthesis. Mercaptopurine is cell cycle, S phase specific. Absorption is 
variable and incomplete (5-37%) and is decreased by the presence of food in the gut.  
Mercaptopurine does distribute into the CSF, with CSF concentrations of ≈ 27% of 
plasma concentrations when given by continuous infusion. Mercaptopurine undergoes 
first pass metabolism in the GI mucosa and the liver. It is metabolized in hematopoietic 
tissues by HPRT to the active nucleotide forms. It is inactivated to methylated 
metabolites by TPMT (thiopurine methyl transferase) and to 6-thiouric acid by xanthine 
oxidase. TPMT is a genetically regulated, polymorphically distributed enzyme and is 
deficient in about 1 in 300 persons who cannot tolerate usual doses of 6-MP. 
Mercaptopurine is eliminated through the urine as both unchanged drug and metabolites. 
 
Formulation and stability: Mercaptopurine is commercially available as a 50 mg tablet 
and as a 20 mg/mL oral suspension; store at room temperature and protect from light. 
 
Supplier: Commercially available.   
 

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Toxicity: The dose-limiting toxicity of mercaptopurine is myelosuppression. 
Mercaptopurine can cause intrahepatic cholestasis and focal centralobular necrosis and is 
usually manifested by hyperbilirubinemia and increased liver function tests. Other 
toxicities include mild nausea and vomiting, skin rash, hyperuricemia, and mild diarrhea. 
 
Guidelines for administration: oral tablets at consistent time each day to maximize 
adherence, 50 mg/m2/day PO days 1-14 of Block B, see Section 4.3. 
 
5.10 
Cytarabine (Ara-C) (Cytosar-U) 
 
Source and pharmacology: Cytarabine is a deoxycytidine analogue. It must be tri-
phosphorylated to its active form, ARA-CTP, by deoxycytidine kinase and other nucleotide 
kinases. Ara-CTP inhibits DNA polymerase. In addition, ara-CTP is incorporated into 
DNA as a false base, causing inhibition of DNA synthesis. It is cell cycle, S phase specific.  
Cytarabine does penetrate the blood brain barrier. It is converted to its inactive form, uracil 
arabinoside, by pyrimidine nucleoside deaminase. Approximately 80% of the dose is 
recovered in the urine, mostly as uracil arabinoside (ara-U). 
 
Formulation and stability: Cytarabine is available in multi-dose vials containing 100, 500, 
1000 and 2000mg of lyophilized drug. Intact vials can be stored at room temperature.  
For IV use, either sterile water for injection or bacteriostatic water for injection can be 
used to reconstitute the lyophilized drug. For intrathecal use, only sterile water for 
injection should be used for reconstitution. The 100 and 500 mg vials are reconstituted 
with 2 and 10 ml respectively resulting in a final concentration of 50mg/ml. The 1000 
and 2000mg vials are reconstituted with 20ml and 40 ml respectively resulting in a final 
concentration of 50mg/ml. After reconstitution, the drug is stable for 8 days at room 
temperature. 
 
Supplier: Commercially available. 
 
Toxicity: Myelosuppression is the dose limiting adverse effect, with leukopenia and 
thrombocytopenia being predominant. Other adverse effects reported commonly include 
nausea and vomiting (may be severe at high doses), diarrhea, mucositis, anorexia, 
alopecia, skin rash and liver dysfunction. A flu-like syndrome characterized by fever, 
muscle and bone aches is common. Less common side effects include allergic reactions 
and cellulitis at the injection site. High doses of cytarabine can cause conjunctivitis, 
hepatitis, and a group of CNS symptoms including somnolence, peripheral neuropathy, 
ataxia, and personality changes. CNS symptoms are usually reversible and are more 
common in patients who have received previous cranial irradiation. In addition, a 
syndrome of sudden respiratory distress progressing to pulmonary edema has occurred. 
 
Guidelines for administration: Intrathecal and intravenous. High dose Ara-C 3g/m2 every 
12 hours Days 15 and 16 of Block B, see Section 4.2. Also given IT with ITMHA during 
Blocks A and B. 

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5.11 
Nelarabine (Arranon®, Compound 506U78) 
 
Source and pharmacology: Nelarabine (compound 506U78) is a water soluble pro-drug 
of 9-β-Darabinofuranosylguanine (ara-G), a deoxyguanosine analog being developed for 
the treatment of patients with T-cell and B-cell leukemias and lymphomas. Nelarabine is 
rapidly converted by adenosine deaminase in the peripheral blood to ara-G. In vitro 
studies and biochemical studies have demonstrated that intracellular ara-G is 
phosphorylated via deoxycytosine kinase (dCK) and deoxyguanosine kinase (dGK) to its 
active 5’-triphosphate (ara-GTP). Ara-GTP incorporation into DNA is a primary cause of 
cell death. 
 
The pharmacokinetics of nelarabine in humans is characterized by a rapid and extensive 
conversion to ara-G. The average elimination half-lives for nelarabine and ara-G were 
approximately 20-25 minutes and 2.6-4.0 hours, respectively. Virtually all nelarabine was 
converted to ara-G. Peak plasma concentration and area under the curve for both 
nelarabine and ara-G was essentially proportional to the administered dose. The steady-
state volume of distribution of ara-G was similar in adult and pediatric patients. Neither 
compound showed accumulation with the dosing studies used in the pre-clinical trials 
with this agent. The pharmacokinetics of both nelarabine and ara-G appeared to be 
independent of diagnosis and gender. Intracellular leukemic blast concentrations of ara-
GTP were characterized by a long elimination half-life (median approximately 24 hours) 
and diagnosis dependent accumulation; with T-lymphoblasts generally demonstrating 
greater accumulation of ara-GTP than other cell types. Nelarabine and ara-G is < 25% 
bound to human plasma proteins. 
 
Formulation and stability: Nelarabine (compound 506U78) is formulated to provide 5 mg 
of nelarabine per mL in 0.45% saline solution. Nelarabine Injection consists of a clear, 
colorless solution, contained in a clear 50 mL glass vial with a gray rubber closure and 
lacquered overseals made of polypropylene and aluminum. The drug is supplied as a 5 
mg/mL liquid in 50 mL vials with a total of 250 mg nelarabine per vial. The pH of the 
solution is between 5 and 7. Intact 50 mL glass vials containing 250 mg of nelarabine for 
injection should be stored at or below 30 C (86 F). Do not store vials in the refrigerator as 
crystallization of the product may occur. Nelarabine as a clear colorless solution is stable 
in glass vials for at least 30 months at 30 C.  
 
All vials should be visually inspected for any particulate matter prior to use. The solution 
is intended to be used full strength directly from the vials with no further dilution. 
Glass or plastic containers may be used. Nelarabine is stable in polyvinylchloride (PVC) 
infusion bags and glass containers for up to 8 hours at up to 30°C. Nelarabine is stable in 
normal saline for up to 8 hours.  CAUTION: The single-use dosage form contains no 
antibacterial preservatives. Therefore, it is advised that the product be discarded 8 hours 
after initial entry. 
 
Supplier: Commercially available. 
 
Toxicity: Nelarabine contains a “black-box” warning regarding severe neurological 
events that occurred in clinical trials, including severe somnolence, CNS effects 
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paresthesias to motor weakness and paralysis. Over 60% of the patients who received 
nelarabine had some nervous system event (e.g., headache, somnolence, and peripheral 
neuropathy). Providers should closely monitor for signs and symptoms of neurological 
events. Other common adverse effects include fatigue, hematologic disorders (e.g., 
anemia, thrombocytopenia and neutropenia), gastrointestinal (GI) disorders (e.g., 
diarrhea, vomiting, and nausea), pulmonary disorders (e.g., cough and dyspnea) and 
fever. A small percentage of patients (4%) have complained of experiencing blurred 
vision while receiving nelarabine. Fatal opportunistic infections have also been reported 
periodically in patients receiving nelarabine. 
 
Patients receiving nelarabine should receive intravenous hydration according to standard 
medical practice for the management of hyperuricemia in patients at risk for tumor lysis 
syndrome. Consideration should be given to the use of allopurinol in patients at risk of 
hyperuricemia. See package insert for further details. 
 
Dosage and route of administration: 650 mg/m2/day IV on Days 1-5 of Block B, see 
Section 4.3. 
 
5.12 
Clofarabine (Clolar™, Clofarex) 
 
Clofarabine will be given instead of nelarabine for patients with B-lymphoblastic 
leukemia and lymphoma in Stratum II. 
 
Source and pharmacology: Clofarabine is a purine nucleoside analog. It is intracellularly 
metabolized to the active metabolite clofarabine 5’-triphosphate which competes with 
deoxyadenosine triphosphate for binding to ribonucleotide reductase and DNA 
polymerase. It inhibits DNA synthesis, terminates DNA chain elongation and inhibits 
DNA repair. Clofarabine also disrupts the mitochondrial membrane which results in the 
release of proteins, cytochrome C and apoptosis-inducing factor leading to cell death. It is 
mainly excreted in the urine as unchanged drug. 
 
Formulation and stability: Clofarabine is available in the parenteral form as a 
preservative-free solution that is 1 mg/mL. It is available in 20 mL vials. The undiluted 
drug should be stored at room temperature. The diluted solution is stable for 24 hours at 
room temperature. Clofarabine injection should be filtered through sterile 0.2 micrometer 
syringe filter and then further diluted with 5% dextrose or 0.9% NaCl containing 
solutions. 
 
Supplier: The injection is commercially available. 
 
Toxicity: The most common side effects are nausea, vomiting, diarrhea, headache, fever 
and pruritus. Also reported are pericardial effusion, tachycardia, hypotension, left 
ventricular systolic dysfunction, edema, flushing, hypertension, fatigue, anxiety, pain, 
dizziness, depression, irritability. Patients who receive clofarabine are at risk for tumor 
lysis syndrome and need to be monitored closely.  
 

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Patients may also experience a systemic inflammatory response syndrome (SIRS) or 
capillary leak syndrome. Patients should be monitored for this during the infusion. See 
package insert for further details. 
 
Dosage and route of administration: 40 mg/m2/day IV, Days 1-5. See Block C, section 4.4 
for B-lymphoblastic leukemia and lymphoma in Stratum II only. 
 
5.13 
Cyclophosphamide (Cytoxan) 
 
Source and pharmacology: Cyclophosphamide is a nitrogen mustard derivative. It acts as 
an alkylating agent that causes cross-linking of DNA strands by binding with nucleic acids 
and other intracellular structures, thus interfering with the normal function of DNA.  
Cyclophosphamide is cell-cycle, phase non-specific. Cyclophosphamide is well absorbed 
from the GI tract with a bioavailability of > 75%. Cyclophosphamide is a prodrug that 
requires activation. It is metabolized by mixed-function oxidases in the liver to 4-
hydroxycyclophosphamide, which is in equilibrium with aldofosfamide. Aldofosfamide 
spontaneously splits into cyclophosphamide mustard, which is considered to be the major 
active metabolite, and acrolein. In addition, 4-hydroxycyclophosphamide may be 
enzymatically metabolized to 4-ketocyclophosphamide and aldofosfamide may be 
enzymatically metabolized to carboxyphosphamide, which are generally considered to be 
inactive. Cyclophosphamide and its metabolites are excreted mainly in the urine. Dosage 
adjustments should be made in patients with a creatinine clearance of <50 ml/min. 
 
Formulation and stability: Cyclophosphamide is available in 25 and 50 mg tablets. 
Cyclophosphamide is also available in vials containing 100, 200, 500, 1000 and 2000mg 
of lyophilized drug and 75 mg mannitol per 100 mg of cyclophosphamide. Both forms of 
the drug can be stored at room temperature. The vials are reconstituted with 5, 10, 25, 50 
or 100 ml of sterile water for injection respectively to yield a final concentration of 20 
mg/ml. Reconstituted solutions may be further diluted in either 5% dextrose or 0.9% 
NaCl containing solutions. Diluted solutions are physically stable for 24 hours at room 
temperature and 6 days if refrigerated, but contain no preservative, so it is recommended 
that they be used within 24 hours of preparation. 
 
Supplier: Commercially available 
 
Toxicity: Dose limiting toxicities of cyclophosphamide are bone marrow suppression and 
cardiac toxicity. Cardiac toxicity is typically manifested as congestive heart failure, cardiac 
necrosis or hemorrhagic myocarditis and can be fatal. Hemorrhagic cystitis may occur and 
necessitates withholding therapy. The incidence of hemorrhagic cystitis is related to 
cyclophosphamide dose and duration of therapy. Forced fluid intake and/or the 
administration of MESNA decrease the incidence and severity of hemorrhagic cystitis. Other 
toxicities reported commonly include nausea and vomiting (may be mild to severe depending 
on dosage), diarrhea, anorexia, alopecia, immunosuppression and sterility. Pulmonary 
fibrosis, SIADH, anaphylaxis and secondary neoplasms have been reported rarely. 
 
Dosage and route of administration: 300 mg/m2/day IV on Days 1-5 during Block C, see 
Section 4.4. 
 

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5.14 
Etoposide (VP-16) (Vepesid) 
 
Source and pharmacology: Etoposide is an epipodophyllotoxin derived from 
Podophyllum pelatatum. It is thought to act mainly by inhibiting topoisomerase II, 
causing double and single strand DNA breaks. Etoposide is cell cycle, phase-specific, 
with activity in the G2 and S phases. Absorption of etoposide is approximately 30-40% 
and is highly variable and somewhat dose-dependent. It is extensively bound to serum 
proteins and is metabolized in the liver, including cytochrome P4503A metabolism to 
several moieties that include a reactive oxidized species. Etoposide and its metabolites 
are excreted mainly in the urine with a smaller amount excreted in the feces. Dosage 
adjustments should be considered in patients with liver dysfunction, kidney dysfunction 
or hypoalbuminemia. 
 
Formulation and stability: Etoposide is available in multi-dose vials containing 100mg, 
150mg, 500mg and 1000mg of etoposide as a 20 mg/ml solution and 30% alcohol. 
Etoposide is also available as a 50 mg capsule. The intact vials of etoposide solution 
should be stored at room temperature. The capsules should be stored under refrigeration. 
Etoposide solution should be diluted in D5W or 0.9% NaCl prior to administration. 
Solutions with a final concentration of 0.2 and 0.4 mg/ml are stable at room temperature 
for 96 hours and 24 hours respectively. 
 
Supplier: Commercially available. 
 
Toxicity: Dose limiting toxicity is myelosuppression. Nausea and vomiting (usually of 
low to moderate severity), diarrhea, mucositis (particularly with high doses), alopecia and 
anorexia are fairly common. Hypotension can occur with rapid infusions. Other side 
effects reported less commonly include hepatitis, fever and chills, anaphylaxis and 
peripheral neuropathy. Secondary leukemia has been reported. 
 
Dosage and route of administration: 100 mg/m2/day IV on Days 1-5 of Block C, see 
Section 4.4. 
 
5.15 
Etoposide Phosphate (Etopophos®) 
 
To be used in case of etoposide reactions. 
 
Source and pharmacology: Etoposide is an epipodophyllotoxin derived from 
Podophyllum pelatatum. It is thought to act mainly by inhibiting topoisomerase II, 
causing double and single strand DNA breaks. Etoposide is cell cycle, phase-specific, 
with activity in the G2 and S phases. Absorption of etoposide is approximately 30-40% 
and is highly variable and somewhat dose-dependent. It is extensively bound to serum 
proteins and is metabolized in the liver, including cytochrome P4503A metabolism to 
several moieties that include a reactive oxidized species. Etoposide and its metabolites 
are excreted mainly in the urine with a smaller amount excreted in the feces. Dosage 
adjustments should be considered in participants with liver dysfunction, kidney 
dysfunction or hypoalbuminemia. 
 

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Formulation and stability: Etoposide phosphate is a water-soluble ester of etoposide. The 
higher water solubility of etoposide phosphate than that of etoposide lessens the potential 
for precipitation following dilution and during administration. Etoposide phosphate is 
available in single-dose vials containing etoposide phosphate equivalent to 100mg 
etoposide. The intact vials of etoposide solution should be stored at 2 to 8 degrees 
Celsius. Etoposide phosphate solution should be diluted in D5W or 0.9% NaCl prior to 
administration. Solution is stable at room temperature for 24 hours. 
 
Supplier: Commercially available. 
 
Toxicity: Dose limiting toxicity is myelosuppression. Nausea and vomiting (usually of 
low to moderate severity), diarrhea, mucositis (particularly with high doses), alopecia and 
anorexia are fairly common. Hypotension can occur with rapid infusions. Other side 
effects reported less commonly include hepatitis, fever and chills, anaphylaxis and 
peripheral neuropathy. Secondary leukemia has been reported. 
 
Dosage and route of administration: Used in substitution for etoposide in participants that 
experience allergic reaction; IV administration. 
 
5.16 
Intrathecal Triples (ITMHA, methotrexate/hydrocortisone/cytarabine) 
 
Source and pharmacology: The intrathecal route of administration of a drug produces 
more consistent CSF drug concentrations at relatively smaller doses because of the 
volume difference between the CSF and blood compartments (140 mL vs. 3500 mL in an 
adult); (The CSF volume of children after the first 3 years is equivalent to that of an 
adult). Drug half-lives are longer as well because clearance is related to flow rather than 
metabolism or protein binding. Intrathecal methotrexate has a biphasic elimination curve 
from the CSF with a t½ of 4.5 and 14 hours respectively. Following IT injection of 
cytarabine the elimination of the drug from the CSF is biphasic with a t½ of 1 and 3.4 
hours respectively, which is 8-fold longer than the clearance from plasma. The 
elimination of hydrocortisone is similarly prolonged. 
 
Formulation and stability: Methotrexate 25 mg/mL preservative free 2 mL vial or 
methotrexate 20 mg preservative free sterile powder for injection vial. Cytarabine 100 mg 
preservative free sterile powder for injection. Hydrocortisone sodium succinate100 mg 
vial sterile powder for injection. 
 
Toxicity:  Nausea, vomiting, fever, headache. 
 
Guidelines for administration: Intrathecal, as ITMHA during Blocks A and B. 
 
5.17 
Drug Shortages and Unavailability 
 
In the case of drug shortages and unavailability of any agent used in this protocol, 
treating investigators are urged to consult with the PI or co-PI and use their best clinical 
judgment in optimizing therapeutic intent and ensuring patient safety in managing the 
protocol-specified therapy.  
 

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Although these decisions may constitute “Protocol Violations,” they are unavoidable and 
made in consideration of the best interest of an individual patient. These will NOT be 
considered monitoring/audit findings if appropriately documented. Most importantly, all 
protocol deviations must be noted in the research database and the alterations in therapy 
due to the agent shortage will be captured. This should be accomplished by entering 
“dose modified” and details noted in the comments field. 
 
 6.0 
TREATMENT MODIFICATIONS 
 
6.1 
PEG-Asparaginase Allergies/Hypersensitivity 
 
Patients with allergic reactions or intolerance to PEG-asparaginase subsequently will be 
given Erwinia L-asparaginase intramuscularly or intravenously over 30-60 minutes 
duration. Each dose of PEG-asparaginase will be replaced by 6 doses of Erwinia L-
asparaginase given at 25,000 units/m2/dose thrice weekly (2 to 3 days apart, e.g., 
Monday, Wednesday and Friday) over 2 weeks. 
 
Participants with possible allergic reactions should have measurements of anti-
asparaginase antibodies and asparaginase at the time of the reaction and if re-challenged, 
after the next dose.  
 
6.2 
Participants with Renal Dysfunction  
 
6.2.1 High Dose Methotrexate 
 
Subclinical renal impairment (normal serum creatinine but decreased GFR) may be 
present in participants receiving concurrent nephrotoxic drugs (e.g., IV acyclovir and 
vancomycin) which, if possible, should be held during and for 20 hours after HDMTX 
infusions or until adequate MTX clearance has been documented.  Consideration to 
delaying MTX should be given if a patient's serum creatinine indicates renal impairment 
(e.g., glomerular filtration rate <50cc/min/1.73 m2, however this will be a clinical 
decision, please contact PI, co-PI and/or PharmD). In the event of toxicity secondary to 
high dose methotrexate, consider carboxypeptidase (glucarpidase).  
 
6.2.2 High Dose Cytarabine 
 
Patients who have received amphotericin B or nephrotoxic antibiotic regimens for at least 7 
days, and patients in whom serum creatinine is greater than two times normal for age, 
should have their glomerular filtration rate (GFR) measured before they receive HDAC. In 
patients with a GFR ≤ 60 ml/min per 1.73m2, we recommend decreasing the dosage of 
cytarabine from 3 g/m2 to 2 g/m2 every 12 hours. 
 
6.3 
Participants with Hepatic Dysfunction 
 
Consider modifying the dosages for mitoxantrone, clofarabine, etoposide, vincristine, and 
bortezomib in participants with elevated direct bilirubin concentrations or other evidence 
of biliary obstruction. 

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Suggested modifications: 
 
• Direct bilirubin 2-4 mg/dl: 50% dosage decrease  
• Direct bilirubin >4-6 mg/dl: 75% dosage decrease 
• Direct bilirubin >6 mg/dl: withhold dose  
 
PEG-asparaginase may need to be withheld in participants with elevated direct bilirubin 
concentrations, especially if there is evidence of mucositis. HDMTX should be withheld 
if there is evidence of existing mucositis or if total bilirubin >2 mg/dl and direct bilirubin 
>1.4 mg/dl. Subclinical hypertransaminasemia (SGPT >500 IU/L) is an indication to 
delay only high dose methotrexate but no other chemotherapy.  
 
6.4 
Cardiotoxicity  
 
Mitoxantrone will be held for fractional shortening < 28%. Consultation with cardiologist 
is suggested if clinically indicated. 
 
All patients must have an assessment of serum potassium, magnesium, and calcium (total 
corrected for albumin, or ionized calcium) ≤ 72 hours prior to the administration of oral 
panobinostat on day 2 of cycle 1 and the results must all be ≥ LLN before the first dose of 
panobinostat is administered. Throughout Days 1-7, serum biochemistry values including 
serum potassium, calcium, phosphorous and magnesium will be monitored closely and 
corrected before administration of panobinostat. 
 
6.5 
Peripheral Neuropathy 
Severity of Peripheral 
Neuropathy (PN) 
VSLI modification 
Bortezomib modification 
Grade 3 or persistent Grade 2 at 
the time of the next dose 
Interrupt VSLI for Grade 3 
 
If PN remains Grade > 3 until 
next dose then discontinue VSLI  
 
If PN recovers to Grade 1 or 2 
from Grade 3, or persistent Grade 
2, then reduce VSLI dose to 2 
mg/m2 
 
No dose reduction if recovery to 
Grade < 2 
Interrupt bortezomib for Grade 3 
and resume at 1.3 mg/m2 if PN 
recovers to Grade 1 or 2 by next 
dose 
Stable Grade < 2 after first VSLI 
dose reduction to 2 mg/m2  
or increase to Grade > 3 
No dose reduction for stable 
Grade 1 or 2 after first VSLI dose 
reduction to 2 mg/m2 
 
Reduce VSLI dose to 1.5 mg/m2 
if Grade 3 PN improves to Grade  
< 2 at the time of the next dose 
Interrupt VSLI for Grade > 3 PN 
No dose reduction if stable Grade 
1 or 2. Interrupt bortezomib for 
Grade 3  
Resume at 1.3 mg/m2 if PN 
recovers to Grade 1 and at 1 
mg/m2 if PN recovers to Grade 2 
before next dose 
Grade 4 
Discontinue VSLI 
Discontinue bortezomib 

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7.0 
REQUIRED EVALUATIONS, TESTS, AND OBSERVATIONS 
 
7.1 
Pretreatment Evaluation 
 
 
All participants should be invited to participate in the tissue banking protocol (TBANK) 
and PGEN5 at the time of study entry. 
 
• Complete history 
• Physical exam with vital signs and complete neurologic exam 
• Height, weight, BSA 
• Pulse oximetry 
• Urinalysis 
• Complete blood count with differential 
• Chemistry profile: glucose, electrolytes, BUN, creatinine, LDH, uric acid, bilirubin, 
ALT, AST, calcium, phosphorous, magnesium, total protein and albumin 
• Coagulation screen 
• G6PD screen 
• Lipid screen: Total cholesterol, triglycerides, free fatty acids and high-density 
lipoprotein cholesterol 
• Thyroid function tests 
• Hepatitis B and C Screen 
• HIV 
• HLA typing 
• Chest x-ray (required for T-cell malignancies, as clinically indicated for B-cell) 
• EKG 
• Echocardiogram or MUGA  
• Bone marrow evaluation: morphology, cytochemistry, immunophenotyping, 
cytogenetics, molecular diagnosis, MRD studies (MRD leukemia patients only) 
• PET/CT (lymphoma patients only) 
• Lumbar puncture with CSF cell count and cytology 
• NK cell receptor studies, except in patients receiving steroids 
• Pregnancy test of females of childbearing potential 
• Other studies as clinically indicated, e.g., sickle cell prep, hemoglobin electrophoresis 
for black children; varicella titer; EBV, TOXO, CMV, HSV titers  

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7.2 
Evaluations during Therapy  
Studies to be Obtained 
During Block A 
During Block B 
During Block C 
Physical exam (includes vital signs, height, 
weight, BSA 
Weekly 
Weekly 
Weekly 
Comprehensive neurologic exam – (see 
note below) 
Prior to Day 6 and Day 
15 
Start of Block 
Start of Block and EOT 
CBC, differential, platelets 
Weekly and as 
clinically indicated 
Weekly and as clinically 
indicated 
Weekly and as clinically 
indicated 
GFR or creatinine clearance  
(in pts. with elevated serum creatinine, see 
Section 6.2.1 and 6.2.2) 
--- 
Prior to HDMTX and 
HD Ara-C 
--- 
Chemistries* 
Weekly 
Weekly 
Weekly 
Electrolytes# 
Weekly 
Weekly 
Weekly 
Lipase and amylase 
Prior to each dose of 
asparaginase 
--- 
--- 
Chest x-ray (T-cell patients) 
Baseline 
As clinically indicated 
As clinically indicated 
Pulse oximetry 
Baseline 
 
As clinically indicated 
As clinically indicated 
Urine or serum pregnancy test (if 
applicable) 
Start of Block 
Start of Block 
Start of Block 
EKG 
Baseline 
 
As clinically indicated 
As clinically indicated 
CSF cell count and differential 
With each dose of 
ITMHA 
With each dose of 
ITMHA 
--- 
Bone marrow aspirate and/or biopsy for 
morphology for leukemia and lymphoma 
with marrow disease.  MRD for leukemia 
patients. 
Start of Block 
(and optional Day 7 pre 
VSLI and MITO; see 
Section 8.2) 
Start of Block 
(after count recovery 
from Block A) 
Start of Block (after count 
recovery from Block B) 
and EOT (after count 
recovery Block C) 
PET/CT scan of involved areas for 
lymphoma patients 
Start of Block 
Start of Block 
Start of Block (if not in CR 
after Block A) and EOT 
Optional pharmacokinetics studies 
(see Section 8.1) 
Day 2 and 6** 
--- 
--- 
Optional pharmacodynamic, genomic and 
research MRD studies 
(see Section 8.2) 
 Start of Block,  
Day 2, 3 and 7 
 
 
Optional NK cell receptor studies 
(see Section 8.3) 
Start of Block 
--- 
Start of Block 
Optional intestinal microbiome studies 
(see Section 8.4) St. Jude participants only 
Start of Block 
Start of Block 
Start of Block and 
Completion of Block 
Optional neuropathy & function  
(see Section 8.5 and Appendix IV) 
Day 6 and 15 
Start of Block 
Start of Block and EOT  
*BUN, creatinine, ALT, AST, LDH, alkaline phosphatase, glucose, total bilirubin, albumin, total protein, uric acid.   
#Sodium, potassium, calcium, magnesium and phosphorous.  See Section 6.4 for daily monitoring serum potassium, magnesium, and 
calcium (total corrected for albumin, or ionized calcium) ≤ 72 hours prior to the administration of oral panobinostat on day 2 of cycle 1 
of Block A, and the results must all be ≥ LLN before the first dose of panobinostat is administered.  
 ¥Post-menarchal females, per hospital policy. 
**PK blood samples will be collected after the first dose (day 2) and third dose (day 6) of panobinostat at the following time points: 
pre-dose, 30 min, 1 h, 3 h, 6 h, 24 ± 3 h, and 48 ± 3h.   
• Neurologic exam more often if clinically indicated.  Comprehensive assessment of peripheral neuropathy and sensorimotor function 
prior to first dose of liposomal vincristine (VSLI) (day 6), prior to staring Bortezomib (day15), and on day of beginning of each block of 
therapy.  Exam may be conducting within 4 days prior to the suggested day if scheduling necessitates (e.g., holidays etc.) If patients 
have Grade 4 neutropenia then CBCs should be checked at least every 3 to 4 days until recovery to Grade 3. 
• Bone marrow procedures not required for lymphoma patients without marrow disease. 
 
Obtain other studies as needed for clinical care. 

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8.0 
CORRELATIVE RESEARCH STUDIES 
 
8.1 
Pharmacokinetic Studies 
 
Optional pharmacokinetic studies will be done on peripheral blood. Samples will be 
collected after the first dose (day 2) and third dose (day 6) of panobinostat at the 
following time points: pre-dose, 30 min, 1 h, 3 h, 6 h, 24 ± 3 h, and 48 ± 3h. 
 
8.1.2 Sample Collection and Processing 
 
Draw 4 mL of blood in a pre-cooled green top (heparinized) tube. Samples may be drawn 
from a central catheter using local hospital guidelines for flushing. Place samples on ice.  
Within 30 minutes of obtaining the sample, centrifuge in a refrigerated centrifuge for 10 
minutes at 2000x g to separate blood cells and platelets from the plasma. The upper 
plasma layer will be split into 2 aliquots. Each aliquot should be transferred by pipette 
into a polypropylene screw-cap freezing vial. Each vial should be labeled with study ID 
number, and the DATE and TIME the specimen was drawn. Samples should be frozen 
immediately at -20 until shipping and analysis. Panobinostat will be measured in plasma 
using a validated LC-MS/MS assay in the St. Jude Children’s Research Hospital 
Pharmacokinetics Shared Resource. Plasma samples will be batched for shipping.   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.2 
Pharmacodynamic, Genomic and MRD Studies 
 
Blood and bone marrow specimens will be routed through the St. Jude Biorepository for 
processing and distribution for these studies: 
 
• PB and BM for MRD prior to each block 
• Optional BM for PD pre treatment 
• Optional BM for PD and MRD on day 7 of Block A 
• Optional PB for PD pretreatment and on Day 2 (pre-panobinostat), Day 3 
(approximately 24 hours post-panobinostat), and Day 7 of Block A 
 

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8.2.1  Sample collection and processing 
 
In all patients: 
 
Collect 5 mL of bone marrow aspirate in preservative-free heparin stored at ambient 
temperature. Samples will be collected for MRD: 
 
• 
Pre-treatment 
• 
Prior to each block  
 
Collect 10 mL of peripheral blood in preservative-free heparin vacutainer stored at 
ambient temperature. Samples will be collected for MRD: 
 
• 
Pre-treatment 
• 
Day 7 of block A  
• 
Prior to each block 
 
In patients consenting for optional pharmacodynamic studies: 
 
Collect 5 mL of bone marrow aspirate in purple top tubes (EDTA) stored at ambient 
temperature. Samples will be collected: 
 
• 
Pre-treatment (5 mL) 
• 
Day 7 of block A (10 mL: 5mL for PD and 5 mL for MRD) 
 
Collect 15 mL of peripheral blood in purple top tubes (EDTA) stored at ambient 
temperature. Samples will be collected: 
 
• 
Pre-treatment 
• 
Days 2 (pre-panobinostat), 3 (approximately 24 hours post-panobinostat), and 7 of 
Block A 
 
Note that flow cytometric studies are not performed on weekends. Hence, samples should 
be drawn Monday through Thursday and sent by overnight delivery. Samples that arrive 
on weekends are processed on Monday, but such delay may affect the quality of the 
assay. 
 
 
 
 
 
 
 
 
Please send specimens Monday through Thursday only. Please do NOT ship Friday or 
before holidays. Send specimens via FedEx Priority Overnight. Notify the Biorepository 
of pending shipment 
 with tracking number. 

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8.3 
NK Cell Receptor Studies 
 
Peripheral blood (3 ml) will be obtained pre-treatment for immunophenotyping and (8.5 
ml) before Block C for immunophenotyping and genotyping for NK cell receptors as 
described previously58,64. Blood samples will be collected in ACD (yellow-top) tubes and 
sent to 
 laboratory. We will assess NK cell receptors including KIRs, NCRs, 
NKG2D, DNAM-1, 2B4, and NTBA. The sample should be obtained before the 
administration of steroids. 
 
8.4 
Intestinal Microbiome Research 
 
To participate in this research, participants cannot have a clinical or microbiologically-
proven diarrheal illness. 
 
Four stool specimens will be collected from research participants, one is during a time 
period before starting Block A (or until the first 72 hours after starting Block A), the 
second sample will be collected within 72 hours prior to starting Block B, the third within 
72 hours prior to starting Block C, and the fourth within 3-4 weeks from starting Block C 
chemotherapy (post chemo). Paired stool samples will be batched to be analyzed 
simultaneously. Bacterial genomic DNA will be harvested from these samples and 
utilized for ribosomal DNA sequencing to determine the overall bacterial microflora prior 
to and following chemotherapy. These two methodologies will provide a preliminary 
investigation into any notable alterations in bacterial diversity resulting from therapeutic 
interventions. In tandem, we will also isolate RNA from these samples for sequencing in 
order to identify novel RNA viruses. Once notable differences in the microbiome before 
and after chemotherapy are determined, we will then attempt to describe the 
gastrointestinal complications during the 3 treatment blocks. Stool samples will be used 
to run the laboratory investigation in 
research laboratories. 
 
Medical records will be reviewed to collect data about infectious diseases, probiotics, 
antacids and antimicrobial use during the study period. Only descriptive statistics such as 
median, range and percentages will be used as appropriate. The proposed study is 
intended to be a pilot investigation to test feasibility of this approach and optimize 
experimental procedures. The data and information obtained in these investigations will 
be utilized as preliminary data for a larger scale study and future grant applications.  
 
8.4.1 Laboratory Methods and Materials  
 
Fecal samples will be collected and immediately placed into RNA Protect, a stabilization 
reagent. Tubes will be prepared in advance and stored until sample collection. Samples will 
then be processed within 6 hours of collection. Fecal samples will be stored at -80˚C until 
processing at a later time in batched runs. DNA and RNA will be extracted from the sample 
by bead-beating followed by phenol chloroform extraction or column purification methods. 
Any left-over stool specimens after the completion of the DNA and RNA extraction will be 
discarded. 
 

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The gut microbiota will be sequenced using two independent methodologies. One 
methodology will utilize universal primers and subcloning to amplify the ribosomal 
sequences from the isolated bacterial DNA. These subclones will then be utilized to 
generate an Illumina genomic library. The other approach will utilize DNA and RNA that 
has been enriched from any eukaryotic contamination without any subcloning. Our 
methodology should yield approximately 100 μgs of DNA and 20 μgs of RNA, sufficient 
for approximately ten independent sequencing runs. This will allow for the determination 
of bacterial diversity in the gut as well as the identification of novel, gut associated viruses 
that correlate with downstream clinical outcomes. 
 
For the sequencing, 3pM of each small library will be loaded onto a flow cell on the 
Illumina Cluster Station. A 3pM PhiX DNA sample was used as a cluster and sequencing 
control. The reads on the single read flow cell will then be subjected to 152 cycles of 
sequencing on the Illumina Genome Analyzer platform. The base calls were analyzed using 
Illumina's Pipeline version 1.4.0. This methodology allows for the generation of 
approximately 10 million reads of an average length of 100 base pairs, providing excellent 
genetic coverage. 
 
The reads will then be analyzed by a number of readily available software programs 
specifically designed for metagenomic analysis and phylogenetic reconstruction. This will 
allow for the determination of changes in overall bacterial diversity and population 
dynamics. This methodology will also allow for the detection of any known or previously 
uncharacterized viruses in the sample. 
 
8.5 
Neuropathy and Function Assessments 
 
8.5.1 Sensory, Motor and Autonomic Impairment 
 
Peripheral sensory and motor integrity will be evaluated with the Pediatric Modified 
Total Neuropathy Scale (Ped-mTNS). This instrument includes a pediatric specific 
sensory, motor and autonomic symptoms inquiry and five-item neurologic exam (light 
touch, vibration, pin sensation, distal strength and deep tendon reflexes) designed to 
evaluate the integrity of the peripheral nervous system65. This assessment has been tested 
in children exposed to neurotoxic chemotherapy agents and has good internal 
consistency, inter-rater and test-retest reliability. Scores are associated with measures of 
balance and manual dexterity66. Scores range from 0-32; a score of zero indicates no 
impairment. This test requires a standard set of Semmes Weinstein monofilaments, a 
Medipin, a handheld Bioethesiometer, and a reflex hammer. Autonomic function will be 
evaluated using power spectral analysis of heart rate variability (PS/HRV) from time 
series during a thirty minute supine ECG and with heart rate and blood pressure 
responses from a tilt table test. 
 
8.5.2 Balance and Manual Dexterity 
 
The balance and manual dexterity subtests of the Bruininks-Oseretsky Test of Motor 
Proficiency, version 2 (BOT2) will be used to evaluate peripheral sensory and motor 
function67. This instrument has been evaluated for psychometric properties in 1,520 
children with established inter-rater and test-retest reliability for each subtest, by sex and 

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age (4-21 years)68. Points are received for performance on each subtest and converted to 
sex- and age-standardized scores with a mean of 15 and a standard deviation of 5. 
Published standards will be used to administer the balance and manual dexterity sub-tests 
in our patient population67. This test requires a standard BOT2 Test Kit. 
 
8.5.3 Energy Expenditure Requirements for Ambulation 
 
The energy expenditure required for ambulation will be evaluated by calculating the 
physiologic cost of walking over a six minute time period. Children are asked to walk as 
fast as possible for six minutes on a level surface while pushing a measuring wheel that 
records the distance walked69. Heart rate (HR) and distance walked in meters will be 
recorded for each minute and a physiologic cost index determined [(HR during walking – 
HR at rest)/meters per minute]. The mean physiologic cost index over the last three minutes 
of walking will be used for analysis. This measure has been used to evaluate the ability of 
ankle foot orthoses to decrease the energy expenditure of walking in children with spastic 
diplegia,70 to evaluate energy required for walking in persons with stroke,71 and to compare 
different reciprocating gait orthoses in persons with paraplegia72. This test requires a stop 
watch, a corridor reasonably free of obstacles, rating of perceived exertion scale, 
measurement wheel, a heart rate monitor, and a lap counter.   
 
9.0 
EVALUATION CRITERIA 
 
9.1 
Response Criteria for Lymphoblastic Leukemia 
 
The response after each course of chemotherapy will be determined by the examination 
of the bone marrow. For the purposes of this protocol, MRD-negative is defined as 
<0.01% blasts with a leukemia associated phenotype detected by flow cytometry in a 
CLIA certified clinical laboratory. Because morphologic examination of the bone marrow 
during periods of hematopoietic recovery after intensive chemotherapy may be 
unreliable, response will be based on blast percentage by flow cytometry. Blast 
percentages determined by morphology will be used in cases that are not evaluable by 
flow cytometry. If the blast percentage is less than 5% in such cases, they will be 
classified as complete response, MRD not evaluable. 
 
• Complete response (CR): MRD-negative, < 0.01% blasts by flow cytometry 
• Complete response (CRM): MRD-positive, 0.01% to < 5% blasts by flow cytometry 
• Partial response (PR): A decrease of at least 50% in the percentage of blasts and 5% 
to 25% blasts by flow cytometry. 
• No response (NR): No change in clinical or laboratory status. 
• Progressive disease (PD): Deterioration of initial disease status 
• Relapse: 
o Bone marrow relapse: Subsequent appearance, after achievement of CR, 
of ≥ 5% blasts in the bone marrow with confirmation by flow cytometry.  
o CNS relapse: ≥ 5 WBC/µL of CSF with definite blasts on cytospin. 
o Other extra-medullary relapse: Development of extra-medullary disease 
after achievement of CR. 
 

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9.2 
Response Criteria for Lymphoblastic Lymphoma 
 
• Complete response (CR): Disappearance of all evidence of disease from all sites 
as determined by physical exam and appropriate imaging studies. Bone marrow 
aspirate/biopsy as well as CSF examination should be normal. Any macroscopic 
nodules in any organs detectable on imaging studies should no longer be present. 
PET scan should be negative if initially positive. 
• Complete response unconfirmed (CRu): Residual lymph node mass >1.5 cm in 
greatest transverse diameter (GTD) that has regressed by >75% in sum of the 
products of greatest perpendicular diameter or any residual lesions in organ have 
decreased by >75% with negative PET scan if initially positive. 
• Partial response (PR): >50% decrease in SPD and no new lesions. 
• Stable disease (SD): No new lesions and failure to qualify for partial response. 
• Progressive disease (PD): 25% increase in lesions or any new lesions. 
 
10.0 
CONCOMITANT THERAPY 
 
Concurrent anti-cancer therapy not defined within this protocol, including chemotherapy, 
radiation therapy, immunotherapy, or biologic therapy may NOT be administered to 
participants receiving treatment on this study. If these treatments are administered, the 
participant will be removed from protocol therapy. No other investigational agents may 
be given while the participant is on protocol therapy. 
 
In general, the use of any concomitant medication/therapies deemed necessary for the 
care of the patient are allowed, including drugs given prophylactically (e.g., anti-emetics) 
with the following exceptions: 
 
1) Any medications listed in Appendix II that may cause QTc prolongation or 
inducing torsade’s de pointes should not be used unless clinically indicated and 
cleared by PI. 
2) Any medications that have the potential to alter serum electrolytes (e.g., diuretics) 
should be monitored very closely for electrolyte abnormalities as these can 
contribute to the risk of QT prolongation and ventricular arrhythmias. 
3) Hydroxyurea may be given per institutional guidelines prior to initiating protocol 
therapy and during the first course of therapy to help manage elevated white counts. 
4) If the patient develops painful sites of disease that may benefit from localized 
radiation, the treating physician should contact the study chair to discuss the case. 
In certain circumstances, localized radiation will be allowed provided there are 
other sites of disease that can be evaluated for response. 
5) Patients with diabetes may require close monitoring of blood glucose and 
adjustment of anti-diabetic medication. 
6) Drugs that can inhibit CYP3A4/5: the concomitant use of strong CYP3A 
inhibitors should be avoided when possible (e.g., ketoconazole, itraconazole, 
voriconazole, posaconazole, clarithromycin, atazanavir, indinavir, nefazodone, 
nelfinavir, ritonavir, saquinavir, telithromycin).  
7) Drugs that are potent CYP3A4/5 inducers: Similarly, the concomitant use of 
strong CYP3A inducers should be avoided (e.g., phenytoin, carbamazepine, 

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rifampin, rifabutin, rifapentine, phenobarbital, St. John’s Wort). If given 
concomitantly, clinical judgment is to be exercised when medications that are 
metabolized by CYP3A are given with CYP3A4 inducers. 
8) Patients with a prior seizure disorder requiring anti-convulsant therapy are not 
eligible to receive nelarabine. In addition, patients with Grade > 2 peripheral 
neurotoxicity, as determined prior to Block C by the treating physician or a 
neurologist, are not eligible to receive nelarabine and will receive clofarabine 
instead. These restrictions in eligibility are designed to prevent excessive 
nelarabine-induced central and peripheral neurotoxicity in at-risk patients. 
 
11.0 
SUPPORTIVE CARE GUIDELINES 
 
Best supportive care and treatment will be given as appropriate to each participant and 
according to current institutional practice (transfusions, oxygen therapy, nutritional 
support, palliative treatment for pain or cough, etc.). Participants may experience 
profound myelosuppression and immune suppression during this time. Steroids may 
mask fever as well as other components of the inflammatory response caused by sepsis 
during induction and 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 
principal investigator of any unexpected or unusually severe complications. 
 
11.1 
Management of Hyperleukocytosis 
 
In participants with WBC >400 x 109/L and symptoms of hyperviscosity, leukapheresis 
or exchange transfusion may be used according to local institutional guidelines. 
 
11.2 
Metabolic Derangements  
 
It is important to prevent or treat hyperuricemia and hyperphosphatemia with secondary 
hypocalcemia resulting from spontaneous or chemotherapy-induced leukemic cell lysis, 
especially in T-cell ALL.  
 
Patients with large leukemic cell burden should receive hydration and oral phosphate binder.  
 
Patients with large leukemic cell burden with or without hyperuricemia (e.g., WBC > 100 
x 109/L, uric acid > 7.5 mg/dl or > 6.5 mg/dl in patients <13 years old) may be treated 
with Rasburicase if they have no history of G6PD deficiency or ongoing pregnancy. For 
patients not at high risk of hyperuricemia, hydration, allopurinol, and judicious use of 
alkalinization (keeping urine pH between 6.5 and 7.4) may be sufficient. 
 
11.3 
Bacterial, Fungal and Viral Prophylaxis 
 
Patients should receive prophylactic antibiotics (levofloxacin or ciprofloxacin; or 
vancomycin + ciprofloxacin or cefepime) and antifungals (micafungin during Block A and 

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during chemotherapy in Blocks B and C, or voriconazole if patient has completed all 
chemotherapy in the treatment phase). Antimicrobials may be given by the parents or other 
caregivers at home, according to institutional guidelines. All patients must receive 
prophylaxis for pneumocystis jiroveci pneumonia. Participants who have Herpes simplex 
virus (HSV) antibodies may receive prophylactic acyclovir or famcyclovir daily (PO or IV). 
 
11.4 
Management of Febrile Neutropenia 
 
Episodes of fever and neutropenia should be managed according to institutional 
guidelines. Participants with fever (defined as a single temperature ≥38.3° C (101°F) or 
temperature of ≥38.0° C (100.4°F) sustained over a one hour period and neutropenia 
(defined as ANC <500 cells/µL or WBC <1,000 x 109/L) should be given IV broad-
spectrum antibiotics immediately, after obtaining appropriate cultures. 
 
11.5 
Drug Interactions  
 
Because concurrent use of enzyme inducing anticonvulsants (e.g., phenytoin, 
phenobarbital, and carbamazepine) with anti-leukemic therapy has recently been 
associated with inferior EFS, every effort should be made to avoid these agents, which 
induce many drug metabolizing enzymes. Keppra (levetiracetam) does not induce hepatic 
drug metabolizing enzymes and may be a suitable alternative anticonvulsant. 
 
Azole antifungals (fluconazole, itraconazole, voriconazole, and ketoconazole) and the 
macrolide group of antibiotics (e.g., erythromycin, rifampin, and Zithromax) may have 
potent inhibitory effects on drug-metabolizing enzymes, and the doses of some anti-
leukemic drugs (e.g., vincristine, anthracyclines, steroids, etoposide) may need to be 
reduced in some patients on chronic azole antifungals or antibiotics. Consult 
Pharmacokinetics if long-term use of these interacting drugs is unavoidable.  
 
11.6 
Growth Factors 
 
Prophylactic use of hematopoietic growth factors (GM-CSF or G-CSF) is not 
recommended. However, GM-CSF (250 µg/m2/day) or G-CSF (5-10 µg/kg/day) may be 
considered for participants who have life threatening fungal infections or bacterial sepsis 
after discussion with PI or medical designee. 
 
11.7 
Etoposide Reactions 
 
Cardiovascular effects: Transient hypotension has occurred in about 1 to 2 % of 
participants following rapid IV administration of etoposide during clinical trials. 
However, hypotension has not been associated with cardiac toxicity or electrocardiogram 
changes. Blood pressure usually normalizes within a few hours after discontinuation of 
the infusion. To avoid this complication, etoposide should be infused over 30 – 60 
minutes. If hypotension should occur, stop the infusion, and if necessary, give 10 mL/kg 
NS bolus over 15 minutes. Repeat as necessary. Once symptoms resolve, resume infusion 
at ½ the previous infusion rate until the full dose administered. If hypotension recurs, 
stop infusion and administer 10 mL/kg NS bolus as indicated. Once hypotension resolves, 

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resume infusion at ½ previous infusion rate until complete. Consider infusing NS at 1 – 
1.5 x maintenance during remainder of infusion. For all subsequent doses, further dilute 
and infuse over 2 hours. 
 
Sensitivity reactions: Anaphylactoid reactions consisting principally of chills, rigors, 
diaphoresis, pruritis, loss of consciousness, nausea, vomiting, fever, bronchospasm, 
dyspnea, tachycardia, hypertension, and/or hypotension have occurred in 0.7 – 3% of 
patients receiving etoposide. Other manifestations include flushing, rash, substernal chest 
pain, lacrimations, sneezing, coryza, throat pain, back pain, abdominal cramps, and 
auditory impairment. Facial/lingual swelling, coughing, diaphoresis, cyanosis, tightness 
in the throat, and laryngospasm have also occurred.   
 
If an anaphylactoid reaction should occur: 
 
1. Stop the infusion immediately and notify H/O Fellow or Attending MD 
2. Administer the following as indicated: 
a) diphenhydramine 1mg/kg IV  (max dose 50 mg) 
b) hydrocortisone 50 – 100 mg/m2 IV 
c) epinephrine 0.01 mg/kg of a 1:1000 concentration for SQ administration 
(max. 0.5 mg) 
d) fluid bolus 10 mL/kg NS infused over 15 minutes 
3. Once symptoms have resolved, resume infusion at ½ previous rate until infusion 
complete. Consider infusing NS at 1 – 1.5 x maintenance during remainder of 
infusion. 
4. If anaphylaxis recurs, stop the infusion and re-treat as above. Do not administer 
remainder of dose. Consider substituting etoposide with etoposide phosphate 
(Etopophos®) for all subsequent doses. 
5. If anaphylaxis does not recur, pre-medicate all subsequent doses with 
diphenhydramine 1mg/kg (max 50 mg) and hydrocortisone 50 – 100 mg/m2. 
Consider slowing the loading dose to be administered over 1 hour. 
6. Have at bedside all of the following for all subsequent infusions: 
a) Diphenhydramine 1mg/kg IV (max 50 mg) 
b) Hydrocortisone 50 – 100 mg/m2 IV 
c) Epinephrine 0.01 mg/kg of a 1:1000 concentration for SQ administration 
(max 0.5 mg) 
 
Please note: anaphylactoid reactions are still possible with etoposide phosphate. If the 
patient cannot tolerate the substitution, drug is contraindicated and must be discontinued. 
 
11.8 
Nelarabine-Related Neurotoxicity 
 
If neurologic toxicity develops prior to the completion of 5 days of therapy, nelarabine 
should be halted and the study chair should be called immediately. If Grade 4 nelarabine-
related neurotoxicity develops, the patient will be taken off nelarabine indefinitely. 
 
Investigators are cautioned to monitor patients carefully for the development of signs and 
symptoms of peripheral neuropathy. In the event that a patient develops initial signs or 

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symptoms of peripheral neuropathy attributed to the administration of nelarabine, the 
agent should be discontinued for the course. 
 
Only resume nelarabine if peripheral neuropathy resolves to less than Grade 2 toxicity.  
Nelarabine should NOT be continued in patients who develop signs or symptoms 
suggestive of an ascending polyneuropathy, including a Guillain-Barré-like syndrome, 
even if these symptoms resolve. It is recommended that patients who develop 
neurotoxicity in association with nelarabine undergo a thorough neurologic evaluation to 
establish a diagnosis and to exclude other potential etiologies (e.g., disease progression, 
concomitant illness, etc.). If a Guillain-Barré-like syndrome is suspected, therapeutic 
measures considered appropriate for the individual patients (i.e., intravenous 
immunoglobulin, plasmapheresis, steroids, and supportive care) should be instituted as 
soon as possible. Neurology consult is recommended. 
 
In patients who develop Grade 3 CNS events (e.g., somnolence, mood alteration, 
irritability, confusion, etc.) that return to < Grade 2 severity prior to the next planned 
course of nelarabine, the nelarabine dose is to be prescribed without treatment 
interruption. Nelarabine will not be made up if any doses are missed during a 5-day 
treatment course. Patients who are unable to receive a 5-day course of nelarabine because 
of toxicity should proceed to the next planned course of protocol therapy as soon as 
recovery allows. 
 
If patient(s) develop myalgia or myoglobinuria, they should be evaluated for the potential 
of having rhabdomyolysis. The patient should receive a workup that includes AST, ALT, 
creatinine, and creatine kinase (CK)/ (CPK) at a minimum. Consideration should be 
given to consulting a nephrologist. The PI should be notified if the patient develops either 
of the above symptoms, and the nelarabine should be held. If the patient is stable, other 
protocol therapy may continue while the patient is undergoing evaluation. Following 
study chair notification and evaluation for rhabdomyolysis, a decision should be rendered 
regarding permanently discontinuing the nelarabine. 
 
11.9 
Bortezomib-Related Toxicities 
 
Special criteria will be followed for peripheral neuropathy and pulmonary toxicities 
thought to be related to bortezomib. Bortezomib (and VSLI) will be decreased for 
sensory peripheral neuropathy as described in Section 6.5. 
 
There have been rare reports of acute diffuse infiltrative pulmonary disease of unknown 
etiology such as pneumonitis, interstitial pneumonia, lung infiltration and acute 
respiratory distress syndrome (ARDS) in patients receiving bortezomib. For this reason, 
pulmonary toxicity will be monitored carefully during Block A treatment. Pulmonary 
symptoms such as increased respiratory rate may indicate toxicity related to bortezomib 
and pulse oximetry should be checked for persistent, unexplained hyperpnoea. 
Respiratory symptoms such as cough, hypoxia and dyspnea or chest infiltrates should be 
aggressively evaluated. 
 

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11.10 Special Considerations for Administration of Clofarabine 
 
Patients with B-lymphoblastic leukemia and lymphoma in stratum II 
 
Clofarabine is excreted primarily by the kidneys. Therefore, drugs with known renal 
toxicity should be avoided during the 5 days of clofarabine treatment in each cycle. 
Additionally, the liver is a known target organ for clofarabine toxicity. Therefore, 
concomitant use of medications known to induce hepatic toxicity should be avoided. 
Hepatic and renal function should be assessed prior to and during treatment with 
clofarabine and it is recommended that the patient’s fluid status and hepatic and renal 
function be carefully monitored during the drug administration period. All patients should 
receive hydration each day of clofarabine treatment, giving careful consideration to the 
cardiac and renal function of the patient. To the extent possible, use of nephrotoxic (e.g., 
vancomycin, amphotericin B, etc.) and hepatotoxic (e.g., voriconazole, cyclosporine, etc.) 
agents is to be avoided during clofarabine administration. 
 
Prophylactic steroid administration has been administered by some investigators and has 
been reported to minimize the occurrence and/or severity of the following potential 
clofarabine-related toxicities: nausea, vomiting, skin rash/desquamation, and capillary 
leak syndrome. Therefore, methylprednisolone, 0.5 to 1 mg/kg/dose IV, should be given 
prior to each dose of clofarabine.  
 
12.0 
OFF TREATMENT AND OFF STUDY CRITERIA 
 
12.1 
Off Treatment Criteria 
 
• Research participants who fail to achieve complete remission after induction 
block C of treatment  
• Progressive disease 
• Second malignancy 
• Development of unacceptable toxicity during treatment (with concurrence of the 
PI or medical designee) 
• Participant/family decision to withdraw from protocol treatment at any time for 
any reason 
• Discretion of the study PI or co-PI, such as the following: 
o The researcher decides that continuing in the study would be harmful 
o A treatment is needed that is not allowed on this study 
o The participant misses so many appointments that the data cannot be used 
in the study 
o The participant’s condition gets worse 
o New information is learned that a better treatment is available, or that the 
study is not in the participant’s best interest 
• Completion of all protocol prescribed treatment 
 

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12.2 
Off Study Criteria 
 
• Death 
• Lost to follow-up 
• Withdrawal of consent 
 
13.0 
SAFETY AND ADVERSE EVENT REPORTING REQUIREMENTS 
 
13.1 
Reporting Adverse Experiences and Deaths to St. Jude IRB 
 
Only “unanticipated problems involving risks to participants or others” referred to 
hereafter as “unanticipated problems” are required to be reported to the St. Jude IRB 
promptly, but in no event later than 10 working days after the investigator first learns of 
the unanticipated problem. Regardless of whether the event is internal or external (for 
example, an IND safety report by the sponsor pursuant to 21 CFR 312.32), only adverse 
events that constitute unanticipated problems are reportable to the St. Jude IRB. As 
further described in the definition of unanticipated problem, this includes any event that 
in the PI’s opinion was: 
 
• Unexpected (in terms of nature, severity, or frequency) given (1) the research 
procedures that are described in the protocol-related documents, such as the IRB-
approved research protocol and informed consent document, as well as other 
relevant information available about the research; (2) the observed rate of 
occurrence (compared to a credible baseline for comparison); and (3) the 
characteristics of the subject population being studied; and 
• Related or possibly related to participation in the research; and 
• Serious; or if not serious suggests that the research places subjects or others at a 
greater risk of harm (including physical, psychological, economic, or social harm) 
than was previously known or recognized.  
 
Unrelated, expected deaths that occur after patient has completed protocol treatment do 
not require reporting to the IRB. Though death is “serious”, the event must meet the other 
two requirements of “related or possibly related” and “unexpected/unanticipated” to be 
considered reportable. However, all deaths while on active protocol treatment (or within 
30 days of last protocol treatment) will be require reporting to the IRB. Deaths meeting 
reporting requirements are to be reported immediately to the St. Jude IRB, but in no event 
later than 48 hours after the investigator first learns of the death.   
 
The following definitions apply with respect to reporting adverse experiences:  
 
Serious adverse event (SAE): Any adverse event temporally associated with the subject’s 
participation in research that meets any of the following criteria: 
 
• results in death; 
• is life-threatening (places the subject at immediate risk of death from the event as 
it occurred); 
• requires inpatient hospitalization or prolongation of existing hospitalization; 

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• results in a persistent or significant disability/incapacity; 
• results in a congenital anomaly/birth defect; or any other adverse event that, based 
upon appropriate medical judgment, may jeopardize the subject’s health and may 
require medical or surgical intervention to prevent one of the other outcomes listed 
in this definition (examples of such events include: any substantial disruption of 
the ability to conduct normal life functions, allergic bronchospasm requiring 
intensive treatment in the emergency room or at home, blood dyscrasias or 
convulsions that do not result in inpatient hospitalization, or the development of 
drug dependency or drug abuse), a congenital anomaly/birth defect, secondary or 
concurrent cancer, medication overdose, or is any medical event that requires 
treatment to prevent any of the medical outcomes previously listed. 
 
Unexpected adverse event:  
• Any adverse event for which the specificity or severity is not consistent with the 
protocol-related documents, including the applicable investigator brochure, IRB 
approved consent form, Investigational New Drug (IND) or Investigational 
Device Exemption (IDE) application, or other relevant sources of information, 
such as product labeling and package inserts; or if it does appear in such 
documents, an event in which the specificity, severity or duration is not consistent 
with the risk information included therein; or  
• The observed rate of occurrence is a clinically significant increase in the expected 
rate (based on a credible baseline rate for comparison); or  
• The occurrence is not consistent with the expected natural progression of any 
underlying disease, disorder, or condition of the subject(s) experiencing the adverse 
event and the subject’s predisposing risk factor profile for the adverse event.  
 
Internal events: Events experienced by a research participant enrolled at a site under the 
jurisdiction of St. Jude IRB for either multicenter or single-center research projects. 
 
External events: Events experienced by participants enrolled at a site external to the 
jurisdiction of the St. Jude Institutional Review Board (IRB) or in a study for which St. 
Jude is not the coordinating center or the IRB of record. 
 
Unanticipated problem involving risks to subjects or others: An unanticipated problem 
involving risks to subjects or others is an event, which was not expected to occur and 
which increases the degree of risk posed to research participants. 
 
Such events, in general, meet all of the following criteria:  
 
• unexpected;  
• related or possibly related to participation in the research; and  
• suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was previously 
known or recognized. An unanticipated problem involving risk to subjects or 
others may exist even when actual harm does not occur to any participant.  
 

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Consistent with FDA and OHRP guidance on reporting unanticipated problems and 
adverse events to IRBs, the St. Jude IRB does not require the submission of external 
events, for example IND safety reports, nor is a summary of such events/reports required; 
however, if an event giving rise to an IND safety or other external event report constitutes 
an “unanticipated problem involving risks to subjects or others” it must be reported in 
accordance with this policy. In general, to be reportable external events need to have 
implications for the conduct of the study (for example, requiring a significant and usually 
safety-related change in the protocol and/or informed consent form). 
 
Although some adverse events will qualify as unanticipated problems involving risks to 
subjects or others, some will not; and there may be other unanticipated problems that go 
beyond the definitions of serious and/or unexpected adverse events.   
 
Examples of unanticipated problems involving risks to subjects or others include: 
• Improperly staging a participant’s tumor resulting in the participant being 
assigned to an incorrect arm of the research study; 
• The theft of a research computer containing confidential subject information 
(breach of confidentiality); and  
• The contamination of a study drug.  Unanticipated problems generally will 
warrant consideration of substantive changes in the research protocol or informed 
consent process/document or other corrective actions in order to protect the 
safety, welfare, or rights of subjects or others.  
 
The principal investigator has the obligation to report all serious adverse events to the 
FDA, IRB, and Novartis Pharmaceuticals Clinical Safety and Epidemiology Department 
(CS&E). 
 
13.2 
Reporting to Novartis Pharmaceuticals and Spectrum Pharmaceuticals 
 
This is an investigator-initiated study. The principal investigator, Sima Jeha, and St. Jude 
are conducting the study and acting as the sponsor. Therefore, the legal/ethical 
obligations of the principal investigator include both those of a sponsor and those of an 
investigator. 
 
Any unanticipated problem that is serious, at least possible related and unexpected 
occurring in a patient after providing informed consent, while receiving study drug, and 
until four weeks after stopping study drug will be reported by FAX 
 to 
Novartis Pharmaceuticals CS&E Department (panobinostat) and by FAX to Spectrum 
Pharmaceuticals (liposomal vinCRIStine, VSLI) within 24 hours of learning of its 
occurrence, even if it is not felt to be drug related.  
 
Novartis instructions for rapid notification of unanticipated problems 
 
The principal investigator has the obligation to report all unanticipated problems to the 
FDA, IRB, and Novartis Pharmaceuticals Integrated Medical Safety (IMS) Department. 
All events reported to the FDA by the investigator are to be filed utilizing the Form FDA 
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All events must be reported, by FAX 
 to Novartis Pharmaceuticals IMS 
Department within 24 hours of learning of its occurrence. This includes serious, at least 
possibly related and unlabeled (unexpected) adverse experiences. All deaths during 
treatment or within 30 days following completion of active protocol therapy must be 
reported within 24 hours. 
 
Any unanticipated problem occurring after the patient has provided informed consent and 
until 4 weeks after the patient has stopped study participation must be reported. This 
includes the period in which the study protocol interferes with the standard medical 
treatment given to a patient (e.g. treatment withdrawal during washout period, change in 
treatment to a fixed dose of concomitant medication). 
 
Serious adverse events occurring more than 4 weeks after study discontinuation need 
only be reported if a relationship to the Novartis study drug (or therapy) is suspected.  
For Comparator Drugs/Secondary Suspects (Concomitant Medications), all serious 
adverse experiences will be forwarded to the product manufacturer by the investigator. 
 
Pregnancies 
 
To ensure patient safety, each pregnancy in a patient on study drug (or their partner) must 
be reported to Novartis within 24 hours of learning of its occurrence, provided the 
conception occurred between the time the patient started taking study drug, and 12 
months after the discontinuation of study drug. The pregnancy should be followed up to 
determine outcome, including spontaneous or voluntary termination, details of birth, and 
the presence or absence of any birth defects, congenital abnormalities or maternal and 
newborn complications. 
 
Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the 
investigator to the local Novartis Clinical Safety and Epidemiology Department. 
Pregnancy follow-up should be recorded on the same form and should include an 
assessment of the possible relationship to the Novartis study drug of any pregnancy 
outcome. Any SAE experienced during pregnancy must be reported on the SAE Report 
Form. Pregnancy outcomes must be collected for female patients who took study drug in 
this study. 
 
Consent to report information regarding these pregnancy outcomes should be obtained 
from the patient. 
 
Pregnancy outcomes should be collected for the female partners of any males who took 
study drug in this study. Consent to report information regarding these pregnancy 
outcomes should be obtained from the mother. 
 
13.3 
Reporting to Regulatory Affairs Office and FDA 
 
Any unanticipated fatal or unanticipated life-threatening event judged by the PI to be at 
least possibly due to the study treatment, will be reported to the FDA by telephone or fax 
as soon as possible but no later than seven calendar days after notification of the event 

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and followed by a written safety report as complete as possible within eight additional 
calendar days (i.e. full report 15 calendar days total after notification of event). 
 
Unanticipated, non-fatal and non-life-threatening adverse events that occur in on-study 
patients and that are considered due to or possibly due to the investigational agent, will be 
reported to the FDA by written safety report as soon as possible but no later than 15 
calendar days of the notification of the occurrence of the event. Expected SAEs, even 
unexpected fatal SAEs, considered by the PI to be not related to the study, will be 
reported to the FDA in the Annual Review Report along with non-serious AEs. All FDA 
correspondence and reporting will be conducted through the St. Jude Office of 
Regulatory Affairs. 
 
Copies of all correspondence to the St. Jude IRB, including SAE reports, are provided to 
the St. Jude Regulatory Affairs office by the St. Jude study team. FDA-related 
correspondence and reporting will be conducted through the Regulatory Affairs office. 
 
13.4 
Recording Adverse Events and Serious Adverse Events 
 
Adverse events (AEs) will be evaluated and documented by the clinical staff and 
investigators throughout inpatient hospitalizations and each outpatient visit. CRAs are 
responsible for reviewing documentation related to AEs and entering directly into CRIS 
protocol-specific database for all adverse events grade 3 or higher. Peripheral neuropathy 
will be captured if Grade 2 or higher. The data to be recorded are 1) the event description, 
2) the NCI CTCAE v4.0 code and grade, 3) the onset date, 4) the resolution date (or 
ongoing if it has not resolved at time of off study), 4) action taken for event, 5) patient 
outcome 6) relationship of AE to protocol treatment/interventions, 7) if AE was expected 
or unexpected, and 8) comments, if applicable. AEs that are classified as serious, 
unexpected, and at least possibly related will be notated as such in the database as 
“SAEs”. These events will be reported expeditiously to the St. Jude IRB within the 
timeframes as described above. 
 
Cumulative summary of Grade 2 clinically relevant events and all Grades 3-5 events will 
be reported as part of the progress reports to IRB at the time of continuing review. 
Specific data entry instructions for AEs and other protocol-related data will be 
documented in protocol-specific data entry guidelines, which will be developed and 
maintained by study team and clinical research informatics. 
 
Patients with abnormal blood counts due to bone marrow involvement by disease (i.e. all 
leukemia patients and lymphoma patients with bone marrow involvement) will be 
considered non-evaluable for hematological toxicities. 
 
The study team will meet regularly to discuss AEs (and other study progress as required 
by institutional DSMP). The PI will review Adverse Event reports generated from the 
research database, and corrections will be made if applicable. Once the information is 
final the PI will sign and date reports, to acknowledge his/her review and approval of the 
AE as entered in the research database. 
 

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13.5 
Process for Reporting Adverse Events from and to Collaborating Sites 
 
Adverse events from collaborating sites will also be reviewed by the PI and discussed in 
study team meetings as described above. SAE reports from collaborating sites for AEs 
that are serious, unexpected, and at least possibly related to protocol treatment or 
interventions will be reported to site IRB and the St. Jude IRB within the reporting 
requirements described above. The PI will determine if this is an event that will need to 
be reported expeditiously to all participating sites, considering the following criteria: 
 
• Is the AE serious, unexpected, and related or possibly related to participation in 
the research? 
• Is the AE expected, but occurring at a significantly higher frequency or severity 
than expected? 
• Is this an AE that is unexpected (regardless of severity that may alter the IRB’s 
analysis of the risk versus potential benefit of the research and, as a result, 
warrant consideration of substantive changes in the research protocol or informed 
consent process/document? 
 
With the submission of the “Reportable Event” in St. Jude TRACKS application, the PI 
will indicate if all sites should be notified to report to their IRBs, and if the protocol 
and/or consent should be amended (consent will be amended if event is information that 
should be communicated to currently enrolled subjects). Generally, only events that 
warrant an amendment to the protocol and/or consent will be reported expeditiously to all 
sites. However, any event may be reported expeditiously to all sites at the discretion of 
the PI. A cumulative summary of Grade 2-5 AEs and expected/unrelated deaths that 
occur more than 30 days after protocol treatment will be reported to all sites with study 
progress report at the time of continuing review.  
 
For collaborating sites: Serious AND unexpected events are to be reported to the St. Jude 
PI (Dr. Sima Jeha) within 48-72 hours via fax or email.   
 
Unexpected deaths must be reported to the St. Jude PI at 
 or 
phone call to Dr. Jeha within 24 hours of the event. A written report must follow. The study 
team should be copied on all correspondence regarding the event.  
 
 
 
 
 
 
 
 
 
  

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14.0 
DATA COLLECTION, MONITORING AND CONFIDENTIALITY 
 
14.1 
Data Collection  
 
Electronic case report forms (e-CRFs) will be completed by the clinical trials staff from 
the Cancer Center Comprehensive Center, Hematological Malignancies Program. Data 
will be entered from record directly into a secure CRIS database, developed and 
maintained by St. Jude Clinical Research Informatics.  
 
Data Management will be supervised by the Director of Clinical Trials Management, and 
Manager of Clinical Research Operations for the Hematological Malignancies Program, 
working with Dr. Jeha or her designee. All protocol-specific data and all grade 2-5 
adverse events will be recorded by the clinical research associates into the CRIS 
database, ideally within 2-4 weeks of completion of study phase. All questions will be 
directed to the attending physician and/or PI and reviewed at regularly-scheduled 
working meetings. The attending physicians (or their designees) are responsible for 
keeping up-to-date roadmaps in the patient’s primary SJCRH medical chart. 
 
Regular (at least monthly) summaries of toxicity and protocol events will be generated 
for the PI and the department of Biostatistics to review. 
 
14.2 
Study Monitoring 
 
Monitoring of this protocol is considered to be in the high-risk 3 category (HR-3). The 
study specific Monitoring Plan is a separate document from this protocol. The study team 
will meet at appropriate intervals to review case histories or quality summaries on 
participants. Highlights of the protocol monitoring plan are below: 
 
The Clinical Research Monitor will assess protocol and regulatory compliance as well as 
the accuracy and completeness of all data points for the first two participants then 15% of 
study enrollees every six months. Accrual will be tracked continuously for studies that 
have strata. All SAE reports will be monitored for type, grade, attribution, duration, 
timeliness and appropriateness on all study participants semi-annually. 
 
The monitor will also verify 100% of all data points on the first two participants and on 
15% of cases thereafter. Protocol compliance monitoring will include participant status, 
eligibility, the informed consent process, demographics, staging, study objectives, 
subgroup assignment, treatments, evaluations, responses, participant protocol status, off-
study, and off-therapy criteria. The Monitor will generate a formal report which is shared 
with the Principal Investigator (PI), study team and the Internal Monitoring Committee 
(IMC). Monitoring may be conducted more frequently if deemed necessary by 
administration, the Institutional Review Board (IRB), or the IMC. 
 
Continuing reviews by the IRB and CT-SRC will occur at least annually. In addition, 
SAE reports in TRACKS (Total Research and Knowledge System) are reviewed in a 
timely manner by the IRB/ OHSP. 
 

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Source document verification of eligibility for all SJCRH cases will be performed within 
two weeks of completion of enrollment. This will include verification of appropriate 
documentation of consent. Monitoring of timeliness of serious adverse event reporting 
will be done as events are reported in TRACKS.  
 
St. Jude affiliates and domestic collaborating study sites will be monitored on-site by a 
representative of St. Jude at intervals specified in the Data and Safety Monitoring Plan. 
 
14.3 
Confidentiality 
 
Study numbers will be used in place of an identifier such as a medical record number.  
No research participant names will be recorded on the data collection forms. The list 
containing the study number and the medical record number will be maintained in a 
locked file and will be destroyed after all data have been analyzed.  
 
The medical records of study participants may be reviewed by the St. Jude IRB, FDA, 
and clinical research monitors. 
 
15.0 
STATISTICAL CONSIDERATIONS  
 
15.1 
Analysis of Primary Objective 
 
Primary objective: To estimate the complete remission (CR) rate for patients with T-cell 
lymphoblastic leukemia or lymphoma in first relapse. 
 
CR is assessed at the end of each remission re-induction Block. CR is defined as CR or 
CRM in section 9.1 for ALL, and as CR in section 9.2 for lymphoma. All patients who 
start re-induction Block A therapy are considered evaluable. 
 
Definition of Success and Failure: The same as in our previous practice (ALL-R16 and 
ALL-R17), CR is assessed at the end of each block; a patient in CR either goes to 
transplant if a matched donor is available and is consequently off the chemotherapy, or 
put on maintenance with the subsequent chemotherapy block while waiting for a donor. 
Therefore, any patient who at any time point achieves CR and goes to transplant is 
considered as a success; or any patient who successfully reaches the end of block C 
and achieves/remains CR is considered a success; all other cases are considered as 
failure. For example, a patient who achieves CR at the end of block A but put on block B 
while waiting for a donor, remains in CR, and then goes to transplant, is a success. An 
unlikely (and unfortunate) case of failure is that the patient achieves CR at the end of 
block A, but put on block B while waiting for a donor, and develops  severe toxicities 
while on block B that the patient has be taken off treatment. A patient who could not find 
a matched donor but successfully reaches the end of block C with CR is a success. 
 
Sample size: Logistically it is feasible to enroll 24 relapsed T cell ALL patients in 6 
years. Thus the total sample size is set at 24. 
 

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Statistical Analysis: Analysis will be done by point and interval estimation of the Success 
(as defined above) rate/probability using the sample proportion and the Blyth-Casella 
exact 95% confidence interval. 
 
Secondarily a comparison with historical Success (CR) rate from ALL-R16 and ALL-
R17 (Table 1) will be done using Fisher’s exact test. 
 
Table 1: Induction response in R16 and R17 T-cell patients 
  
R16 (n = 9 ) 
R17 ( n= 7) 
Total 
CR 
7 (77.8%) 
5 (71.4%) 
12 (75.0%) 
No CR 
2 (22.2%) 
2 (28.6%) 
4 (25.0%) 
Total 
9 
7 
16 
 
Historical “control” is formed by combining ALL-R16 and ALL-R17, to give a sample 
(Sample1) of size n1=16 and number of success (CR) 12. 
 
To safeguard against the possibility that the novel re-induction therapy is much inferior to 
the prior approaches, the following group-sequential design with interim analyses 
monitoring for early evidence of inferior re-induction will be applied. The historical data 
give an estimate of the CR probability 12/16=0.75 and the Blyth-Casella exact 95% 
confidence interval [0.5, 0.91]. Therefore we deem the novel re-induction therapy as 
unacceptable if there is evidence that the CR probability is less than 0.5. The following 
ad-hoc stopping rule is generated based on an analysis using the Binomial distribution, 
and has power of 0.79, 0.66, and 0.53 to stop the trial if the true Success rate of the novel 
treatment is 0.35, 0.4, and 0.45 respectively. 
 
Table 2: Interim Analysis Plan  
Interim Sample Size 
Stop the trial if the number 
Failure is ≥ 
12 
7 
24 
13 
 
Monitoring of severe toxicities: Severe toxicities rendering patients’ death or being taken 
off treatment will be monitored in a group-sequential manner the same as the interim 
analysis for CR, namely: 
 
Table 3: Monitoring Plan for Severe Toxicities 
Interim Sample SStop the trial if the number of  
SAE is ≥ 
12 
7 
24 
13 
 

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15.2 
Analysis of Secondary Objectives 
 
To determine minimal residual disease (MRD) levels present at end of each block of 
therapy in patients with leukemia 
 
Minimal residual disease (MRD) will be studies at each cycle of therapy. MRD is 
considered as positive (i.e., prevalent) if its level is ≥0.01% for ALL. The prevalence of 
MRD at end of each cycle is defined as proportion of MRD positives; we will estimate 
these proportions with point and interval estimates.  
 
To characterize the toxicities of VSLI when used in combination with chemotherapy. 
 
Proportions (probabilities) of relevant toxicities will be estimated with point and interval 
estimates. 
 
15.3 
Analysis of Exploratory Objectives 
 
To identify molecular determinants and biomarkers of histone deacetylase (HDAC) 
inhibitor response 
 
Global differential gene expression (and possibly genomic) profiling will be performed to 
identify genes differentially expressed and methylated (by H3K27 and H3K9 Acetylation 
markers) in xenograft cells treated with HDAC inhibitors vs. those untreated. Levels of 
gene expression will be generated by total-strand RNA-seq and measured by FPKM (or 
possibly the latest technology available at the time). Gene differential expression and 
methylation between treated and untreated cells will be detected by general linear models 
(upon proper transformation) and linear rank procedures such as the Wilcoxon test. 
 
To study the pharmacokinetics of panobinostat  
 
Panobinostat PK parameters (e.g. Cmax, Tmax, AUC, half-life, and clearance) will be 
estimated using population-based modeling techniques. 
 
To establish xenografts of relapsed T-cell lymphoblastic leukemia for downstream studies 
of cytotoxicity and therapy resistance 
 
This is a resource objective that does not require Statistical considerations. 
 
To perform genomic studies of leukemic cells at relapse, diagnosis and MRD (where 
available) to investigate clonal evolution and identify targets for therapeutic intervention 
 
This is a fast-evolving field capitalizing on the maturation of the whole-genome 
sequencing technologies. We will utilize the latest and most effective approach to 
modeling clonal evolution at the time of analysis.  
 

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To validate new markers and methods for MRD detection 
 
Comparisons to the current gold standard by association (e.g., correlation) and agreement 
statistics (such as the kappa coefficient) will be applied to assess the new markers’ ability 
in MRD detection. 
 
To genotype natural killer (NK) cell receptors and measure their expressions at diagnosis 
and before Block C, and to associate these features with treatment outcome 
 
Genotype-outcome and gene expression-outcome associations will be analyzed using 
proper statistical procedures such as the log-rank test and Cox regression modeling. 
 
To perform a comprehensive analysis of the intestinal microflora in patients with 
relapsed hematologic malignancies prior to and subsequent to each block of intensive 
salvage chemotherapy using next generation sequencing technologies as an exploratory 
approach  
 
Summary statistics (e.g. percentages) describing the intestinal microflora will be computed. 
 
To describe the frequency and severity of gastrointestinal illnesses during 3 blocks of 
intensive salvage chemotherapy in patients who did and those who did not have changes 
in intestinal microbiota 
 
Summary statistics describing the frequency and severity of gastrointestinal illnesses will 
be computed. Comparisons of gastrointestinal illnesses between patients who did and 
those who did not have changes in intestinal microbiota will be done by two-sample 
Binomial test or logistic regression.  
 
15.4 
Accrual and Study Duration 
 
T-cell ALL or lymphoma in first relapse: n=24 evaluable 
ALL or Lymphoblastic Lymphoma in second or third relapse: n=10 evaluable.   
Total number or participants:  n=40 
Study duration: 6 years 
 
16.0  OBTAINING INFORMED CONSENT 
 
16.1 
Consent Prior to Research Interventions  
 
Initially, informed consent will be sought for the institutional banking protocol (TBANK 
research study), PGEN5, and for other procedures as necessary for standard medical care.  
During the screening process for eligibility, informed consent for SCREEN protocol OR 
for TSALV is required before any research tests are performed.   
 
16.2 
Consent at Enrollment 
 
The process of informed consent for TSALV will follow institutional policy. The 
informed consent process is an ongoing one that begins at the time of diagnosis and ends 

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after the completion of therapy. Informed consent should be obtained by the attending 
physician or his/her designee, in the presence of at least one non-physician witness.  
Initially, informed consent will be sought for the institutional banking protocol (research 
study), blood transfusion and other procedures as necessary. After the diagnosis of 
relapsed or refractory leukemia/lymphoma is established, we will invite the patient to 
participate in the TSALV protocol.   
 
Throughout the entire treatment period, participants and their parents receive constant 
education from health professionals at SJCRH and collaborating sites, and are 
encouraged to ask questions regarding alternatives and therapy. All families have ready 
access to chaplains, psychologists, social workers, and the St. Jude ombudsperson for 
support, in addition to that provided by the primary physician and other clinicians 
involved in their care. We will also obtain verbal assent from children 7 to 14 years old 
and written assent for all participants >14 years of age. 
 
16.3 
Consent at Age of Majority 
 
Participants who reach the age of majority while on study will be re-consented for 
continued participation on TSALV at the time of their next clinic visit after turning 18 
year according to Cancer Center and institutional policy. 
 
16.4 
Consent When English is Not the Primary Language 
 
When English is not the participant, parent, or legally authorized representative’s primary 
language, the Social Work department will determine the need for an interpreter. This 
information will be documented in the participant’s medical record. Either a certified 
interpreter or the telephone interpreter’s service will be used to translate the consent 
information. The process for obtaining an interpreter and for the appropriate use of an 
interpreter is outlined on the Interpreter Services, OHSP, and CPDMO websites. 

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17.0 
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Oncol 31:224-5, 2009. 
35. Kager L, Cheok M, Yang W, et al: Folate pathway gene expression differs in subtypes of 
acute lymphoblastic leukemia and influences methotrexate pharmacodynamics. J Clin Invest 
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36. Galpin AJ, Schuetz JD, Masson E, et al: Differences in folylpolyglutamate synthetase and 
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lymphoblasts: mechanisms for lineage differences in methotrexate polyglutamylation and 
cytotoxicity. Mol Pharmacol 52:155-63, 1997. 
37. Synold TW, Relling MV, Boyett JM, et al: Blast cell methotrexate-polyglutamate 
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39. Commander LA, Seif AE, Insogna IG, et al: Salvage therapy with nelarabine, etoposide, and 
cyclophosphamide in relapsed/refractory paediatric T-cell lymphoblastic leukaemia and 
lymphoma. Br J Haematol 150:345-51, 2010. 
40. Campana D: Minimal residual disease in acute lymphoblastic leukemia. Hematology Am Soc 
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41. Coustan-Smith E, Gajjar A, Hijiya N, et al: Clinical significance of minimal residual disease 
in childhood acute lymphoblastic leukemia after first relapse. Leukemia 18:499-504, 2004 
42. Khan O, Fotheringham S, Wood V, et al: HR23B is a biomarker for tumor sensitivity to 
HDAC inhibitor-based therapy. Proc Natl Acad Sci U S A 107:6532-7, 2010. 
43. Fantin VR, Loboda A, Paweletz CP, et al: Constitutive activation of signal transducers and 
activators of transcription predicts vorinostat resistance in cutaneous T-cell lymphoma. 
Cancer Res 68:3785-94, 2008. 
44. Chung EJ, Lee S, Sausville EA, et al: Histone deacetylase inhibitor pharmacodynamic 
analysis by multiparameter flow cytometry. Ann Clin Lab Sci 35:397-406, 2005. 
45. Giles F, Fischer T, Cortes J, et al: A phase I study of intravenous LBH589, a novel cinnamic 
hydroxamic acid analogue histone deacetylase inhibitor, in patients with refractory 
hematologic malignancies. Clin Cancer Res 12:4628-35, 2006. 
46. Rigby L, Muscat A, Ashley D, et al: Methods for the analysis of histone H3 and H4 
acetylation in blood. Epigenetics 7:875-82, 2012. 
47. Notta F, Mullighan CG, Wang JC, et al: Evolution of human BCR-ABL1 lymphoblastic 
leukaemia-initiating cells. Nature 469:362-7, 2011 
48. Clappier E, Gerby B, Sigaux F, et al: Clonal selection in xenografted human T cell acute 
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49. Anderson K, Lutz C, van Delft FW, et al: Genetic variegation of clonal architecture and 
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52. Tzoneva G, Perez-Garcia A, Carpenter Z, et al: Activating mutations in the NT5C2 
nucleotidase gene drive chemotherapy resistance in relapsed ALL. Nat Med 19:368-71, 2013. 
53. Meyer JA, Wang J, Hogan LE, et al: Relapse-specific mutations in NT5C2 in childhood 
acute lymphoblastic leukemia. Nat Genet 45:290-4, 2013. 
54. Imai K, Matsuyama S, Miyake S, et al: Natural cytotoxic activity of peripheral-blood 
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55. Costello RT, Sivori S, Marcenaro E, et al: Defective expression and function of natural killer 
cell-triggering receptors in patients with acute myeloid leukemia. Blood 99:3661-7, 2002 
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Amendment 1.0, dated: 12-14-2015 
 
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APPENDIX I: KARNOFSKY AND LANSKY 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 by 
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 self-care but 
unable to carry out any 
work activities; up and 
about more than 50% of 
waking hours 
60 
Requires occasional 
assistance, but is able to 
care for most of his/her 
needs 
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 
self-care; totally 
confined to bed or chair 
20 
Very sick, hospitalization 
indicated.  Death not 
imminent 
20 
Often sleeping; play 
entirely limited to very 
passive activities 
10 
Moribund, fatal processes 
progressing rapidly 
10 
No play; does not get out 
of bed 
 

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Amendment 1.0, dated: 12-14-2015 
 
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APPENDIX II:  TESTS PERFORMED FOR ROUTINE CARE AND FOR RESEARCH 
 
Routine care  
 
History & physical (including vital signs, height, weight, BSA) 
CBC, differential, platelets 
Chemistries 
Serum Electrolytes 
Pregnancy testing 
Infectious disease screening 
Echocardiogram/MUGA 
EKG 
Lumbar puncture for IT chemotherapy, CSF cell count and differential 
Bone marrow procedure for morphology, response assessment, MRD 
Peripheral blood for MRD, if done 
Commercially available agents 
 
Research 
 
Investigational agents – panobinostat and liposomal vincristine (VSLI) 
Pharmacokinetic studies 
Pharmacodynamic studies 
NK cell studies 
Genomic studies 
Intestinal microbiome studies 
Neuropathy studies 
Research MRD studies 
 
 

TSALV 
 
 
Amendment 1.0, dated: 12-14-2015 
 
IRB Approval date: 02-01-2016 
Protocol document dated: 01-28-2016 
APPENDIX III:  MEDICATIONS TO AVOID OR BE USED WITH CAUTION WITH 
PANOBINOSTAT 
 
I. Medications that have a risk of causing Torsade’s de pointes ventricular arrhythmia 
should be avoided. 
 
Patients who are currently receiving treatment of the medications in Table 1-1 and cannot either 
discontinue from this treatment or switch to an alternative medication prior to enrollment in a 
panobinostat clinical study, will be excluded from the study. Patients may not begin panobinostat 
treatment with any of the medications listed in Table 1-1 unless this is discussed with the PI and 
Novartis. 
 
NOTE: It is of great importance to avoid combining drugs listed below in Table 1-1 and Table 2-1 
(CYP3A inhibitors) especially in the presence of electrolyte abnormalities, notably decreased 
potassium or magnesium levels commonly associated with diuretic usage. 
 
In generally, medications listed in Table 1-1 should be avoided while medications listed in 
Tables 2-1 and 3-1 are to be used with caution when co-administered with panobinostat. Please 
select the most stringent recommendation for concomitant medications (i.e., to be avoided), 
which are common among the tables (e.g., erythromycin, clarithromycin) 
 
Table 0-1  Medications that have a risk of causing Torsade’s de pointes to be avoided during 
treatment with panobinostat 
All Class IA anti-arrythmics 
• 
quinidine 
• 
procainamide 
• disopyramide 
• any other class IA antiarrhythmic drug 
All Class III anti-arrythmics 
• 
amiodarone 
• 
sotalol 
• 
bretylium 
• disopyramide 
• dofetilide 
• ibutilide 
• any other class III antiarrhythmic drug 
Antibiotics 
Macrolide antibiotics* 
• erythromycin 
• clarithromycin 
• 
telithromycin 
• 
Quinolone antibiotics* 
• 
sparfloxacin 
Antipsychotics 
• thioridazine 
• mesoridazine 
• chlorpromazine 
• pimozide 
Anti-malarials 
• halofantrine 
• chloroquine 
 

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Amendment 1.0, dated: 12-14-2015 
 
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Protocol document dated: 01-28-2016 
Medications that have a risk of causing Torsade’s de pointes to be avoided during treatment with 
panobinostat 
 
Miscellaneous drugs 
• arsenic trioxide 
• astemizole 
• bepridil 
• domperidone 
• levomethadyl 
• methadone 
• pentamidine 
• droperidol 
*Note: azithromycin, ciprofloxacin, levofloxacin, pefloxacin, ofloxacin, tosufloxacin, 
difloxacin, temafloxacin, fleroxacin, acrosoxacin, nalidixic acid and enoxacin are allowed. 
 
This is not a comprehensive list of medications which may prolong the QT interval or have a risk 
of causing Torsade’s de pointes. This list of medications was developed in collaboration with an 
external cardiology consultant, and represents those medications which are deemed to have an 
unacceptable risk of co-administration with panobinostat. 
 
The following website may be referenced as a supplemental guide for drugs which have been 
associated with Torsade’s de pointes or prolonging the QT interval but at this point lack 
substantial evidence for causing Torsade’s de pointes: 
 
http://www.qtdrugs.org/medical-pros/drug-lists/drug-lists.htm#. 
 
Medications listed on the website which do not appear in Table 1-1 above may be used with 
caution at the discretion of the investigators.  
 
The serotonin (5HT3) antagonists, often used as anti-emetics, such as ondansetron dolasetron, 
(also are known CYP2D6 substrates, see Table 3-1), or granisetron have been associated with 
Torsade’s de points and QT prolongation but have not been shown to cause Torsade’s de pointes. 
Therefore, 5HT3 antagonists are not per se prohibited but close monitoring for signs and 
symptoms of QT prolongation is recommended. Caution is to be exercised when using these or 
other agents that may prolong QT intervals in combination with panobinostat.  
 
II. Medications that are known strong CyP3A4/5 Inhibitors to be used with caution 
 
Medications that are known strong CYP3A4/5 inhibitors should be used with caution.  
Panobinostat is a substrate of CYP3A4 with minor involvement of CYP2D6, and CYP2C19 in in 
vitro evaluation of its metabolism. Thus, a clinical drug-drug interaction study was conducted 
using ketoconazole, a strong CYP3A inhibitor, in combination with panobinostat in Novartis 
study CLBH589B2110.  
 
Multiple ketoconazole doses at 400 mg increased Cmax and AUC of panobinostat by 1.6- and 1.8-
fold, respectively, but with no change in Tmax or half-lives in 14 cancer patients. The less than 2-
fold increase in panobinostat AUC upon co-administration of a strong CYP3A inhibitor is 
considered a weak drug inhibition and not clinically relevant, as panobinostat doses at least 2-
fold greater than the evaluated 20 mg dose (i.e., 40 mg and 60 mg) have been safely administered 
in patients. Thus, co-administration of panobinostat with a moderate or weak CYP3A inhibitor is 
allowed. However, clinical monitoring of signs and symptoms of panobinostat treatment related 
adverse events is recommended when long-term (≥ 1 week) concomitant administration of any 

TSALV 
 
 
Amendment 1.0, dated: 12-14-2015 
 
IRB Approval date: 02-01-2016 
Protocol document dated: 01-28-2016 
strong CYP3A inhibitors and panobinostat is medically indicated or investigated in a clinical 
study.  
 
Patients with impaired liver function (as defined by NCI CTEP criteria)1 are recommended not to 
receive panobinostat concomitantly with strong CYP3A inhibitors because potential interaction 
has not been established in this population. 
 
Table 2-1: Medications that are known strong CYP3A4/5 inhibitors to be used with caution 
Macrolide antibiotics* 
• clarithromycin 
• telithromycin 
• troleandomycin  
• erythromycin 
Antifungals (azoles)* 
• ketoconazole 
• itraconazole  
• fluconazole  
Antidepressants 
• nefazodone 
Calcium channel blockers* 
• diltiazem 
• verapamil 
HIV protease inhibitors 
• indinavir 
• nelfinavir 
• ritonavir 
• saquinavir  
Miscellaneous drugs or products 
• aprepitant 
• grapefruit product or juice 
*azithromycin, voriconazole, regular orange juice and dihydropyridine calcium channel 
blockers (e.g. amlodipine, felodipine, nicardipine and nifedipine) are allowed. 
 
This is not a comprehensive list of medications which may inhibit CYP3A4/5. Additional 
updated versions with moderate and weak CYP3A inhibitors, which are meant to be used as a 
guide, may be found at the following website: http://medicine.iupui.edu/clinpharm/DDIs 
 
III. Medications that are known CYP2D6 substrates to be used with caution 
 
Panobinostat was also shown to be a CYP2D6 inhibitor (Ki 0.17 µM) in vitro. Thus, clinical 
drug-drug interaction study with panobinostat as CYP2D6 inhibitor and dextromethorphan as 
CYP2D6 substrate was recently conducted in Novartis study CLBH589B2109. 
 
Multiple panobinostat doses increased Cmax and AUC of dextromethorphan by a mean of 1.8- 
and 1.6-fold respectively, but with no change in Tmax in 17 cancer patients. An approximately 2-
fold increase in dextromethorphan AUC upon co-administration with panobinostat indicated that 
in vivo CYP2D6 inhibition of panobinostat is weak.  

TSALV 
 
 
Amendment 1.0, dated: 12-14-2015 
 
IRB Approval date: 02-01-2016 
Protocol document dated: 01-28-2016 
As the study was conducted using a sensitive CYP2D6 substrate which resulted in a weak 
inhibition, drugs with a large therapeutic index such as anti-emetics, anti-hypertensives, and anti-
depressants are generally safe to be co-administered with panobinostat.  
 
Patients should be carefully monitored for potential signs and symptoms of toxicity and may 
require dose titration or dose reduction of a sensitive CYP2D6 substrate which also have a 
narrow therapeutic window (e.g., the ratio of toxicity exposure is ≤ 2-fold higher than the 
efficacious or therapeutic exposure).  
 
Table 3-1: Medications that are known CYP2D6 substrates to be used with caution 
Beta blockers (listed below): 
Antipsychotics (listed below): 
• carvedilol 
• metoprolol 
• propafenone 
• timolol 
• Antidepressants (listed below): 
• amitriptyline 
• chlormipramine 
• desipramine 
• imipramine 
• fluoxetine 
• paroxetine 
• venlafaxine 
• bupropion 
• duloxetine  
• Antiemetics (listed below): 
• dolasetron 
• ondansetron 
• metoclopramide 
• aripiprazole 
• haloperidol 
• perphenazine 
• risperidone 
• thioridazine 
• zuclopenthixol 
• amphetamine  
• alprenolol 
• bufuralol 
• chloropheniramine 
• Anti-arrythmics (listed below): 
• quinidine 
• lidocaine 
• mexiletine 
• propafenone 
• Others: 
• oxycodone 
• codeine 
• hydrocodone 
• terbinafine 
• promethazine 
• tamoxifen 
• tramadol 
This is not a comprehensive list of CYP2D6 substrates. Additional updated versions of this list, 
which are meant to be used as a guide, may be found at the following website: 
http://medicine.iupui.edu/clinpharm/DDIs  
 
Synold TW, Takimoto CH, Doroshow JH, Gandara D, Mani S, Remick SC, Mulkerin DL, Hamilton A, Sharma S, 
Ramanathan RK, Lenz HJ, Graham M, Longmate J, Kaufman BM, Ivy SP. Dose-Escalating and Pharmacological 
Study of Oxaliplatin in Adult Cancer Patients with Impaired Hepatic Function: A National Cancer Institute Organ 
Dysfunction Working Group Study, Clin Cancer Res. 2007 13; 3660  
 

TSALV 
 
 
Amendment 1.0, dated: 12-14-2015 
 
IRB Approval date: 02-01-2016 
Protocol document dated: 01-28-2016 
PEDIATRIC - MODIFIED TOTAL NEUROPATHY SCALE 
 
DATE OF EXAM:       
PATIENT NAME:       
MRN:        
 
Evaluation time point: 
 
  Block A Day 6 
 
  Prior to Block B  
  Prior to Block C 
  Block A Day 15 
 
 
 
 
  Completion of Block C 
 
1. Sensory Symptoms:       (record worst score for the three sensations) 
 
“Do you have any parts of your body that are tingly, numb (can hardly feel), or hurt?”  
 
      Tingly       Numb        Hurts    (record number for each) 
 
If yes, “Where you have those feelings?” 
 
 
 
0 
None 
1 
Symptoms limited to fingers or toes 
2 
Symptoms extend to ankles or wrists 
3 
Symptoms extend to knee or elbow 
4 
Symptoms above knee or elbow 
 
 
2. Functional Symptoms:        (record worst score of the three questions) 
 
“Do you have trouble buttoning shirts or tying shoes (zipping zippers)?”        
“Do you have trouble walking such as tripping frequently?”        
“Do you have trouble going up or down stairs?”       
          
  If yes to any, “Is it….. (read choices)” and record after each question: 
 
0 
Not difficult 
1 
A little difficult 
2 
Somewhat difficulty 
3 
I need help 
4 
I can’t do that at all 
 
3. Autonomic Symptoms:       (record worst score of the three questions) 
 
 
“Do you feel dizzy or light-headed when you get up out of bed?”       
 
“Do your hands or feet feel hotter or colder than normal?”       
 
0 
Never 
1 
A little bit 
2 
Sometimes 
3 
Very much 
4 
Almost always 

TSALV 
 
 
Amendment 1.0, dated: 12-14-2015 
 
IRB Approval date: 02-01-2016 
Protocol document dated: 01-28-2016 
DATE OF EXAM:       
PATIENT NAME:       
MRN:       
 
4. Clinical Testing: 
 
Light Touch Sensation:        
 
 
 
 
0 
Normal 
1 
Reduced in fingers/toes 
2 
Reduced up to   
         wrist/ankle 
3 
Reduced up to elbow/knee 
4 
Reduce to above elbow/knee 
 
 
Pin Sensibility:       
 
0 
Normal 
1 
Reduced in fingers/toes 
2 
Reduced up to wrist/ankle 
3 
Reduced up to elbow/knee 
4 
Reduce to above elbow/knee 
 
Vibration Sensibility:       (worst score)  
 
0 
Normal 
1 
Reduced in fingers/toes   
2 
Reduced up to wrist/ankle 
3 
Reduced up to elbow/knee    
4 
Reduce to above elbow/knee   
 
 
 
 
Strength:       (worst score) 
   (MRC Score R / L)  
 
 
 
 
 
    
MRC level:  
Great toe      /      
 
Ankle DF      /        
 
Finger abd.      /       
 
Wrist ext.       /        
 
0 
Normal 
1 
Mild weakness (MRC 4) 
2 
Moderate weakness (MRC 3) 
3 
Severe weakness (MRC 2) 
4 
Paralysis (MRC 1-0) 
Semmes 
Semmes 
Toes        R 
 
Finger  R 
 
                L 
 
             L 
 
Med Mal R 
 
Wrist    R 
 
                L 
 
             L 
 
Knee        R 
 
Elb       R 
 
                L 
 
             L 
 
Bioesth 
Bioesth 
Toes        R 
/ 
Finger  R 
/ 
                L 
/ 
             L 
/ 
Med Mal R 
/ 
Wrist    R 
/ 
                L 
/ 
             L 
/ 
Knee        R 
/ 
Elb       R 
/ 
                L 
/ 
             L 
/ 

TSALV 
 
 
Amendment 1.0, dated: 12-14-2015 
 
IRB Approval date: 02-01-2016 
Protocol document dated: 01-28-2016 
DATE OF EXAM:       
PATIENT NAME:       
MRN:       
 
 
DTR:       (Achilles, patellar) 
 
 
 
 
 
0 
Normal 
1 
Ankle reflex reduced  (Achilles +1) 
2 
Ankle reflex absent (Achilles 0, others +2) 
3 
Ankle reflex absent, others reduced (Achilles 0, others +1) 
4 
All reflexes absent (all 0) 
 
 
TOTAL SCORE:      / 32 
 

TSALV 
 
 
Amendment 1.0, dated: 12-14-2015 
 
IRB Approval date: 02-01-2016 
Protocol document dated: 01-28-2016 
DATE OF EXAM:       
PATIENT NAME:       
MRN:       
 
 
TSALV SIX MINUTE WALK CRF 
 
Time 
Heart rate 
Distance (meters) 
Rating of Perceived 
exertion (6-20) 
Rest 
 
 
 
1 minute 
 
 
 
2 minutes 
 
 
 
3 minutes 
 
 
 
4 minutes 
 
 
 
5 minutes 
 
 
 
6 minutes 
 
 
 
1 minute recovery 
 
 
 
2 minutes recovery