Epigenetic Reprogramming in Relapse AML: A Phase 1 Study of Decitabine and Vorinostat Followed by Fludarabine, Cytarabine and G-CSF (FLAG) in Children and Young Adults With Relapsed/Refractory AML
Phase: PHASE1
Conditions: Acute Myelogenous Leukemia
Sponsor: Therapeutic Advances in Childhood Leukemia Consortium

TACL Protocol: T2016-003 
 
Orginal Version Date: 1-20-2017 
 Activated: 07-21-2017 
 
Amendment 1 version date: 09-06-2017 
 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
Amendment 4 version date: 07-01-2019 
 
 
T2016-003 Protocol version 1-20-2017  
 
CONFIDENTIAL 
Amendment 1 version date: 09-06-2017 
 
TACL Internal Distribution Only 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 03-12-2018 
Amendment 4 version date: 07-01-2019 
 
 
 
 
 
 
 
Epigenetic Reprogramming Study 
 
Epigenetic Reprogramming in Relapse AML:  A Phase 1 Study of Decitabine and Vorinostat Followed by 
Fludarabine, Cytarabine and G-CSF (FLAG) in Children and Young Adults with Relapsed/Refractory AML 
 
Protocol Chairperson 
                    Michael J. Burke, MD 
 
Protocol Vice-Chair 
Deepa Bhojwani, MD 
 
Protocol Biology Chair 
Sridhar Rao, MD, PhD 
 
TACL Member Institutions 
 
All Children’s Hospital 
Nationwide Children’s Hospital 
British Columbia Children’s Hospital 
National Cancer Institute, Pediatric Oncology Branch 
Children's Healthcare of Atlanta at Egleston 
Oregon Health & Science University 
Children’s Hospital and Clinics of Minnesota 
Primary Children’s Hospital 
Children’s Hospital Los Angeles 
Rainbow Babies & Children’s Hospital 
Children’s Hospital New York-Presbyterian 
Royal Children’s Hospital, Melbourne 
Children’s Hospital Orange County 
Sainte-Justine University Hospital Center  
Children’s Hospital of Philadelphia 
Seattle Children’s Hospital 
Children’s National Medical Center 
Sidney Kimmel Cancer Center at Johns Hopkins 
Cincinnati Children’s Hospital 
St. Jude Children’s Research Hospital Memphis 
Cook Children’s Medical Center 
Sydney Children’s Hospital 
CS Mott Children’s Hospital, Ann Arbor 
Texas Children’s Cancer Center, Baylor 
Dana-Farber Cancer Institute 
The Children’s Hospital at Westmead 
Hospital for Sick Children, Toronto 
The Children’s Hospital, University of Colorado  
Levine Children's Hospital  
UCSF School of Medicine 
Lurie Children’s Hospital of Chicago 
University of Miami 
Medical College of Wisconsin 
University of Texas Southwestern Medical Center 
 
TACL OPERATIONS CENTER 
CHLA, 4650 Sunset Blvd, MS-54, Los Angeles, CA 90027 
Phone: (323) 361-8725 or (323) 361-3022 Fax: (877) 904-2166 
https://tacl.chla.usc.edu  
Protocol Disclaimer 
TACL protocols and their content are for research purposes only and should not be copied, 
redistributed or used for any other purpose. The procedures in this protocol are intended only for use at 
TACL member institutions under the direction of TACL physicians. The most current version of the 
protocol should be accessed at https://tacl.chla.usc.edu 
TACL 
Therapeutic Advances in 
Childhood Leukemia and Lymphoma 

 
 
 
 
Original  version date: 1-20-2017  
Amendment 1 version date: 09-06-2017 
 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
Amendment 4 version date: 07-01-2019 
 
 
 
 
 
Original Protocol version 1-20-2017 
Amendment 1 version date: 09-06-2017 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
 
Amendment 4 version date: 07-01-2019 
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TABLE OF CONTENTS 
 
TABLE OF CONTENTS .............................................................................................................................................2 
STUDY COMMITTEE .................................................................................................................................................5 
1.0 
GOALS AND OBJECTIVES ..........................................................................................................................7 
1.1 
Primary Objectives .......................................................................................................................................7 
1.2 
Secondary Objectives ..................................................................................................................................7 
2.0 
BACKGROUND .............................................................................................................................................8 
2.2.5 
Study Rationale .......................................................................................................................................... 13 
3.0 
PATIENT ELIGIBILITY CRITERIA AND ENROLLMENT .......................................................................... 15 
3.1 
Patient Reservation ................................................................................................................................... 15 
3.2 
Enrollment .................................................................................................................................................. 15 
3.3 
Inclusion Eligibility Criteria ...................................................................................................................... 17 
3.4 
Exclusion Eligibility Criteria ..................................................................................................................... 19 
4.0 
TREATMENT PROGRAM ........................................................................................................................... 21 
4.1 
Course 1 and 2 ........................................................................................................................................... 21 
4.2 
Disease Evaluation During Course 1 and 2 ............................................................................................ 22 
4.3 
Dose-limiting Toxicity (DLT) ..................................................................................................................... 23 
4.4 
Dose Modifications for Toxicity ............................................................................................................... 24 
5.0 
SUPPORTIVE CARE .................................................................................................................................. 25 
5.1 
Concurrent Therapy .................................................................................................................................. 25 
5.2 
Blood Products .......................................................................................................................................... 26 
5.3 
Infection Control ........................................................................................................................................ 26 
6.0 
DRUG INFORMATION ................................................................................................................................ 28 
6.1  
Decitabine (Dacogen™) ............................................................................................................................ 28 
6.2 
Vorinostat (Zolinza®, SAHA, suberoylanilide acid) ............................................................................... 31 
6.3 
FLUDARABINE ........................................................................................................................................... 33 
6.4 
Cytarabine (Cytosine arabinoside, Ara-C, Cytosar®) ............................................................................ 39 
6.5 
Filgrastim (G-CSF, Neupogen) ................................................................................................................. 41 
7.0 
REQUIRED OBSERVATIONS/MATERIAL AND DATA TO BE ASSESSIONED ..................................... 43 
7.1 
Clinical and Laboratory Studies ............................................................................................................... 43 

 
 
 
 
Original  version date: 1-20-2017  
Amendment 1 version date: 09-06-2017 
 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
Amendment 4 version date: 07-01-2019 
 
 
 
 
 
Original Protocol version 1-20-2017 
Amendment 1 version date: 09-06-2017 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
 
Amendment 4 version date: 07-01-2019 
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7.2 
Disease Evaluation During Therapy ........................................................................................................ 44 
7.3 
Bone Marrow Sample for MRD ................................................................................................................. 45 
7.4 
Required Observations Following Completion of Protocol Therapy ................................................... 46 
8.0 
CORRELATIVE STUDIES .......................................................................................................................... 46 
8.1 
Determination of Baseline ........................................................................................................................ 46 
9.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY, OFF STUDY CRITERIA AND STUDY 
TERMINATION ........................................................................................................................................... 49 
9.1 
Criteria for Removal from Protocol Therapy .......................................................................................... 49 
9.2 
Off Study Criteria ....................................................................................................................................... 49 
9.3 
Termination of Study by TACL ................................................................................................................. 49 
10.0 
STATISTICAL CONSIDERATIONS ............................................................................................................ 49 
10.1 
Statistical Considerations for Dose Escalation Criteria ........................................................................ 50 
10.2 
Study Stopping Rules ............................................................................................................................... 50 
10.3 
Definitions .................................................................................................................................................. 50 
10.4 
Patient Accrual and Study Duration ........................................................................................................ 51 
10.5 
Interim Monitoring of Toxic Death ........................................................................................................... 51 
10.6     Analysis of Correlative Studies................................................................................................................ 51 
10.7 
Inclusion of Women and Minorities ......................................................................................................... 52 
11.0 
RESPONSE CRITERIA ............................................................................................................................... 53 
11.1 
Bone Marrow Response Criteria .............................................................................................................. 53 
11.2 
CNS Response Criteria ............................................................................................................................. 54 
12.0 
ADVERSE EVENT REPORTING REQUIREMENTS .................................................................................. 55 
12.1 
Definitions .................................................................................................................................................. 55 
12.2 
Data Collection ........................................................................................................................................... 56 
12.3 
Reporting Serious Adverse Events or Serious Suspected Adverse Reactions.................................. 56 
12.4 
Institutional Reporting to the IRB ............................................................................................................ 58 
13.0 
DATA AND SAFETY MONITORING .......................................................................................................... 59 
13.1 
Data Submission ........................................................................................................................................ 59 
13.2 
Weekly Safety Review ............................................................................................................................... 59 
13.3     Data Safety and Monitory Committee ...................................................................................................... 59 

 
 
 
 
Original  version date: 1-20-2017  
Amendment 1 version date: 09-06-2017 
 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
Amendment 4 version date: 07-01-2019 
 
 
 
 
 
Original Protocol version 1-20-2017 
Amendment 1 version date: 09-06-2017 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
 
Amendment 4 version date: 07-01-2019 
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14.0 
SAMPLE INFORMED CONSENT ............................................................................................................... 60 
APPENDIX I: DISEASE CLASSIFICATION ........................................................................................................... 84 
APPENDIX II: PERFORMANCE STATUS SCALES/SCORES ............................................................................. 85 
APPENDIX III: ORAL SUSPENSION RECIPE ....................................................................................................... 86 
APPENDIX IV: DOSING SCHEDULE ..................................................................................................................... 87 
15.0 
REFERENCES ............................................................................................................................................ 89 
 
 
 
 
 

 
 
 
 
Original  version date: 1-20-2017  
Amendment 1 version date: 09-06-2017 
 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
Amendment 4 version date: 07-01-2019 
 
 
 
 
 
Original Protocol version 1-20-2017 
Amendment 1 version date: 09-06-2017 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
 
Amendment 4 version date: 07-01-2019 
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STUDY COMMITTEE 
 
STUDY CHAIR 
Michael Burke, MD 
Phone: 414-955-4198 
Email: mmburke@mcw.edu 
 
STUDY VICE CHAIR 
Deepa Bhojwani, MD 
Phone: 323-361-5992 
Email: dbhojwani@chla.usc.edu 
 
PHYSICIAN STUDY COMMITTEE MEMBER 
Eric Schafer, MD, MHS 
Phone : (832) 824-4241 
Email : esschafe@txch.org 
 
PHYSICIAN STUDY COMMITTEE MEMBER 
Nathan Gossai, MD 
Phone: (612) 813-6023 
Email : Nathan.Gossai@childrensmn.org 
 
STATISTICIANS 
Richard Sposto, PhD 
Phone: 323-361-8582 
Email: rsposto@chla.usc.edu 
 
Jemily Malvar, MS 
Phone : 323-361-8720 
Email : jmalvar@chla.usc.edu 
 CORRELATIVE BIOLOGY CHAIR  
Sridhar Rao, MD, PhD 
Phone: 414-955-4993 
Email: sridhar.rao@mcw.edu 
 
TACL OPERATIONS 
CLINICAL RESEARCH CONSORTIA 
COORDINATOR 
Ellynore Florendo 
Phone: 323-361-3022  
FAX: (877) 904-2166 
Email: tacl@chla.usc.edu 
SUPPORTIVE CARE COMMITTEE MEMBER 
Van Thu Huynh, MD 
Phone: (714) 509-4592 
Fax: (714) 509-8699 
Email: vahuynh@choc.org 

 
 
 
 
Original  version date: 1-20-2017  
Amendment 1 version date: 09-06-2017 
 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
Amendment 4 version date: 07-01-2019 
 
 
 
 
 
Original Protocol version 1-20-2017 
Amendment 1 version date: 09-06-2017 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
 
Amendment 4 version date: 07-01-2019 
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EXPERIMENTAL DESIGN SCHEMA 
 
A total of 2 courses will be planned. 
 
Days (Courses 1 and 2) 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
… 
35 
Decitabine 
 
• 
• 
• 
• 
• 
 
 
Vorinostat 
 
• 
• 
• 
• 
• 
 
 
 
 
 
 
 
 
 
Fludarabine 
 
• 
• 
• 
• 
• 
 
 
Cytarabine 
 
• 
• 
• 
• 
• 
 
Filgrastim (G-CSF) 
 
• 
• 
• 
• 
• 
• 
• 
• 
•# 
IT Cytarabine 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ITT Therapy* 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bone Marrow Asp/Bx 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
*Patients who are CNS(Centeral Nervous System) positive can receive twice weekly or three times weekly IT 
ARA-C or   ITT therapy at the discretion of the treating physician.  IT therapy should continue until negative x2 
# G-CSF will continue until evidence of post-nadir ANC recovery (>500/µL) 
 
 

 
 
 
 
Original  version date: 1-20-2017  
Amendment 1 version date: 09-06-2017 
 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
Amendment 4 version date: 07-01-2019 
 
 
 
 
 
Original Protocol version 1-20-2017 
Amendment 1 version date: 09-06-2017 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
 
Amendment 4 version date: 07-01-2019 
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1.0 
GOALS AND OBJECTIVES 
 
1.1 
Primary Objectives 
 
1.1.1 
To determine the maximum tolerated dose (MTD) of decitabine when used in this combination with 
vorinostat, fludarabine, high dose cytarabine and G-CSF (FLAG) for children and young adults with 
relapsed or refractory AML. 
 
1.1.2 
To evaluate the ability to safely deliver the combination of decitabine and vorinostat followed by 
fludarabine, high dose cytarabine and G-CSF (FLAG) in pediatric and young adult patients with relapsed 
or refractory AML. 
 
 
 
1.2 
Secondary Objectives 
 
1.2.1 
To determine preliminarily the extent of hypomethylation of peripheral blood (PB) and bone marrow 
(BM) pre- and post- decitabine and vorinostat treatment by: 
 
LINE-1 methylation assay as a surrogate marker of global DNA methylation.  
 
Direct Comprehensive DNA methylation analysis 
 
Gene expression profiling to assess genetic changes 
 
1.2.2 
To analyze the correlation between DNA methylation and gene expression pre- and post-treatment with 
decitabine and vorinostat. 
1.2.3 
To examine peripheral blood mononuclear cells for immunophenotypic changes. 
1.2.4 
To analyze plasma for cytokine content. 
1.2.5 
To analyze the correlation between biological changes and clinical response. 
1.2.6 
To evaluate the ability to safely deliver this treatment combination in Down syndrome patients with 
relapse/refractory AML 
 
 
. 
 
 
 

 
 
 
 
Original  version date: 1-20-2017  
Amendment 1 version date: 09-06-2017 
 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
Amendment 4 version date: 07-01-2019 
 
 
 
 
 
Original Protocol version 1-20-2017 
Amendment 1 version date: 09-06-2017 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
 
Amendment 4 version date: 07-01-2019 
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2.0 
BACKGROUND 
 
2.1 
Relapse AML in Children and Adults 
 
Despite progress in the treatment of AML in the past few decades, the long-term survival of children and adults 
younger than 601 with AML remains poor with survival around 30-60% depending on age.  The majority of 
treatment failure is secondary to relapse, and relapse remains the primary cause of death in these patients2, 3.  
Elimination of the residual leukemia cells that survived front line chemotherapy remains a major challenge.  Once 
relapse occurs, leukemia is more resistant to chemotherapy, and therefore, outcomes are poor.  (Table 1)  In 
addition, about 10-20% of AML patients are refractory to therapy and report equally dismal outcomes.  Therefore, 
there is an urgent need to incorporate new strategies to overcome drug resistance and improve survival in our 
patients with relapse/refractory AML. 
 
Once patients relapse with their disease, the complete response (CR) rate after a 2nd re-Induction attempt is 
around 50 – 60% in children and declines rapidly when a 3rd (17% – 32%) or > 4th attempt is made (10% - 24%).4  
In an analysis of data from three European trials for the initial treatment of adult AML, Breems et al identified a 
small group of adults with relapsed AML whose re-induction CR rate was as high as 80%.5  However, the 
average CR rate for all adults patients with relapsed AML is around 30%,5, 6 and 12-month survival is only 29%.5  
Improving upon these relatively poor re-Induction rates will make more patients eligible for potentially curative 
therapy in allogeneic hematopoietic cell transplantation. 
 
Table 1:  Overall Survival Rate for Pediatric Relapsed/Refractory AML1-6 
 
 
MRC AML10  
TACL  
St. Jude 
LAME89/91  
CCG 2951  
NOPHO  
Refractory 
N/A 
19% at 5 yrs. 
N/A 
N/A 
6% at 2 yrs. 
N/A 
CR ≤12 mo.  
11% at 3 yrs. 
23% at 5 yrs. 
21.5% at 5 yrs. 
24% at yrs. 
13% at 2 yrs. 
29% at 5 yrs. 
CR >12 mo. 
49% at 3 yrs. 
49% at 5 yrs. 
26.1% at 5 yrs. 
54% at 2 yrs. 
75% at 2 yrs. 
51% at 5 yrs. 
Total 
24% at 3 yrs. 
29% at 5 yrs. 
26.6% at 5 yrs. 
33% at 2 yrs. 
24% at 2 yrs. 
40% at 5 yrs. 
  
Table 2:  Overall Survival for Adults with Relapsed AML7 
 
1 Year 
5 Year 
CR ≤ 6 mo. 
14% 
5% 
CR 7-18 mo. 
36% 
12% 
CR >18 mo. 
57% 
26% 
 
2.2 
Overview of Epigenetics in AML 
 
2.2.1 5-AZA-2’-Deoxycytidine (Decitabine) 
 
Decitabine is a demethylating agent that has the potential to reverse the aberrant DNA methylation that takes 
place in a variety of human cancers including acute leukemias (ALL and AML).  Epigenetic changes in AML are 

 
 
 
 
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Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
Amendment 4 version date: 07-01-2019 
 
 
 
 
 
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Amendment 1 version date: 09-06-2017 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
 
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common, particularly hypermethylation and silencing of tumor suppressor genes.8  Decitabine has been 
previously shown to cause demethylation and gene re-expression with subsequent hematopoietic differentiation 
and clinical response at doses ≥ 1 log below the maximum tolerated dose (MTD).9   
 
Mechanism of Action:  Decitabine is a cytidine anti-metabolite analogue that acts as a demethylating agent with 
anti-neoplastic activity.  It is incorporated into cellular DNA thereby trapping DNA methyltransferase in the form of 
a covalent protein DNA adduct.10  This leads to degradation of the DNA methyltransferase and further 
hypomethylation of the genomic DNA during ongoing cellular DNA replication.  The demethylation process is 
thought to re-activate genes that were previously inactivated during the oncogenic transformation that may be 
involved with tumor suppressor, apoptotic, DNA repair, and growth inhibitory pathways, thereby suppressing 
further tumor genesis.   
 
Summary of Toxicology:  Decitabine is very well tolerated at doses below its MTD with the most commonly 
reported toxicities being neutropenia, anemia, thrombocytopenia, fatigue, pyrexia, nausea, cough, petechiae, 
constipation, diarrhea and hyperglycemia. 
 
In Vitro Studies of Decitabine:  The methylation status of acute leukemia and the role of demethylating agents 
(e.g. decitabine) have recently been reported by several investigators.10,11  Yang et al. described the impact of 
decitabine as a single agent on cell viability using the MOLT4 ALL cell line where a reduction of 65% was seen 
and 90% when decitabine was given in combination with the histone deacetylase inhibitor, valproic acid (VPA).9  
Similar results were shown in apoptotic assays where three consecutive days of decitabine exposure induced cell 
death in 26% of cells and 50% with the combination of decitabine and VPA. 
 
Clinical Studies of DNA Methyltransferase Inhibitors (DNMTi) in Acute Leukemia:  Issa et al. reported Phase 
1 results with decitabine as a single agent in 30 relapsed/refractory AML patients.12 The treatment was very well 
tolerated among the group without a MTD achieved with doses ranging from 5 mg/m2 to 20 mg/m2 and reported a 
CR/PR rate of 14%/8% respectively.  The dose which provided the greatest response (83%) among the patient 
group was 15 mg/m2.  Using a 10-day regimen of 20 mg/m2/day as upfront therapy in older adults, Blum et al 
reported an overall CR rate of 47%.13  In a retrospective review by Ritchie et al, the same regimen had a CR rate 
of 40% and 15.7% in newly diagnosed and relapsed/refractory patients respectively14. Based on these 
encouraging data, the US National Cancer Comprehensive Network and the European LeukemiaNet both support 
the use of decitabine for treatment of older adults with AML (>60 years) primarily due to its favorable side effect 
profile and the positive impact it has on overall survival for a patient group lacking in therapeutic alternatives.15 
 
Studies with decitabine in combination with chemotherapy in AML are more limited.  Blum et al. investigated the 
combination of valproic acid and decitabine in 25 AML patients (median age 70 years). They reported greater 
toxicity when the combination was given, with three patients acquiring encephalopathy, compared to decitabine 
treatment alone.16  Scandura et al. investigated the combination of decitabine (3 dose levels: 3 days, 5 days and 7 
days) followed by standard induction therapy with daunorubicin and cytarabine in an adult phase 1 study17.  Thirty 
patients enrolled (median age 54.5 years). The combined therapy was tolerable, with a MTD of decitabine not 
being reached, although the authors noted an increase in gastrointestinal toxicity with the 7-day cycle of 
decitabine compared to the same dose given for 5 or 3-days prior to standard induction chemotherapy17. Of the 
30 patients enrolled, 27 (90%) responded to the first cycle of induction therapy reporting 17 CR (57%) and an 
additional 10 PR (33%). Of the patients with a PR, 8 (80%) achieved a CR after their 2nd induction cycle.  
 
Decitabine has been combined with CAG (cytarabine, aclarubicin and G-CSF) or CAG-like regimens in 53 adults 
with relapsed/refractory AML reporting overall survival at 1-year as high as 59%.18 In newly diagnosed adult 
patients with high-risk (HR) myeloid neoplasms including (HR) myelodysplastic syndrome and AML, decitabine 

 
 
 
 
Original  version date: 1-20-2017  
Amendment 1 version date: 09-06-2017 
 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
Amendment 4 version date: 07-01-2019 
 
 
 
 
 
Original Protocol version 1-20-2017 
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Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
 
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has been successfully given followed by low dose idarubicin and cytarabine in 30 patients (median age 55 years) 
as reported by Ye et al.19 The overall CR rate was 67% with a manageable toxicity profile and no treatment 
related deaths. 
 
Given the number of adults studies in AML investigating decitabine which report good tolerability and promising 
response, further investigation in children with high-risk myeloid neoplasms is warranted. 
 
Pediatric Studies:  The Children’s Oncology Group (COG) piloted a Phase 1 trial investigating decitabine in 
children with refractory/relapsed acute leukemia that closed prematurely secondary to low patient accrual.  In this 
study, no MTD was identified, with all patients receiving the same starting dose of 10 mg/m2/d of decitabine.  
There were 5/15 patients with Grade 3/4 cytopenias (anemia, thrombocytopenia and leukopenia) that were 
reported as possibly being related to the study drug.  There were no toxicities reported in this study that were 
directly related to decitabine exposure. 
 
There has been only a single clinical trial published to date in pediatric AML testing a DNMTi followed by 
chemotherapy. This study, operated through the Therapeutic Advances in Childhood Leukemia & Lymphoma 
(TACL) Consortium, investigated 5-azacytidine followed by fludarabine and cytarabine in children and young 
adults ages 1 to 21 years with relapsed or refractory leukemia [NCT01861002]. Fifteen patients enrolled (13 AML, 
2 ALL) with 14 evaluable for treatment related toxicity and response. Five patients with AML had received a prior 
bone marrow transplant. Non-hematologic Grade >3 toxicities at least possibly related to 5-azacytidine included 
febrile neutropenia (n=6), infection (n=3) AST elevation (n=1), oral hemorrhage (n=1) and hypokalemia (n=1). 
There were no dose limiting toxicities reported on study and 7/12 (58%) patients with AML reported a complete 
response (CR). Demethylation analysis on 4 patients with adequate samples submitted observed persistent 
hypermethylation in 2 patients who were non-responders and successful demethylation in 2 patients who reported 
a CR. Overall the therapy was well tolerated and reported encouraging response rates in a very high-risk group of 
patients with relapse AML. Based on the feasibility of this study and encouraging response rates reported, future 
epigenetic trials in pediatric AML are warranted. 
 
 
2.2.2 
Suberoylanilide Hydroxyamic Acid (Vorinostat; SAHA) 
 
Alterations in histone acetylation status have been implicated in carcinogenesis.  The ability to acetylate histones 
may play a pivotal role in disrupting tumor genesis.  Vorinostat is a histone deacetylase inhibitor with known 
clinical activity in cutaneous T-cell lymphoma and preclinical activity in leukemia.  It has been used both as a 
single agent and in combination with demethylating agents for the treatment of both solid tumors and hematologic 
malignancies.  
 
Mechanism of Action:  Vorinostat’s main mechanism of action is in restoring histone acetylation by inhibiting 
deacetylase.  This action may further reactivate aberrantly silenced genes and allow gene transcription to 
proceed.  Vorinostat has been shown to induce growth inhibition and apoptosis in cancer cell lines but not non-
malignant cells via caspase-3/caspase-9 and Fas/Fas ligand pathways.20 
 
Summary of Toxicology:  Vorinostat has been very well tolerated with acceptable side effect profiles reported.  
The most common toxicities have been diarrhea, nausea, fatigue, anorexia, vomiting, low magnesium, 
constipation, hypokalemia, thrombocytopenia, elevated liver enzymes, hyperglycemia, peripheral edema, 
elevated creatinine and dyspnea. 
 

 
 
 
 
Original  version date: 1-20-2017  
Amendment 1 version date: 09-06-2017 
 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
Amendment 4 version date: 07-01-2019 
 
 
 
 
 
Original Protocol version 1-20-2017 
Amendment 1 version date: 09-06-2017 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
 
Amendment 4 version date: 07-01-2019 
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Clinical Studies of Vorinostat in Acute Leukemia:  Vorinostat, like decitabine, has been previously investigated 
as a single agent for the treatment of adult AML.  Garcia-Manero et al. reported 7/31 (23%) patients having 
hematological improvement with > 50% decrease in their blast count.21  The doses of vorinostat in this study 
ranged from 100 mg to 300 mg given up to three times daily and were well tolerated overall.  The reported dose 
limiting toxicities were fatigue, nausea, vomiting and diarrhea.  These were seen in 1/12 patients treated with 200 
mg TID compared to 3/5 patients treated with 300 mg TID.   
 
Vorinostat followed by chemotherapy has been tested in adults with HR AML. In an adult Phase 1 trial, increasing 
doses of vorinostat were given for 7 days prior to etoposide and cytarabine in 21 patients (median age 61 years) 
with relapsed/refractory AML. DLTs were observed at dose level 2 (vorinostat 200mg TID) and included 
hyperbilirubinemia/septic death (n=1) and anorexia/fatigue (n=1). Seven of 21 patients achieved a CR (33%) with 
a median duration of remission at 7 months. Given the relatively high CR rate observed in these patients and the 
overall tolerability of the regimen, vorinostat followed by chemotherapy is a promising approach to improve 
response rates in adults with poor-risk AML. Studies combining vorinostat with idarubicin in 41 adult patients 
(median age 59 years) with relapsed leukemia also reported tolerability with some clinical efficacy with 17% of 
patients having a response.22 A subsequent Phase II trial combined cytarabine with idarubicin following vorinostat 
in 75 adult patients (median age 52 years) where no excess vorinostat related toxicity was observed and the 
overall response rate was 85%, including 76% CR and another 9% CR without platelet recovery. Impressively, 
patients with FLT3-ITD AML (n=11) had CR rates of 100%.23 
 
Given the number of adults studies in AML investigating vorinostat which report good tolerability and promising 
response, further investigation in children with high-risk myeloid neoplasms is warranted. 
 
Pediatric Studies:  The Children’s Oncology Group (COG) piloted a Phase 1 study investigating vorinostat +/- 13 
Cis-Retinoic Acid in children with refractory/recurrent solid tumors. Vorinostat was administered starting at 
180mg/m2 with escalations planned in 30% increments. Sixty-four patients enrolled (median age 11 years). They 
reported 4/12 patients experiencing dose limiting toxicities (hypokalemia, neutropenia and thrombocytopenia) 
related to vorinostat at a dose of 300 mg/m2/d.  The MTD for vorinostat as a single agent in patients with solid 
tumors was defined as 230 mg/m2/d with 1/6 patients having a DLT (hypokalemia) at this dose. The MTD for 
vorinostat in the leukemia cohort was 180mg/m2 based on 2 patients reporting DLT at the starting dose (elevated 
AST (n=1), hyperbilirubinemia (n=1), elevated GGT (n=1) and hypokalemia (n=1).  
 
 
2.2.3 
Vorinostat and Decitabine in Combination 
 
The combination of vorinostat and decitabine has been tested in in vitro studies using both human leukemia24 and 
hepatoblastoma25 cell lines.  Both studies showed evidence of cell growth inhibition and gene silencing.  In vivo 
studies have also been performed.  
 
Two recent Phase 1 studies evaluated the tolerability of combination therapy with decitabine and vorinostat.  In a 
study by Yee et al., 27 adult patients with AML, median age of 67 years (range, 32-82 years), were treated with 
escalating doses of vorinostat (100 mg BID; 200 mg BID; 200 mg TID) either sequentially or concurrently with 
decitabine (20 mg/m2/d IV Days 1-5).26  There were no Grade 3 or Grade 4 toxicities reported with the most 
common toxicities being nausea (71%), fatigue (54%), diarrhea (54%), vomiting (42%), anorexia (25%), 
constipation (13%), abdominal pain (13%), dehydration (13%), and headache (13%).  Of the 25 evaluable 
patients, one patient achieved an incomplete CR (without neutrophil recovery), one a morphologic remission 
(without blood count recovery), and three partial remissions. 
 

 
 
 
 
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A second Phase 1 study investigated the sequential therapy of decitabine (10, 15, 20 and 25 mg/m2 IV daily × 5) 
followed by SAHA (100 mg PO TID × 14 in the first cohort and 200 mg PO TID × 14 in all subsequent cohorts) in 
31 refractory/relapsed adult leukemia patients with a median age of 62 years (range, 22-82 years).27 30 patients 
were evaluable for toxicity.  The toxicities reported included syncope, neutropenic fever, diarrhea, fatigue, renal 
failure, rash, nausea, thrombosis, and angioedema.  Of the 30 evaluable patients, 1 patient achieved a complete 
remission lasting 5.5 weeks, 4 had significant reductions in the bone marrow blasts, 4 had stable disease, 7 are 
too early for response evaluation, and 14 had no response/disease progression.  
 
A recent Phase 1 trial was completed testing two schedules of escalating vorinostat in combination with 
decitabine (sequential administration of decitabine followed by vorinostat and concurrent administration of 
decitabine and vorinostat) in 36 adult patients with relapsed/refractory or previously untreated AML.28 MTDs were 
not reached on either schedule. The overall response rates were greater for patients with relapsed/refractory AML 
and previously untreated AML who received concurrent administration of vorinostat and decitabine (n=20) 
compared to sequential (n=16) (30% and 36% versus 13% and 0%; p=0.26, respectively). The authors concluded 
that concurrent administration of these two epigenetic agents appeared more effective than sequential dosing.  
 
A pediatric Pilot Study investigating decitabine and vorinostat in combination with chemotherapy was studied in 
relapse/refractory acute lymphoblastic leukemia (ALL) (NCT02412475). In this trial, decitabine and vorinostat 
were given prior to (decitabine days 1-5, vorinostat days 2-7) and concurrently (decitabine days 15-19, vorinostat 
days 16-21) with an intensive re-induction regimen consisting of vincristine, dexamethasone, PEG-asparaginase, 
and mitoxantrone (ALL UKR3) days 8 through 35. This Pilot Study was operated through the TACL consortium. 
23 patients with >2nd relapse or refractory B-ALL enrolled. Median age was 12 years (range, 20 months to 21 
years). 11 patients (47.8%) had a prior HSCT and 6 had refractory disease (failing >2 prior re-induction attempts). 
3 patients had a DLT reported which included Grade 3 cholestasis, Grade 3 steatosis, Grade 4 bilirubin (patient 
#3); Grade 3 delirium, Grade 3 seizure, Grade 4 depressed level of consciousness (patient #5); and Grade 3 
bilirubin (patient #6). Of the 23 patients, 15 were evaluable for response with 9 achieving a CR (60%). The 
remaining 6 patients reported SD (40%). 6/9 patients who achieved a CR were evaluable for MRD analysis 
reporting a median MRD of 0.056% (range, <0.001 to 1.6%; flow cytometry). However, the infectious toxicities 
reported on this study were significant with 82.6% (n=19) of patients reporting at least 1 infection including 34.8% 
with an invasive fungal infection.29 Despite these toxicities, in part believed to be due to the highly pretreated 
patient population and the intensive chemotherapy regimen (ALL UKR3), the clinical response and in particular 
the depth of MRD reduction was impressive and much better than expected in comparison to historical controls.30  
 
Although there have been clinical studies reporting the combination of a histone deacetylase inhibitor 
(suberoylanilide hydroxyamic acid, SAHA) and a demethylating agent (5-Aza-2’-deoxycytidine, decitabine) in AML 
patients, there has yet to be a trial reporting this combination followed by re-induction chemotherapy in children 
and AYA with relapsed/refractory AML.  This study aims to establish feasibility of the regimen and improved 
efficacy in terms of greater re-induction remission rates using combination therapy of a DNMTi agent and HDACi 
followed by cytotoxic therapy in children and AYA with relapsed/refractory AML. 
 
2.2.4 
Re-Induction with Fludarabine, Cytarabine and G-CSF (FLAG) in Relapsed Leukemia 
 
Fludarabine, cytarabine and G-CSF (FLAG) has previously been shown to be an effective and tolerable regimen 
in adult patients with relapse/refractory AML. An analysis of 65 patients in an adult Phase II trial (median age 47.5 
years), reported complete remission (CR) rates of 81% (17/21) in those with a late relapse and 30% (13/44) in 
early relapse (<6 months from end of therapy) or refractory disease.28 All patients experienced severe 
myelosuppression however the only grade >3 non-hematologic toxicity reported included nausea, vomiting, 
alopecia and elevated ALT. The greatest toxicity was observed in elderly patients who had on average 4 days and 

 
 
 
 
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8 days longer for neutrophil and platelet recovery. The effect of G-CSF on the in vitro cytotoxicity of pediatric AML 
samples supports its use in combination with fludarabine and cytarabine in children29 and in a trial of 197 pediatric 
patients with relapse AML receiving FLAG, 59% achieved a CR, 10% suffered a toxic death, 19% relapsed, 
resulting in a 4-year overall survival of 36% (95% CI, 29-43).30 Based on these encouraging results, this study will 
use FLAG  as the backbone of therapy for which epigenetic modifying agents will be tested in children and AYA 
with relapsed/refractory AML.31 
 
2.2.5 
Study Rationale 
 
The use of DNMTi agents (e.g. decitabine) and HDACi (e.g. vorinostat) in combination have been previously 
shown to have synergistic effects in altering neoplastic pathways of cancer cells25, 39 and be well tolerated in 
human clinical studies.26, 27 This study proposal is based on the hypothesis that the greatest impact of combining 
DNMTi and HDACi agents together for the treatment of leukemia, may rely on their further combination with 
cytotoxic therapy (i.e. chemotherapy).  With the ability of decitabine and vorinostat to alter the abnormal cellular 
pathways of leukemic blasts and essentially turn off anti-apoptotic proteins, the leukemia cells have become 
primed for cytotoxic cell kill via chemotherapeutic agents.  Therefore this study concept will ask the question as to 
whether or not the combination of decitabine and vorinostat followed by standard re-Induction chemotherapy is 
feasible and whether it can positively impact outcome. 
 
The initial doses of decitabine and vorinostat to be investigated in this study (decitabine, 7.5 mg/m2; vorinostat, 
180 mg/m2 for patients < 18 years and 200 mg twice daily for > 18 years) are both at or below their identified 
MTDs and based on their tolerable side effect profile, are not likely to add further toxicity to patients receiving the 
additional chemotherapy agents on this study.   
 
Dosing Rationale: 
  
This study has a dose escalation of decitabine at 4 dose levels (starting at 7.5mg/m2), as well as potential for 
dose de-escalation to dose level 0 (5mg/m2) based on toxicity. Patients will receive decitabine [dose levels 0-4 (5, 
7.5, 10, 15, 20mg/m2)] in combination with vorinostat days 1-5 (180mg/m2 daily ages <18 years, 200 mg twice 
daily ages 18-25 years). There has been no MTD previously identified for decitabine in children and AYA. Doses 
of 5mg/m2 to 20mg/m2 of decitabine as a single agent have been well tolerated in adult leukemia studies and 
resulted in demethylation of blasts and clinical responses.12 The pediatric MTD for vorinostat in patients with 
hematologic malignancies is 180mg/m2 once daily based on results from the Children’s Oncology Grouyp (COG) 
phase I study.32 The dose of vorinostat has varied greatly in adults ranging from 100mg BID to 500mg TID.21 The 
dose of 200mg BID for patients >18 years was chosen in this study based on ease of dosing/adminstration as well 
as this dose having good efficacy in maintaining histone acetylation.32 
 
Correlative biology studies: 
 
Determination of Baseline “functional epigenetic profile” on leukemic blasts isolated at study entry using the 
following triad of assays:   
 
To quantitatively assess global changes in DNA methylation, a LINE-methylation assay will also be utilized and 
specific genes monitored through advanced Infinium MethylationEPIC BeadChip from Illumina; 
 
Chromatin immunoprecipitation (ChIP) with antibodies specific for histone modifications associated with 
transcriptional activation (H3K4me3, H3K27ac) and repression (H3K9me3 and H3K27me3) and isotype controls, 
followed by DNA sequencing (ChIP-seq) and total levels will be measured by western blotting; 

 
 
 
 
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RNA sequencing analysis will be used to measure global transcriptome changes. Correlation between DNA 
methylation and gene expression using RNA seq pre/post treatment with decitabine/vorinostat will be performed 
and correlated with clinical response, for which it is likely that over- or under-expression is truly driven by 
epigenetic regulation. Profiles of CD33+ umbilical cord blood cells, whole bone marrow, or Peripheral Blood Stem 
Cells (PBSCs) will be used as normal controls for each sample.  
 
Immune assessment: Peripheral blood immune cell phenotyping and serum cytokine analysis.  
 
Assessment of the in Vivo Effects  
 
Assessment of the in vivo effects of combined DNMTi/HDACi on the functional epigenetic profile by comparing 
the following in paired pre- (Day 0) and post-exposure (Day 5, Day 14 and Day 35) leukemic blasts: 
 
2.2.5.1 Reversal of DNA promoter hypermethylation of “repressed” genes of interest using Infinium 
MethylationEPIC BeadChip, validated with Pyrosequencing-based methylation assay; 
2.2.5.2 Increase in H3K27m3 and H3K9me3 or descrese H3K27ac and H3K4m3 in association with 
“repressed” genes of interest using H3K4m3, H3K27ac, H3K27m3, and H3K9m3 ChIP-seq, 
validated with ChIP-qPCR;  
2.2.5.3 Reversal of transcriptional silencing of “repressed” genes of interest using RNA seq, validated by 
qRT-PCR.  Since significant acute cell kill is unlikely during the 5-day “window” of DNMTi/HDACi, we 
will have a unique opportunity to assess the in vivo effects of epigenetic therapy with the Day 5 
sample.  The Day 14 peripheral blood and Day 35 marrow samples will also contribute in patients 
whose leukemic blasts persist at these time points.  
2.2.5.4 Changes in peripheral blood immune cell subsets and serum cytokines. 
 
Correlations of Baseline functional epigenetic phenotype and pharmacodynamic modulation of repressed genes 
of interest with clinical responses:  While the ability to definitively correlate either baseline epigenetic phenotypes 
or successful reversal of epigenetic phenotypes with clinical response will be limited by small patient numbers, the 
descriptive data we generate will be invaluable in developing biomarkers to be validated in future trials.  
 
2.2.6  
Chemo-Sensitivity Profiling 
 
We hypothesize that vorinostat and decitabine may influence sensitivity of leukemic cells to the standard re-
induction chemotherapy.  We will test blasts isolated at baseline (pre-treatment) vs. those isolated at Day 5 (post-
exposure to DNMTi/HDACi) and compare cytotoxic IC50 for fludarabine and cytarabine using enzyme-based 
proliferation assays (WST-1, e.g.) and flow-based apoptosis assays (annexin V and 7-AAD). 
 
 
2.2.7 
Immune monitoring 
 
It is now clear that the immune system can have an important role in controlling cancer progression.  Epigenetic 
modifying drugs and many chemotherapeutic agents are known to have both positive and negative effects on the 
immune system.  The combination of agents being used here could have either beneficial or detrimental effects 
on immune cell function and composition.  We hypothesize that immune cell subsets and serum cytokines levels 
will be impacted by the treatment regimen.  Plasma will be quantitatively analyzed for 65 different cytokines and 
chemokines in multi-plex assays.  We will also immunophenotype peripheral blood mononuclear cells using multi-

 
 
 
 
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color (8 parameters) flow cytometry.  Cell subsets to be analyzed will include T cells (naïve, effector and 
regulatory), B cells, NK cells, dendritic cells and myeloid cells. 
 
3.0 
PATIENT ELIGIBILITY CRITERIA AND ENROLLMENT 
 
3.1 
Patient Reservation 
 
Investigators should consult the Member’s Section of the TACL web site to determine if the study is currently 
open for accrual before approaching patients for participation.  Before enrolling a patient on study, a reservation 
must be made with the TACL Operations Center.  In order to make a reservation you may call (323) 361-3022 or 
send an email to tacl@chla.usc.edu with the following information (if sending an email, please put “Reservation 
Request” in the subject line): 
 
 Study for which you want to make a reservation:  
 Name of the institution requesting reservation with contact information 
 Patient Initials (Last, First) 
 Patient month and year of birth 
 
If an enrollment slot is available, you will receive an email from the TACL Operations Center to confirm your 
reservation.  All reservations are good for 5 full calendar days starting with the next full day after the day the 
reservation is made. 
 
3.2 
Enrollment  
 
An enrollment guide is available on the web site (https://tacl.chla.usc.edu). Patients must be enrolled prior to 
beginning treatment on this study.  It is allowable to enroll a patient that has received IT ARA-C, IT MTX or triple IT 
therapy within 7 days of enrollment as part of their evaluation to diagnose disease relapse.  Patients will be enrolled 
by contacting the TACL Operations Center Monday through Friday, 8:30 am – 5:00 pm Pacific Time at (323) 361-
3022, except holidays.  You will be asked to complete the eligibility form on the TACL Database System prior to 
making your call.  In addition, the supporting documentation, which confirms eligibility, should be scanned and 
emailed to the TACL Operations Office through tacl@chla.usc.edu.  
 
Each patient will be assigned a unique TACL registration and study subject number. An email confirming eligibility 
and assigned dose level will be sent to the treating facility, Study Chair, and Study Vice-Chair. Patients should 
begin treatment within 3 calendar days of study enrollment.   
 
 Contact Person: 
Clinical Research Coordinator: Ellynore Florendo 
 
 
 
 
TACL Operations Center 
 
 
 
 
Children’s Hospital Los Angeles 
 
 
 
 
4650 Sunset Blvd, MS #54 
 
 
 
 
Los Angeles, CA 90027 
 
 
 
 
Phone: (323) 361-3022 
 
 
 
 
FAX: (877) 904-2166 
 
 
 
 
Pager: (213) 209-5592 
 
 
 
 
Email: tacl@chla.usc.edu 
 

 
 
 
 
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3.3 
Inclusion Eligibility Criteria  
 
The eligibility criteria listed below are interpreted literally and cannot be waived. 
 
3.3.1 
Age 
Patients must be ≥ 1 and ≤25 years of age.  
 
3.3.2 
Diagnosis 
 
Patients with relapse or refractory AML must have measurable disease ( >M1 marrow) 
- 
1st or greater relapse, OR  
- 
Failed to go into remission after 1st or greater relapse, OR 
- 
Failed to go into remission from original diagnosis after 2 or more induction 
attempts 
a) Eligibility for patients with an M1 marrow; defined as >0.1% by flow or molecular testing (e.g. 
PCR). 
 
must include two serial marrows (at least 1-week apart) demonstrating stable or rising 
minimal residual disease (MRD) (i.e. not declining). 
 
b) Patients may have CNS or other sites of extramedullary disease. No cranial irradiation is 
allowed during the protocol therapy.   
 
c) Patients with secondary AML are eligible. Of note, these patients will be eligible even without 
prior therapy for AML. 
 
d) Patients with Down syndrome are eligible. 
 
e) Patients with DNA fragility syndromes (such as Fanconi anemia, Bloom syndrome) are 
excluded. 
 
3.3.3 
Performance Level 
Karnofsky > 50% for patients > 16 years of age and Lansky > 50% for patients ≤ 16 years of age. 
(See Appendix II for Performance Scales) 
 
3.3.4 
Prior Therapy 
Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, 
immunotherapy, or radiotherapy prior to entering this study. 
 
 
a) Cytoreduction with hydroxyurea Hydroxyurea can be initiated and continued for up to 
24 hours prior to the start of decitabine/vorinostat. It is recommended to use hydroxyurea 
in patients with significant leukocytosis (WBC >50,000/L) to control blast count before 
initiation of systemic protocol therapy.  
 
b) Patients who relapsed while they are receiving cytotoxic therapy  At least 14 days 
must have elapsed since the completion of the cytotoxic therapy,except Intrathecal 
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A. Hematopoietic stem cell transplant(HSCT): Patients who have experienced their relapse 
after a HSCT are eligible, provided they have no evidence of acute or chronic Graft-versus-
Host Disease (GVHD) and are off all transplant immune suppression therapy for at least 7-
days (e.g. steroids, cyclosporine, tacrolimus). Steroid therapy for non-GVHD and/or non-
leukemia therapy is acceptable. 
 
B. Hematopoietic growth factors: It must have been at least 7 days since the completion of 
therapy with GCSF or other growth factors at the time of enrollment. It must have been at 
least 14 days since the completion of therapy with pegfilgrastim (Neulasta®). 
 
C. Biologic (anti-neoplastic agent): At least 7 days after the last dose of a biologic agent. For 
agents that have known adverse events occurring beyond 7 days after administration, this 
period must be extended beyond the time during which adverse events are known to occur. 
The duration of this interval must be discussed with the study chair. 
 
D. Monoclonal antibodies: At least 3 half-lives of the antibody must have elapsed after the last 
dose of monoclonal antibody. (i.e. Gemtuzumab = 36 days) 
 
E. Immunotherapy: At least 42 days after the completion of any type of immunotherapy, e.g. 
tumor vaccines or CAR T-cell therapy. 
 
F. XRT: Cranio or craniospinal XRT is prohibited during protocol therapy. No washout period is 
necessary for radiation given to non-CNS chloromas; >90 days must have elapsed if prior TBI, 
cranio or craniospinal XRT. 
 
G. Prior Demethylating and/or HDAC Inhibitor Therapy: Patients who have received prior 
DNMTi (e.g. decitabine) and/or HDACi (e.g. vorinostat) therapy are eligible to participate in 
this Phase 1 study. At least 7 days must have passed from prior DNMTi or HDACi as a 
washout period. 
 
 
3.3.5 
Renal and hepatic function 
Patients must have adequate renal and hepatic functions as indicated by the following laboratory 
values: 
 
A. Adequate renal function defined as: Patient must have a calculated creatinine clearance or 
radioisotope GFR  70ml/min/1.73m2 OR a normal serum creatinine based on age/gender in 
the chart below: 
 
Age 
 
Maximum Serum 
Creatinine (mg/dL) 
 
Male 
Female 
1 month to < 6 months 
0.4 
0.4 
6 months to < 1 year 
0.5 
0.5 
1 to < 2 years 
0.6 
0.6 

 
 
 
 
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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 
 
The threshold creatinine values in this Table were derived from the Schwartz formula 
for estimating GFR (Schwartz et al. J. Peds, 106:522, 1985) utilizing child length and 
stature data published by the CDC. 
 
B. Adequate Liver Function Defined as: Direct bilirubin < 1.5 x upper limit of normal (ULN) for 
age or normal, AND alanine transaminase (ALT) < 5 x ULN for age. The hepatic requirements 
are waived for patients with known or suspected liver involvement by leukemia. This must be 
reviewed by and approved by the study chair or vice chair. 
 
 
3.3.6 
Adequate Cardiac Function Defined as: Shortening fraction of  27% by echocardiogram, OR 
ejection fraction of   50% by radionuclide angiogram (MUGA). 
 
3.3.7 
Reproductive Function 
A. Female patients of childbearing potential must have a negative urine or serum pregnancy test 
confirmed within 1 week prior to enrollment. 
 
B. Female patients with infants must agree not to breastfeed their infants while on this study. 
 
C. Male and female patients of child-bearing potential must agree to use an effective method of 
contraception approved by the investigator during the study and for a minimum of 6 months 
after study treatment. 
 
3.3.8 
Informed Consent 
Patients and/or their parents or legal guardians must be capable of understanding the 
investigational nature, potential risks and benefits of the study. All patients and/or their parents or 
legal guardians must sign a written informed consent. Age appropriate assent will be obtained per 
institutional guidelines. To allow non-English speaking patients to participate in this study, 
bilingual health services will be provided in the appropriate language when feasible. 
 
3.3.9 
Protocol Approval 
All institutional, FDA, and OHRP requirements for human studies must be met. 
 
 
3.4 
Exclusion Eligibility Criteria 
 
Patients will be excluded if they meet any of the following criteria 
 
3.4.1 
No NG or G-Tube administration of Vorinostat is allowed.  Capsule must be swallowed whole or 
given as oral suspension. 

 
 
 
 
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3.4.2 
They are currently receiving other investigational drugs.   
 
3.4.3 
There is a plan to administer non-protocol chemotherapy, radiation therapy, or immunotherapy 
during the study period. 
 
3.4.4 
They have significant concurrent disease, illness, psychiatric disorder or social issue that would 
compromise patient safety or compliance, interfere with consent, study participation, follow up, or 
interpretation of study results. 
 
3.4.5 
They have a known allergy to any of the drugs used in the study. 
 
 
3.4.6 
Patients with DNA fragility syndromes are excluded (e.g. Fanconi Anemia, Bloom Syndrome) 
 
3.4.7 
They are receiving valproic acid (VPA) therapy. 
 
3.4.8 
Patients with Acute Promyelocytic Leukemia (APL, APML) are excluded 
 
3.4.9 
Patients with documented active and uncontrolled infection at the time of study entry are not 
eligible 
 
3.4.10 Patients will be excluded if they have had any positive fungal culture within 30 days prior to 
enrollment. 
 
 
 

 
 
 
 
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4.0 
TREATMENT PROGRAM 
 
The following sections detail the treatment plan for each course of therapy.  Please refer to the Drug Information 
section for additional administration guidelines. Treatment should begin within 3 calendar days of enrollment.   
 
 
4.1 
Course 1 and 2 
 
     Table 3:  Overview of Treatment Plan – Courses 1 and 2 
Drug 
Dose 
Route of 
Administration 
Days 
Decitabine A 
See Table 6 
Starting at Hour 0 
IV over 1 hour 
1-5 
VorinostatB 
Age < 18 years 
180 mg/m2/day once daily 
Give after the Decitabine infusion  
PO 
1-5 
Age ≥ 18 years 
200 mg twice daily  
Give after the Decitabine infusion 
PO 
1-5 
Filgrastim C (G-CSF) 
5 μ/kg/dose 
(Starting at Hour 0 )  
IV or SQ 
5-12C 
FludarabineF 
30 mg/m2/day  
(Starting at Hour 0 – Immediately 
after G-CSF) 
IV over 30 minutes 
6-10 
Cytarabine 
2000 mg/m2/day  
(Starting at Hour 4.0) 
IV over 3 hours 
6-10 
Cytarabine D,E 
See Table 4 – Age Specific Dosing 
IT 
0 (or -1 D) 
ITT TherapyD 
See Table 5-Age Specific Dosing 
IT 
See E 
A 
Decitabine will be assigned according to Protocol Dose Escalation Schedule.  Refer to Section 6.2 and 12 for 
further information. 
B 
A compounded liquid formulation of Vorinostat is available.   
C 
G-CSF will begin on Day 5 prior to FLAG and continue until evidence of post-nadir ANC recovery (>500/µL). 
Biosimilars are permitted 
D  Refer to Table 4:  Patient Age Specifications for Intrathecal Cytarabine 
E  
IT Cytarabine can be given up to 72 hours prior to initial dose of decitabine/vorinostat for patient convenience. 
 
Patients who are CNS positive can receive twice weekly or three times weekly IT ARA-C or IT ITT therapy at 
the discretion of the treating physician.  IT therapy should continue until negative x2. 
F 
Dosing for Fludarabine applies only when creatinine clearance >60mL/min/1.73m 
      
 
A bone marrow evaluation to determine study response and remission status will be performed on study Day 35-
42 or upon adequate blood count recovery (ANC > 500/µL AND platelet > 50,000/µL), whichever occurs first.  If 
the marrow is hypocellular and without evidence of normal tri-lineage hematopoiesis the marrow should be 
repeated at Day 42 – 49 (7 days post the last evaluation or when ANC/Plt counts recover whichever is sooner). 
 
Table 4:  Patient Age Specifications for Intrathecal Cytarabine 
 

 
 
 
 
Original  version date: 1-20-2017  
Amendment 1 version date: 09-06-2017 
 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
Amendment 4 version date: 07-01-2019 
 
 
 
 
 
Original Protocol version 1-20-2017 
Amendment 1 version date: 09-06-2017 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
 
Amendment 4 version date: 07-01-2019 
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Patient Age (years) 
IT Cytarabine Dose 
1 to 1.99 
30 mg 
2  to 2.99 
50 mg 
≥ 3   
70 mg 
 
 
 
 
 
Table 5: Patient Age Specific Dosing for Triple Intrathecal Therapy 
 
Patient Age 
(years) 
Methotrexate 
Hydrocortisone 
ARA-C 
1 to 1.99 
8mg  
8mg 
16mg 
2  to 2.99 
10mg 
10mg 
20mg 
3  to 8.99 
12mg 
12mg 
24mg 
≥ 9 
15mg 
15mg 
30mg 
 
 
This study will follow a 3+3 dose escalation design, as described in section 10.1, starting at dose level 1 (7.5 
mg/m2/dose) with possible escalation to dose levels 2 through 3 and possible de-escalation to dose level 0. 
 
Table 6:  Decitabine Dose Levels 
 
 
 
 
 
 
 
 
 
Table 7:  Fludarabine Dose based on Creatinine Clearance 
 
Creatinine Clearance mL/min 
Daily Fludarabine Dose (mg/m2) 
> 60 
30 
46-60 
24 
31-45 
22.5 
21-30 
Withhold Fludarabine 
< 20 
Withhold Fludarabine  
 
4.2 
Disease Evaluation During Course 1 and 2 
A bone marrow aspiration/biopsy to assess remission status should be performed approximately day 35-42 when 
blood counts recover (ANC > 500/uL and PLT > 50,000/uL).  
 
If the marrow is hypoplastic and/or there is little or no evidence of normal hematopoiesis, a repeat marrow should 
be performed after a further 7-21 days (based upon peripheral blood count recovery and the clinician’s judgment) 
Decitabine Dose Level 
Dose 
Days Given 
0 
5 mg/m2 
1-5 
 
 
 
1 
7.5 mg/m2 
1-5 
2 
10 mg/m2 
1-5 
3 
15 mg/m2 
1-5 

 
 
 
 
Original  version date: 1-20-2017  
Amendment 1 version date: 09-06-2017 
 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
Amendment 4 version date: 07-01-2019 
 
 
 
 
 
Original Protocol version 1-20-2017 
Amendment 1 version date: 09-06-2017 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
 
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and remission status assessed at this later time point. If the marrow examination is still hypoplastic and no 
peripheral blood counts recovery (ANC >500 and platelets >50,000) without evidence of malignant infiltration 
beyond day 63, the patient will be considered to have experienced a DLT.  
 
 
4.2.1 
Criteria to begin course 2 
Patients who achieve CR, CRi, PR, or SD may receive a second course of chemotherapy no earlier than 35 days 
after the start of course 1, as soon as clinically acceptable to the treating institution and the following criteria are 
met:  
 
– 
All grade 3 and 4 non-hematologic toxicities have resolved to grade 2 or less 
 
– 
It is recommended but not required that an ANC>750/ul and platelet count >50,000/ul to be 
achieved before proceeding with a second course of therapy EXCEPT patients with CRi or 
SD. These patients, if in good enough clinical condition (based on treating physician’s clinical 
judgment), and at least 42 days have passed from start of Course 1, may begin Course 2 
irrespective of blood counts.  
 
– 
Administration of course 2 intrathecal therapy at the time of the bone marrow evaluations is 
permitted to avoid additional sedation procedures.  
 
 
4.3 
Dose-limiting Toxicity (DLT)  
 
Toxicity will be graded according to the NCI Common Toxicity Criteria (CTC) version 4.0. A copy of the CTCAE 
can be downloaded from the CTEP home page (http://ctep.cancer.gov). Any DLT should be reported immediately 
through the TACL Operation Center to the Study Chair.  
 
DLT will be assessed in the first course only. DLT will be defined as any of the following events that are related to 
DECITABINE with further explanation as follows: 
 
a) Any grade 3 or higher non-hematologic toxicity persisting for >48 hours without resolution to ≤ grade 2, with 
the exception of 
– 
Alopecia 
– 
Anorexia 
– 
Nausea 
– 
Grade 3 mucositis that resolves to ≤ Grade 2 within 14 days 
– 
Grade 3 vomiting or diarrhea that resolves to ≤ Grade 2 within 7 days 
– 
Grade 3 elevation in amylase, lipase, or direct or total bilirubin that is asymptomatic and that returns 
to ≤ Grade 2 elevation or baseline within 14 days 
– 
Grade 3 elevation in hepatic transaminases (AST, ALT or GGT) or alkaline phosphatase that returns 
to ≤ Grade 2 elevation or baseline within 14 days   
– 
Grade 3 or 4 fever with neutropenia, with or without infection 
– 
Grade 3 or 4 infection 
– 
Grade 3 electrolyte abnormalities that are not associated with clinical sequelae 
– 
Grade 3 or 4 hypotension that can be explained by sepsis 

 
 
 
 
Original  version date: 1-20-2017  
Amendment 1 version date: 09-06-2017 
 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
Amendment 4 version date: 07-01-2019 
 
 
 
 
 
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Amendment 1 version date: 09-06-2017 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
 
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– 
Grade 3  injection site reaction 
 
b) Failure to recover a peripheral ANC > 500/ul and platelet count > 20,000/ul due to documented bone marrow 
hypoplasia within 56 days without evidence of active disease or active infection (such as persistent fever or 
positive culture) by bone marrow aspiration. Bone marrow hypoplasia is defined as overall marrow cellularity 
less than 10%. Patients with CRi or SD after course 1 are excluded from this since they may proceed to 
course 2 regardless of blood counts. 
 
No other hematologic grade 3 or 4 adverse events will be considered dose-limiting.  
 
4.4 
Dose Modifications for Toxicity 
 
The intent of this study design is for all patients to receive and complete at least one course of therapy.  Patients 
who exhibit signs of disease progression or experience an unacceptable toxicity will be discontinued from 
treatment.   
 
There will be no dose delays or dose reductions of study drugs for hematologic toxicity during study therapy (Day 
1 through Day 35); however, prolonged hematopoietic recovery or bone marrow aplasia during the first 63 days 
may meet a study stopping rule. 
 
 4.4.1     Fludarabine  
 
Fludarabine dose is based on estimated creatinine clearance (Table 7)  
 
4.4.1.2 Fludarabine Modification for Obesity:  No dose modifications will be made for obesity. Obese 
patients should be dosed based on actual height and weight and not based on ideal or adjusted body 
weight. 
 
 
4.4.2 
Cytarabine 
 
4.4.2.1 Cytarabine Dose Modification for Changes in Renal Function 
 
Cytarabine is not nephrotoxic, although cytarabine clearance is impaired in the setting of decreased renal 
function. Patients whose renal function does not meet the criteria given in Section 3.3.5 at the time they 
are due to start a cycle of cytarabine should have the cytarabine dose reduced by 50%. 
 
With subsequent cycles, if renal function has returned to meet the criteria given in Section 3.3.5., then the 
cytarabine dose should be increased back to assigned dose. 
 
4.4.2.2 Cytarabine Dose Modification for Cerebellar Toxicity 
 
Patients who develop cerebellar symptoms (including, but not limited to, nystagmus, ataxia, dysmetria, 
dysarthria, somnolence, or seizure) of any grade attributable to cytarabine will be removed from protocol 
therapy. No dose reductions will be made for suspected cerebellar toxicity. 
 
4.4.2.3 Dose Modification for Infections Requiring Ongoing Systemic Therapy 

 
 
 
 
Original  version date: 1-20-2017  
Amendment 1 version date: 09-06-2017 
 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
Amendment 4 version date: 07-01-2019 
 
 
 
 
 
Original Protocol version 1-20-2017 
Amendment 1 version date: 09-06-2017 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
 
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Patients who develop a new infection that requires ongoing systemic therapy resulting in a treatment 
delay of > 14 days will be removed from protocol therapy.  Patients who complete their planned antibiotic 
therapy within 14 days of the scheduled start of the next cycle of cytarabine will continue on protocol 
therapy with cytarabine dose reduced by 25%. 
 
4.4.2.4 Cytarabine Dose Modification for Obesity 
 
No dose modifications will be made for obesity. Obese patients should be dosed based on actual height 
and weight and not based on ideal or adjusted body weight. 
 
 
 
5.0 
SUPPORTIVE CARE 
 
Best supportive care and treatment will be given as appropriate to each patient (antiemetics, antibiotics, 
transfusions, oxygen therapy, nutritional support, palliative treatment for pain or cough, etc.). Patients may 
experience profound myelosuppression and immune suppression during this time. 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. 
 
Hospitalization during each course of chemotherapy is strongly recommended until the absolute phagocyte count 
(sum of the neutrophils, bands and monocytes) is rising for two successive days, and the patient is afebrile and 
clinically stable. An additional discharge criterion of an absolute neutrophil count (ANC) of at least 200/μL is also 
suggested. 
 
Aggressive supportive care improves outcome. The following guidelines are intended to give general health 
direction for optimal patient care and to encourage uniformity in the treatment of this patient population. Notify the 
Study Chair of any unexpected or unusually severe complications. 
 
5.1 
Concurrent Therapy 
 
5.1.1 
Chemotherapy or Investigational Therapy 
Patients must not receive any non-protocol chemotherapy, investigational therapy, or immune modulating 
agents.  
 
5.1.2 
Cranial Irradiation for CNS disease is NOT allowed during protocol therapy. 
 
5.1.3 
Radiotherapy to Chloroma is acceptable. No irradiated lesion may be used to assess tumor 
response. 
 
5.1.4 
Administer Steroid Eye Drops or other eye drops per institutional practice prior to the first dose 
of cytarabine and continuing for 24 hours after the last dose. 
 
5.1.5 
Appropriate Antibiotics, Blood Products, Antiemetics, Fluids, Electrolytes and general 
supportive care are to be used as necessary.  See section 5.3 for additional information regarding 
infection control 

 
 
 
 
Original  version date: 1-20-2017  
Amendment 1 version date: 09-06-2017 
 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
Amendment 4 version date: 07-01-2019 
 
 
 
 
 
Original Protocol version 1-20-2017 
Amendment 1 version date: 09-06-2017 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
 
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5.1.6 
Patients May Have Received Hydroxyurea to keep WBC below 50,000/μL prior to beginning 
protocol therapy, but hydroxyurea must be discontinued 24 hours prior to starting systemic protocol 
therapy. 
 
5.1.7 
Alternative Medications: Use of alternative medications (eg, herbal or botanical for anticancer 
purposes) is not permitted during the entire study period. 
 
 
5.1.8 
Drug interactions: Prolonged QT interval is a possible risk with vorinostat. Use caution if 
additional supportive care drugs that prolong QT interval are necessary. Updated list of agents that can 
prolong QT interval is available at  https://crediblemeds.org/index.php/drugsearch 
Also avoid coumarin-derivative anticoagulants to minimize drug interactions with vorinostat. 
Also avoid coumarin-derivative anticoagulants to avoid drug interactions. 
 
 
5.2 
Blood Products 
 
Investigators should follow institutional guidelines regarding the administration of blood products. 
 
 
5.3 
Infection Control 
 
5.3.1 
Pneumocystis Prophylaxis 
All patients are to receive prophylaxis with Trimethoprim/Sulfamethoxazole (TMP-Sulfa) for Pneumocystis 
for two sequential days each week at a dose of 2.5 mg/kg/dose TMP-Sulfa (maximum dose of 160 mg) 
twice daily (BID) or according to institutional policy, unless they have a documented sulfa allergy. Sulfa-
allergic patients should receive dapsone 2 mg/kg orally (PO) q day with a maximum dose of 100 mg/day, 
or monthly pentamidine (IV or aerosolized). Pneumocystis prophylaxis should be continued throughout 
the entire study period. 
 
5.3.2 
Bacterial, Fungal and Viral Prophylaxis 
Prophylaxis for bacterial infections is not universally accepted; therefore, it is not mandatory. However, 
treating physicians should be aware that a high incidence of serious bacterial and fungal infections has 
been observed in patients receiving this combination of cytarabine and fludarabine. The use of 
prophylactic antibacterial and antiviral agents is strongly recommended according to the following 
parameters: 
 
Treating physicians may use institutional guidelines but should strongly consider antibacterial prophylaxis 
during each course of therapy until the post-nadir ANC is >750/μL. Avoid using vancomycin or other 
nephrotoxic antibiotics during high dose cytarabine administration for prophylaxis. 
 
Given the high risk of fungal infections in patients with FLAG-based therapy, it is mandated that 
all  patients  receive antifungal prophylaxis during each course of therapy until the post-nadir 
ANC is >750/μL. It is strongly encouraged to use the drug with anti-mold and anti-yeast activity 
such as liposomal amphotericin B (e.g. AmBisome), an echinocandin (caspofungin, micafungin, 

 
 
 
 
Original  version date: 1-20-2017  
Amendment 1 version date: 09-06-2017 
 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
Amendment 4 version date: 07-01-2019 
 
 
 
 
 
Original Protocol version 1-20-2017 
Amendment 1 version date: 09-06-2017 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
 
Amendment 4 version date: 07-01-2019 
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anidulafungin) or an extended-spectrim azole (voriconazole, posazonazole). The choice of 
antifungal therapy can be selected based on local fungal prevalence and sensitivity patterns, and 
patient’s age and availability of appropriate formulation/route.The doses used should be in the 
treatment range more so than prophylactic as that is when colonization and infection may occur 
with patients at high risk for fungal infection. Close hepatic and renal monitoring with dose 
adjustments is recommended, particularly for those receiving concurrent hepatic and nephrotoxic 
agents. 
 
Patients who have HSV antibodies are recommended to receive prophylactic acyclovir at 750 mg/m2/day 
divided BID or valacyclovir 
 
5.3.3 
Fever and Neutropenia 
 
 
All patients with a fever >38.5°C on a single occasion, or >38°C on 2 occasions within one hour , and an 
ANC <0.50 x 109/L are to be hospitalized and treated immediately with intravenous broad-spectrum 
antibiotics after obtaining appropriate blood cultures. Selection of empiric therapy should be determined 
by institutional pathogen prevalence and susceptibility patterns and should include Pseudomonas 
coverage, (e.g. such as meropenem, imipenem, cefepime, ceftazidine, or piperacillin-tazobactam). 
Duration of therapy should be determined by site of infection, culture results, and response to treatment. 
For  the the persistence of fever, or emergence of a new fever in neutropenic patients after 3 days of 
broad-spectrum antibiotic coverage without an identified source/site, patients on prophylactic dosing of 
antifunal therapy should have their therapy escalated to treatment dosing. Additionally, radiographic 
imaging surveillance for sites of infection should also be performed as clinically indicated and for 
persistent fevers. These scans would include CT sinus, chest, abdomen and pelvis. Additional 
recommendations for initial diagnostic work-up for invasive fungal infection (IFI) include serum fungal 
markers galactomannan (GMN) and beta-d-glucan along with blood fungal cultures. 
 
 
When severe mucositis or a sepsis syndrome is present in patients with febrile neutropenia, or a patient 
has a history of prior alpha hemolytic sepsis, consider inclusion of Vancomycin in the empiric antibiotic 
regimen. 
 
5.3.4 
Empiric Management of Respiratory Symptoms and Pulmonary Infiltrates 
 
Patients with respiratory symptoms should have a viral film array or PCR sent to evaluate for respiratory 
viral infection. CT chest imaging is warranted for patients with hypoxemia and/or pulmonary infiltrates on 
CXR. Pulmonary infiltrates should be evaluated in the context of the patient's clinical and laboratory 
profile as well as institutional infection patterns. If the patient is not neutropenic, and the pulmonary 
lesions on CT scan are not particularly suggestive of a fungal infection (Aspergillus, mucor), consider 
using broad spectrum antibiotics. If the patient develops progressively worsening clinical or laboratory 
features, or if, the pulmonary lesions on CT scan are suggestive of a fungal infection (Aspergillus, mucor), 
then more aggressive diagnostic measures should be undertaken. Pulmonary infiltrates may be evaluated 
with bronchoscopy and biopsy, lavage or open lung biopsy. BAL/biopsy diagnostics should include 
routine culture (acid-fast bacilli, bacterial, and fungal culture), cytology, and GMN and PCR (AFB, 
bacterial, fungal including Pneumocystis jiroveci, and viral).If a procedure cannot be tolerated, and/or if 

 
 
 
 
Original  version date: 1-20-2017  
Amendment 1 version date: 09-06-2017 
 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
Amendment 4 version date: 07-01-2019 
 
 
 
 
 
Original Protocol version 1-20-2017 
Amendment 1 version date: 09-06-2017 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
 
Amendment 4 version date: 07-01-2019 
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there is high clinical suspicion consider beginning empiric treatment with amphotericin B given the high 
likelihood of fungal disease. It is advisable to seek an infectious disease consult under these 
circumstances. Empiric coverage may include treatment of gram-negative and positive bacteria, 
Legionella (erythromycin), Pneumocystis (TMP/SMX), and fungi (amphotericin) pending culture results. 
 
If fungal pulmonary disease is documented, surveillance radiographic imaging studies of the sinuses, 
abdomen/pelvis are indicated. Surgical excision of pulmonary lesions should be considered at the 
discretion of the treating physician. Treatment of fungal infections with amphotericin B and/or other 
antifungal agents with anti-mold and anti-yeast activity such as an echinocandin (caspofungin, 
micafungin, anidulafungin) or an extended-spectrim azole (voriconazole, posazonazole) will be at 
the discretion of the treating physician.  
 
5.3.5 
Management of Mucositis/Perirectal Cellulitis 
 
Mucositis should be managed with IV hydration and hyperalimentation (if indicated), effective analgesia, 
broad-spectrum gram-positive and gram-negative antibiotic therapy and empiric antiviral and antifungal 
therapy as indicated. Management of perirectal cellulitis should include broad-spectrum antibiotic therapy 
with dual gram-negative coverage as well as anaerobic coverage (i.e. ceftazidime + aminoglycoside + 
metronidazole; or piperacillin-tazobactam + aminoglycoside), Sitz baths, a strong barrier technique and 
effective analgesia. 
 
 
 
5.3.6 
Use of G-CSF 
The routine use of G-CSF outside of protocol therapy is not generally recommended, but may be used at 
the discretion of the investigator in situations such as serious infection with neutropenia. 
 
 
6.0 DRUG INFORMATION 
 
6.1  
Decitabine (Dacogen™) 
 
 
6.1.1 
Nomenclature and Molecular Structure Dacogen™ (decitabine) for Injection contains decitabine (5-
aza-2’-deoxycytidine), an analogue of the natural nucleoside 2’-deoxycytidine.  Decitabine is a fine, white 
to almost white powder with the molecular formula of C8H12N4O4 and a molecular weight of 228.21.  Its 
chemical name is 4-amino-1-(2-deoxy-b-D-erythro-pentofuranosyl)-1,3,5-triazin-2(1H )-one and it has the 
following structural formula: 
 
 
 
6.1.2 
Mode of Action and Pharmacology Decitabine is believed to exert its antineoplastic effects after 
phosphorylation and direct incorporation 16 into DNA and inhibition of DNA methyltransferase, causing 
hypomethylation of DNA and cellular 17 differentiation or apoptosis.  Decitabine inhibits DNA methylation 
in vitro, which is achieved at concentrations that do not cause major suppression of DNA synthesis.  
Decitabine-induced hypomethylation in neoplastic cells may restore normal function to genes that are 
critical for the control of cellular differentiation and proliferation.  In rapidly dividing cells, the cytotoxicity of 

 
 
 
 
Original  version date: 1-20-2017  
Amendment 1 version date: 09-06-2017 
 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
Amendment 4 version date: 07-01-2019 
 
 
 
 
 
Original Protocol version 1-20-2017 
Amendment 1 version date: 09-06-2017 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
 
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TACL Internal Distribution Only 
 
decitabine may also be attributed to the formation of covalent adducts between DNA methyltransferase 
and decitabine incorporated into DNA.  Non-proliferating cells are relatively insensitive to decitabine. 
 
Patients with advanced solid tumors received a 72-hour infusion of decitabine at 20 to 30 mg/m2/day.  
Decitabine pharmacokinetics were characterized by a biphasic disposition.  The total body clearance 
(mean ± SD) was 124 ± 19 L/hr/m2, and the terminal phase elimination half-life was 0.51 ± 0.31 hr. 
Plasma protein binding of decitabine is negligible      (< 1%).  The exact route of elimination and metabolic 
fate of decitabine is not known in humans.  One of the pathways of elimination of decitabine appears to 
be deamination by cytidine deaminase found principally in the liver but also in granulocytes, intestinal 
epithelium and whole blood. 
 
 
6.1.3 
Toxicity/Adverse Events 
 
Decitabine 
 
System Organ Class 
Adverse Events Reported in ≥ 10% 
of Patients who received 
decitabine in a Phase 3 MDS trial 
Adverse Events Reported in ≥ 5% 
but < 10% of Patients who received 
decitabine in a Phase 3 MDS trial 
Blood and Lymphatic 
System 
 
Neutropenia 
 
Thrombocytopenia 
 
Anemia 
 
Febrile neutropenia 
 
Leukopenia 
 
Lymphadenopathy 
 
Thrombocythemia 
Gastrointestinal  
 
 
Nausea 
 
Constipation 
 
Diarrhea 
 
Vomiting 
 
Abdominal pain 
 
Decreased appetite 
 
Anorexia 
 
Oral Mucosal petechia 
 
Stomatitis 
 
Dyspepsia 
 
Ascites 
 
Gingival bleeding 
 
Hemorrhoids 
 
Tongue ulceration 
 
Dysphagia 
 
Oral soft tissue disorders 
 
Lip ulceration 
 
Abdominal distention 
 
Upper abdominal pain 
 
Gastro-esophogeal reflux 
disease 
 
Glossodynia 
General Disorders 
 
Pyrexia 
 
Peripheral edema 
 
Rigors 
 
Edema NOS 
 
Pain NOS 
 
Lethargy 
 
Falls 
 
Chest discomfort 
 
Intermittent pyrexia 
 
Malasise 
 
Crepitations 
 
Catheter site erythema 
 
Catheter site pain 
 
Injection site swelling 

 
 
 
 
Original  version date: 1-20-2017  
Amendment 1 version date: 09-06-2017 
 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
Amendment 4 version date: 07-01-2019 
 
 
 
 
 
Original Protocol version 1-20-2017 
Amendment 1 version date: 09-06-2017 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
 
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Decitabine 
 
System Organ Class 
Adverse Events Reported in ≥ 10% 
of Patients who received 
decitabine in a Phase 3 MDS trial 
Adverse Events Reported in ≥ 5% 
but < 10% of Patients who received 
decitabine in a Phase 3 MDS trial 
Infection 
 
Pneumonia NOS 
 
Cellulitis 
 
Candidal infection NOS 
 
Catheter related infection 
 
Urinary tract infection 
 
Staphylococcal infection 
 
Oral candidiasis 
 
Sinusitis 
 
Bacteremia 
Metabolic/Laboratory 
 
Hyperbilirubinemia  
 
Elevated alkaline phophatase 
 
Elevated AST 
 
Elevated BUN 
 
Hyperglycemia 
 
Hypoalbuminemia 
 
Hypomagnesemia 
 
Hypokalemia 
 
Hyponatremia 
 
Hyperkalemia 
 
Dehydration 
 
Lactate dehydrogenase 
increased 
 
Increased blood bicarboanate 
 
Decreased blood bicaroboate 
 
Hypochloremia 
 
Blood protein decreased 
 
Blood bilirubin decreased 
Musculoskeletal 
 
Arthralgia 
 
Limb pain 
 
Back pain 
 
Chest wall pain 
 
Musculoskeletal discomfort 
 
Myalgia 
Neurological 
 
Headache 
 
Dizziness 
 
Hypoesthesia 
 
Insomnia 
 
Confusional state 
 
Anxiety 
 
Pulmonary 
 
Cough 
 
Pharyngitis 
 
Crackles lung 
 
Breath sounds decreased 
 
Hypoxia 
 
Rales 
 
Postnasal drip 
Renal  
 
 
Dysuria 
 
Urinary frequency 
Skin 
 
Ecchymosis 
 
Rash 
 
Erythema 
 
Skin lesions NOS 
 
Pruritus 
 
Petechiae 
 
Pallor 
 
Alopecia 
 
Urticaria 
 
Facial swelling 
Cardiac 
 
Cardiac murmur NOS 
 
 
Hypotension 
 
Hematoma 
 
 
 

 
 
 
 
Original  version date: 1-20-2017  
Amendment 1 version date: 09-06-2017 
 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
Amendment 4 version date: 07-01-2019 
 
 
 
 
 
Original Protocol version 1-20-2017 
Amendment 1 version date: 09-06-2017 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
 
Amendment 4 version date: 07-01-2019 
31 
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TACL Internal Distribution Only 
 
6.1.4 
Pregnancy and Nursing Mothers Decitabine may cause fetal harm when administered to a pregnant 
woman.  Women of childbearing potential should be advised to avoid becoming pregnant while using 
Decitabine.  Men should be advised not to father a child while receiving treatment with Decitabine, and for 
2 months afterwards.  It is not known whether decitabine or its metabolites are excreted in human milk.  
Because many drugs are excreted in human milk, and because of the potential for serious adverse 
reactions from decitabine in nursing infants, breast feeding must be avoided. 
 
6.1.5 
Formulation and Stability Dacogen™ (decitabine) for Injection is supplied as a sterile lyophilized white 
to almost white powder, in a single-dose vial, packaged in cartons of 1 vial.  Each vial contains 50 mg of 
decitabine.  Store vials at 25°C (77°F); excursions permitted to 15 - 30°C (59 - 86°F). 
 
Unless used within 15 minutes of reconstitution, the diluted solution must be prepared using cold (2°C - 
8°C) infusion fluids and stored at 2°C - 8°C (36°F - 46°F) for up to a maximum of 7 hours until 
administration. 
 
6.1.6 
Preparation and Administration Dacogen should be aseptically reconstituted with 10 mL of Sterile 
Water for Injection (USP); upon reconstitution, each mL contains approximately 5.0 mg of decitabine at 
pH 6.7-7.3.  Immediately after reconstitution, the solution should be further diluted with 0.9% Sodium 
Chloride Injection, 5% Dextrose Injection, or Lactated Ringer’s Injection to a final drug concentration of 
0.1 - 1.0 mg/mL.  Unless used within 15 minutes of reconstitution, the diluted solution must be prepared 
using cold (2°C - 8°C) infusion fluids and stored at 2°C - 8°C (36°F - 46°F) for up to a maximum of 7 
hours until administration. 
 
6.1.7 
Supplier Decitabine is commercially available.  See package insert and prescriber information for further 
information. 
 
6.1.8 
Decitabine Modification for Obesity No dose modifications will be made for obesity. Obese patients 
should be dosed based on actual height and weight and not based on ideal or adjusted body weight. 
 
 
6.2      Vorinostat (Zolinza®, SAHA, suberoylanilide acid)      
 
 
6.2.1 Nomenclature and Molecular Structure:  ZOLINZA contains vorinostat, which is described chemically as 
N-hydroxy-N'-phenyloctanediamide.  The empirical formula is C14H20N2O3.  The molecular weight is 264.32. 
 
6.2.2 
Mode of Action and Pharmacology:  Vorinostat inhibits the enzymatic activity of histone deacetylases 
HDAC1, HDAC2 and HDAC3 (Class I) and HDAC6 (Class II) at nanomolar concentrations (IC50 < 86 
nM).  These enzymes catalyze the removal of acetyl groups from the lysine residues of proteins, including 
histones and transcription factors.  In some cancer cells, there is an overexpression of HDACs, or an 
aberrant recruitment of HDACs to oncogenic transcription factors causing hypoacetylation of core 
nucleosomal histones.  Hypoacetylation of histones is associated with a condensed chromatin structure 
and repression of gene transcription.  Inhibition of HDAC activity allows for the accumulation of acetyl 
groups on the histone lysine residues resulting in an open chromatin structure and transcriptional 
activation.  In vitro, vorinostat causes the accumulation of acetylated histones and induces cell cycle 
arrest and/or apoptosis of some transformed cells.  The mechanism of the antineoplastic effect of 
vorinostat has not been fully characterized. 
 

 
 
 
 
Original  version date: 1-20-2017  
Amendment 1 version date: 09-06-2017 
 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
Amendment 4 version date: 07-01-2019 
 
 
 
 
 
Original Protocol version 1-20-2017 
Amendment 1 version date: 09-06-2017 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
 
Amendment 4 version date: 07-01-2019 
32 
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Vorinostat is approximately 71% bound to human plasma proteins over the range of concentrations of 0.5 
to 50 µg/mL.  The major pathways of vorinostat metabolism involve glucuronidation and hydrolysis 
followed by β-oxidation.  Vorinostat is eliminated predominantly through metabolism with less than 1% of 
the dose recovered as unchanged drug in urine, indicating that renal excretion does not play a role in the 
elimination of vorinostat. 
 
6.2.3 
Toxicity/Adverse Events:  The most common drug-related adverse reactions can be classified into 4 
symptom complexes: 
 
1. Gastrointestinal symptoms (diarrhea, nausea, anorexia, weight decrease, 
vomiting, constipation) 
2. Constitutional symptoms (fatigue, chills) 
3. Hematologic abnormalities (thrombocytopenia, anemia) 
4. Taste disorders (dysgeusia, dry mouth) 
 
The most common serious drug-related adverse reactions were pulmonary embolism and 
anemia. 
 
Adverse Events Reported in ≥ 10% of Patients 
With Cutaneous T-cell Lymphoma Who Were Receiving Vorinostat (Regardless of Causality) 
 
Fatigue 
 
Diarrhea 
 
Nausea 
 
Dysguesia 
 
Thrombocytopenia 
 
Anorexia 
 
Weight decrease 
 
Muscle spasms 
 
Alopecia 
 
Dry mouth 
 
Blood creatinine increased 
 
Chills 
 
Vomiting 
 
Constipation 
 
Dizziness 
 
Anemia 
 
Decreased appetite 
 
Peripheral edema 
 
Headache 
 
Pruritus 
 
Cough 
 
Upper respiratory infection 
 
Pyrexia 
Adverse Events Reported in ≥ 5% but < 10% of Patients 
With Cutaneous T-cell Lymphoma Who Were Receiving Vorinostat (Regardless of Causality) 
 
Pulmonary embolism 
 
Hyperglycemia 
Rare Adverse Events Reported in Other Patients Who Were Receiving Vorinostat (Regardless of 
Causality) 
 
Deep vein thrombosis 
 
Abnormal electrolytes (including blood 
creatinine, magnesium, potassium and 
calcium) 
 
Ischemic stroke 
 
Pelviureteric obstruction 
 
Spinal cord injury 
 
Syncope 
 
Ureteric obstruction 
 
Squamous cell carcinoma 
 
Cholecystitis 
 
Death 
 
Blood stream infections (including specifically, 
for example: enterococcal, streptococcal) 
 
Exfoliative dermatitis 
 
Gastrointestinal hemorrhage 
 
Lobar pneumonia 
 
Myocardial infarction 

 
 
 
 
Original  version date: 1-20-2017  
Amendment 1 version date: 09-06-2017 
 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
Amendment 4 version date: 07-01-2019 
 
 
 
 
 
Original Protocol version 1-20-2017 
Amendment 1 version date: 09-06-2017 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
 
Amendment 4 version date: 07-01-2019 
33 
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TACL Internal Distribution Only 
 
 
T-cell lymphoma 
 
Prolonged QT interval 
 
6.2.4 
Pregnancy and Breast Feeding:  Vorinostat may cause fetal harm when administered to a pregnant 
woman.  Women of childbearing potential should be advised to avoid becoming pregnant while using 
vorinostat.  Men should be advised not to father a child while receiving treatment with vorinostat, and for 2 
months afterwards.  It is not known whether vorinostat or its metabolites are excreted in human milk.  
Because many drugs are excreted in human milk, and because of the potential for serious adverse 
reactions from vorinostat in nursing infants, breast feeding must be avoided. 
6.2.5     Formulation and Stability:  100 mg white, opaque, hard gelatin capsules with “568” over “100 mg”  
printed within radial bar in black ink on the capsule body.  Store at 20-25C (68-77F), excursions 
permitted between 15-30C (59-86F). 
 
6.2.6     Preparation and Administration:  Swallow the capsules whole, do not open, chew or crush them.  Take  
             with food the same time each day. If dose is vomited within 30 minutes of administration, the patient may  
             be re-dosed. If patient vomits dose beyond 30 minutes of administration, contact the Study Chair. If dose  
             is forgotten and/or missed, contact the Study Chair. 
 
6.2.7     Supplier:  Vorinostat is commercially available.  See package insert and prescriber information for further  
            information.  
  
6.2.8    Vorinostat Modification for Obesity:  No dose modifications will be made for obesity. Obese patients  
           should be dosed based on actual height and weight and not based on ideal or adjusted body weight. 
 
 
 
6.3       FLUDARABINE  
 
6.3.1  
Nomenclature and Molecular Structure:  FLUDARA FOR INJECTION contains fludarabine phosphate, 
a fluorinated nucleotide analog of the antiviral agent vidarabine, 9-β-D-arabinofuranosyladenine (ara-A) 
that is relatively resistant to deamination by adenosine deaminase.  Each vial of sterile lyophilized solid 
cake contains 50 mg of the active ingredient fludarabine phosphate, 50 mg of mannitol, and sodium 
hydroxide to adjust pH to 7.7.  The pH range for the final product is 7.2-8.2.  Reconstitution with 2 mL of 
Sterile Watr for Injection USP results in a solution containing 25 mg/mL of fludarabine phosphate 
intended for intravenous administration. 
 
The chemical name for fludarabine phosphate is 9H-Purin-6-amine, 2-fluoro-9 (5-0-phosphono-B-D-
arabino furanosyl fludarabine phosphate) (2-fluoro-ara-AMP).  The molecular formula of fludarabine 
phosphate is C10H13FN5O7P (MW 365.2). 
 
6.3.2 
Mode of Action and Pharmacology:  Fludarabine phosphate is rapidly dephosphorylated to 2-fluoro-
ara-A and then phosphorylated intracellularly by deoxycytidine kinase to the active triphosphate, 2-fluoro-
ara-ATP.  This metabolite appears to act by inhibiting DNA polymerase alpha, ribonucleotide reductase 
and DNA primase, thus inhibiting DNA synthesis.  The mechanism of action of this antimetabolite is not 
completely characterized and may be multi-faceted. 
 

 
 
 
 
Original  version date: 1-20-2017  
Amendment 1 version date: 09-06-2017 
 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
Amendment 4 version date: 07-01-2019 
 
 
 
 
 
Original Protocol version 1-20-2017 
Amendment 1 version date: 09-06-2017 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
 
Amendment 4 version date: 07-01-2019 
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Phase 1 studies in humans have demonstrated that fludarabine phosphate is rapidly converted to the 
active metabolite, 2-fluoro-ara-A, within minutes after intravenous infusion.  Consequently, clinical 
pharmacology studies have focused on 2-fluoro-ara-A pharmacokinetics.  After the five daily doses of 25 
mg 2-fluoro-ara-AMP/m2 to cancer patients infused over 30 minutes, 2-fluoro-ara-A concentrations show 
a moderate accumulation.  During a 5-day treatment schedule, 2-fluoro-ara-A plasma trough levels 
increased by a factor of about 2.  The terminal half-life of 2-fluoro-ara-A was estimated at approximately 
20 hours.  In vitro, plasma protein binding of fludarabine ranged between 19% and 29%.  
 
A correlation was noted between the degree of absolute granulocyte count nadir and increased area 
under the concentration × time curve (AUC). 
 
6.3.3 
Toxicity/Adverse Events:  The most common adverse events include myelosuppression, fever and 
chills, infection, and nausea and vomiting.  Other commonly reported events include malaise, fatigue, 
anorexia, and weakness.  Serious opportunistic infections have occurred in CLL patients treated with 
FLUDARA FOR INJECTION.  The most frequently reported adverse events and those reactions which 
are more clearly related to the drug are arranged below according to body system.   
 
Fludarabine 
Frequency of Adverse Event: 
Common: Happens to 21-100 children out of every 100 
Timing of AE Onset in Relation to 
Drug Administration: 
Adverse Events 
Immediate:  Within 1-2 days of 
receiving drug 
Fever, fatigue, weakness, pain, nausea, vomiting, anorexia, cough, 
dyspnea 
Prompt:  Within 2-3 weeks, prior to the 
next course 
Myelosuppression (anemia, neutropenia, thrombocytopenia), Infection 
(urinary tract infection, herpes simplex infection, pneumonia, upper 
respiratory) 
Delayed:  Any time later during 
therapy, excluding the above conditions 
 
Late:  Any time after completion of 
treatment 
 
 
Frequency of Adverse Event: 
Occasional:  Happens to 5-20 children out of every 100 
Timing of AE Onset in Relation to 
Drug Administration: 
Adverse Events 
Immediate:  Within 1-2 days of 
receiving drug 
Edema including peripheral edema, chills, rash, diarrhea, rhinitis, 
diaphoresis, malaise, abdominal pain, headache, back pain, myalgia, 
stomatitis, flu-like syndrome 
Prompt:  Within 2-3 weeks, prior to the 
next course 
Weight loss, gastrointestinal bleeding, hemoptysis, paresthesia, 
allergic pneumonitis, bronchitis, pharyngitis, visual disturbance, 
hearing loss, hyperglycemia 
Delayed:  Any time later during 
therapy, excluding the above conditions 
 
Late:  Any time after completion of 
treatment 
 
 
 

 
 
 
 
Original  version date: 1-20-2017  
Amendment 1 version date: 09-06-2017 
 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
Amendment 4 version date: 07-01-2019 
 
 
 
 
 
Original Protocol version 1-20-2017 
Amendment 1 version date: 09-06-2017 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
 
Amendment 4 version date: 07-01-2019 
35 
CONFIDENTIAL 
 
 
TACL Internal Distribution Only 
 
Fludarabine 
Frequency of Adverse Event: 
Rare:  Happens to < 5 
children out of every 100 
Timing of AE Onset in Relation to Drug Administration: 
Adverse Events 
Immediate:  Within 1-2 days of receiving drug 
Anaphylaxis, tumor lysis 
syndrome, dehydration* 

 
 
 
 
Original  version date: 1-20-2017  
Amendment 1 version date: 09-06-2017 
 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
Amendment 4 version date: 07-01-2019 
 
 
 
 
 
Original Protocol version 1-20-2017 
Amendment 1 version date: 09-06-2017 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
 
Amendment 4 version date: 07-01-2019 
36 
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TACL Internal Distribution Only 
 
Fludarabine 
Frequency of Adverse Event: 
Rare:  Happens to < 5 
children out of every 100 
Prompt:  Within 2-3 weeks, prior to the next course 
 
 
 
 
Sinusitis, dysuria, opportunistic 
infections and reactivation of 
latent viral infections like 
Epstein-Barr virus (EBV), 
herpes zoster and John 
Cunningham (JC) virus 
(progressive multifocal 
leukoencephalopathy [PML])L, 
EBV associated 
lymphoproliferative disorder, 
panycytopenia (can be 
prolonged), pulmonary 
hypersensitivitya (dyspnea, 
cough, hypoxia, interstitial 
pulmonary infiltrate), 
pulmonary toxicity (acute 
respiratory distress syndrome 
[ARDS], pulmonary fibrosis, 
pulmonary hemorrhage, 
respiratory distress, respiratory 
failure), pericardial effusion, 
skin toxicity (erythema 
multiforme, Stevens-Johnson 
syndrome, toxic epidermal 
necrolysis, pemphigus), liver 
failure, renal failure, 
hemorrhage, transfusion-
associated graft-versus-host 
disease has occurred following 
transfusion of non-irradiated 
blood products, phlebitis*, 
sleep disorder*, cerebellar 
syndrome*, depression*, 
mentation impaired*, 
alopecia*, pruritus*, 
seborrhea*, esophagitis*, 
constipation*, mucositis*, 
dysphagia*, hesitancy*, 
cholelithiasis*, abnormal liver 
function tests *, osteoporosis*, 
arthralgia*, abnormal renal 
function test*, proteinuria*, 
epistaxis*, hemorrhagic 
cystitis*, eosinophilia* 

 
 
 
 
Original  version date: 1-20-2017  
Amendment 1 version date: 09-06-2017 
 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
Amendment 4 version date: 07-01-2019 
 
 
 
 
 
Original Protocol version 1-20-2017 
Amendment 1 version date: 09-06-2017 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
 
Amendment 4 version date: 07-01-2019 
37 
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TACL Internal Distribution Only 
 
Fludarabine 
Frequency of Adverse Event: 
Rare:  Happens to < 5 
children out of every 100 
Delayed:  Any time later during therapy, excluding the above conditions 
Fludarabine 
System Organ Class 
Most Frequently Reported Adverse Events 
Hematopoietic System 
 
Neutropenia 
 
Thrombocytopenia 
 
Anemia 
 
Autoimmune hemolytic anemia 
Metabolic  
 
Tumor lysis syndrome 
Nervous System 
 
Weakness 
 
Agitation 
 
Confusion 
 
Visual disturbance 
 
Coma 
 
Peripheral neuropathy  
Pulmonary System 
 
Pneumonia 
 
Pulmonary sensitivity reactions  
(dyspnea, cough, interstitial pulmonary
ARDS) 
 
Pulmonary hemorrhage 
 
Pulmonary fibrosis 
Gastrointestinal System 
 
Nausea 
 
Vomiting 
 
Anorexia 
 
Diarrhea 
 
Stomatitis 
 
Gastrointestinal bleeding 
Cardiovascular 
 
Edema 
Genitourinary System 
 
Hemorrhagic cystitis 
Skin  
 
Rash 
Neurotoxicity (increased with 
high doses): seizures, 
agitation, confusion, 
weakness, visual disturbances, 
optic neuritis, optic 
neuropathy, photophobia, 
blindness, paralysis, coma, 
death, peripheral 
neuropathya); autoimmune 
phenomena: 
thrombocytopenia/thrombocyto
penic purpura (ITP), Evans 
syndrome, hemolytic anemia, 
acquired hemophilia 
Late:  Any time after completion of treatment 
Myelodysplastic 
syndrome/acute myeloid 
leukemia (mainly associated 
with prior or concomitant or 
subsequent treatment with 
other anticancer treatments), 
skin cancer (new onset or 
exacerbation) 
Frequency of Adverse Event: 
Unknown:  Insufficient Data 
Available 
Timing of AE Onset in Relation to Drug Administration: 
Adverse Events 
Unknown:  Insufficient Data Available 
Fetal toxicities and teratogenic 

 
 
 
 
Original  version date: 1-20-2017  
Amendment 1 version date: 09-06-2017 
 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
Amendment 4 version date: 07-01-2019 
 
 
 
 
 
Original Protocol version 1-20-2017 
Amendment 1 version date: 09-06-2017 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
 
Amendment 4 version date: 07-01-2019 
38 
CONFIDENTIAL 
 
 
TACL Internal Distribution Only 
 
Fludarabine 
Frequency of Adverse Event: 
Rare:  Happens to < 5 
children out of every 100 
effects of cytarabine have 
been noted in humans.  It is 
unknown whether the drug is 
excreted in breast milk 
*   Reported in ≤ 3% of subjects.  Since these are not considered life threatening they are not included in the 
consent. 
 
 
6.3.4 
Drug Interactions:  The use of FLUDARA FOR INJECTION in combination with pentostatin is not 
recommended due to the risk of severe pulmonary toxicity. 
 
6.3.5 
Pregnancy and Breast Feeding:  Pregnancy Category D:  Fludara for Injection may cause fetal harm 
when administered to a pregnant woman.  Fludarabine phosphate was teratogenic in rats and in rabbits.  
Dose-related teratogenic effects manifested by external deformities and skeletal malformations were 
observed in the rabbits at 5 and 8 mg/kg/day.  Drug-related deaths or toxic effects on maternal and fetal 
weights were not observed.  There are no adequate and well-controlled studies in pregnant women.  If 
Fludara for Injection is used during pregnancy, or if the patient becomes pregnant while taking this drug, 
the patient should be apprised of the potential hazard to the fetus.  Women of childbearing potential 
should be advised to avoid becoming pregnant. 
 
It is not known whether this drug is excreted in human milk.  Because many drugs are excreted in human 
milk and because of the potential for serious adverse reactions in nursing infants from Fludara for 
Injection, a decision should be made to discontinue nursing or discontinue the drug, taking into account 
the importance of the drug for the mother. 
 
6.3.6 
Formulation and Stability:  Fludara for Injection is supplied as a white, lyophilized solid cake.  Each vial 
contains 50 mg of fludarabine phosphate, 50 mg of mannitol, and sodium hydroxide to adjust pH to 7.7.  
The pH range for the final product is 7.2-8.2.  Store under refrigeration, between 2-8 °C (36-46 °F).  
 
Fludara for Injection is supplied in a clear glass single dose vial (6 mL capacity) and packaged in a single 
dose vial carton in a shelf pack of five. 
 
6.3.7 
Preparation and Administration:  Fludara for Injection should be prepared for parenteral use by 
aseptically adding Sterile Water for Injection USP.  When reconstituted with 2 mL of Sterile Water for 
Injection, USP, the solid cake should fully dissolve in 15 seconds or less; each mL of the resulting 
solution will contain 25 mg of fludarabine phosphate, 25 mg of mannitol, and sodium hydroxide to adjust 
the pH to 7.7.  The pH range for the final product is 7.2-8.2.  In clinical studies, the product has been 
diluted in 100 cc or 125 cc of 5% Dextrose Injection USP or 0.9% Sodium Chloride USP.  Reconstituted 
Fludara for Injection contains no antimicrobial preservative and thus should be used within 8 hours of 
reconstitution.  Care must be taken to assure the sterility of prepared solutions.  Parenteral drug products 
should be inspected visually for particulate matter and discoloration prior to administration. 
 
Procedures for proper handling and disposal should be considered.  Consideration should be given to 
handling and disposal according to guidelines issued for cytotoxic drugs.  The use of latex gloves and 

 
 
 
 
Original  version date: 1-20-2017  
Amendment 1 version date: 09-06-2017 
 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
Amendment 4 version date: 07-01-2019 
 
 
 
 
 
Original Protocol version 1-20-2017 
Amendment 1 version date: 09-06-2017 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
 
Amendment 4 version date: 07-01-2019 
39 
CONFIDENTIAL 
 
 
TACL Internal Distribution Only 
 
safety glasses is recommended to avoid exposure in case of breakage of the vial or other accidental 
spillage.  If the solution contacts the skin or mucous membranes, wash thoroughly with soap and water; 
rinse eyes thoroughly with plain water.  Avoid exposure by inhalation or by direct contact of the skin or 
mucous membranes. 
 
6.3.8 
Supplier:  Fludarabine is commercially available.  See package insert and prescriber information for 
further information. 
 
6.4     Cytarabine (Cytosine arabinoside, Ara-C, Cytosar®) 
 
 
6.4.1 
Source and Pharmacology:  Cytarabine appears to act through the inhibition of DNA polymerase.  A 
limited, but significant, incorporation of cytarabine into both DNA and RNA has also been reported.  It 
exhibits cell phase specificity, primarily killing cells undergoing DNA synthesis (S-phase) and under 
certain conditions blocking the progression of cells from the G1 phase to the S-phase.  Cytarabine is 
metabolized by deoxycytidine kinase and other nucleotide kinases to the nucleotide triphosphate (Ara-
CTP), an effective inhibitor of DNA polymerase.  Ara-CTP is inactivated by a pyrimidine nucleoside 
deaminase, which converts it to the nontoxic uracil derivative (Ara-U).  It appears that the balance of 
kinase and deaminase levels may be an important factor in determining sensitivity or resistance of the cell 
to cytarabine.  It has an initial distributive phase t½ of about 10 minutes, with a secondary elimination 
phase t½ of about 1 to 3 hours.  Peak levels after intramuscular or subcutaneous administration of 
cytarabine occur about 20 to 60 minutes after injection and are lower than IV administration. Intrathecally 
administered doses are metabolized and eliminated more slowly with a t½ of about 2 hours. 
 
6.4.2     Toxicity/Adverse Event:  (Intravenous,) 
 
Cytarabine Intravenous 
 
Common 
Happens to 21-100 
children out of every 
100 
Occasional 
Happens to 5-20 
children out of every 
100 
Rare 
Happens to < 5 children out of every 
100 
Immediate:  Within 1-
2 days of receiving 
drug  
Nausea, vomiting, 
anorexia  
Flu-like symptoms 
with fever, rash  
Ara-C syndrome (fever, myalgia, 
bone pain, occasionally chest pain, 
maculopapular rash, malaise, 
conjunctivitis), anaphylaxis  
Prompt:  Within 2-3 
weeks, prior to the 
next course  
Myelosuppression 
(anemia, 
thrombocytopenia, 
leukopenia, 
megaloblastosis, 
reticulocytopenia), 
stomatitis, alopecia  
Diarrhea, 
hypokalemia, 
hypocalcemia, 
hyperuricemia  
Hepatotoxicity, sinusoidal 
obstruction syndrome (SOS, 
formerly VOD), urinary retention, 
renal dysfunction, pain and 
erythema of the palms and soles  
Delayed:  Any time 
later during therapy, 
excluding the above 
conditions 
 
 
Asymptomatic nonoliguric 
rhabdomyolysis 
Unknown Frequency 
and Timing:  
Fetal toxicities and teratogenic effects of cytarabine have been noted in humans. It 
is unknown whether the drug is excreted in breast milk. 

 
 
 
 
Original  version date: 1-20-2017  
Amendment 1 version date: 09-06-2017 
 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
Amendment 4 version date: 07-01-2019 
 
 
 
 
 
Original Protocol version 1-20-2017 
Amendment 1 version date: 09-06-2017 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
 
Amendment 4 version date: 07-01-2019 
40 
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TACL Internal Distribution Only 
 
 
 
6.4.3    Toxicity/Adverse Event:  (Intrathecal) 
 
Cytarabine Intrathecal 
 
Common 
Happens to 21-100 
children out of every 
100 
Occasional 
Happens to 5-20 
children out of every 
100 
Rare 
Happens to < 5 children out of every 
100 
Immediate:  Within 1-
2 days of receiving 
drug  
Nausea, vomiting, 
fever, headache 
Arachnoiditis  
 
Rash, somnolence, meningismus, 
convulsions, paresis 
Prompt:  Within 2-3 
weeks, prior to the 
next course  
 
 
Myelosuppression, ataxia 
Delayed:  Any time 
later during therapy, 
excluding the above 
conditions 
 
 
Necrotizing leukoencephalopathy, 
paraplegia, blindness (in 
combination with XRT & systemic 
therapy) 
 
6.4.4 
Formulation and Stability:  Cytarabine for Injection is available in vials of 100 mg, 500 mg, 1 g, and 2 g 
containing a sterile powder for reconstitution.  It is also available at a 20 mg/mL concentration with benzyl 
alcohol (25 mL per vial) or as a preservative free solution (5 mL, 50 mL per vial), and at a 100 mg/mL 
concentration with benzyl alcohol (20 mL vial) or as preservative free solution (20 mL vial).  Hydrochloric 
acid and/or sodium hydroxide may be added to adjust the pH. Store at 25°C (77°F); excursions permitted 
to 15-30°C (59-86°F).  Cytarabine solutions should be protected from light. 
 
6.4.5 
Preparation and Administration: 
 
IV Infusion:  Reconstitute the lyophilized powder with Bacteriostatic Water for Injection or NS injection.  
Solution containing bacteriostatic agent should not be used for the preparation of doses > 200 mg/m2.  
May be further diluted with dextrose or sodium chloride containing solutions.  May be administered by IV 
push injection, by IV infusion, or by continuous infusion. 
 
High Dose (≥ 1000 mg/m2/dose):  Administer steroid eye drops (dexamethasone or prednisolone), 2 
drops each eye q.6.h. beginning immediately before the first dose and continuing 24 hours after the last 
dose.  If patient does not tolerate steroid eye drops, administer artificial tears on a q. 2-4 hour schedule. 
 
Stability:  When reconstituted with Bacteriostatic Water for Injection, cytarabine is stable for 48 hours at 
room temperature.  Solutions reconstituted without a preservative should be used immediately.  Discard if 
solution appears hazy.  Diluted solutions in D5W or NS are stable for 8 days at room temperature; 
however, the diluted cytarabine should be used within 24 hours for sterility concerns. 
 
Intrathecal:  For intrathecal administration, dilute with 5-10 mL (or volume per institutional practice) 
preservative free 0.9% sodium chloride injection, lactated Ringer’s injection, Elliot’s B solution.  The 
volume of CSF removed should be equal to at least ½ the volume delivered. 
 

 
 
 
 
Original  version date: 1-20-2017  
Amendment 1 version date: 09-06-2017 
 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
Amendment 4 version date: 07-01-2019 
 
 
 
 
 
Original Protocol version 1-20-2017 
Amendment 1 version date: 09-06-2017 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
 
Amendment 4 version date: 07-01-2019 
41 
CONFIDENTIAL 
 
 
TACL Internal Distribution Only 
 
Stability:  Intrathecal cytarabine mixed in NS, lactated Ringer’s injection, or Elliot’s B solution is stable for 
24 hours at 25 ºC but contains no preservative and should be administered as soon as possible after 
preparation. 
 
6.4.6 
Supplier:  Cytarabine is commercially available. See package insert and prescriber information for further   
Information 
 
 
6.5       Filgrastim (G-CSF, Neupogen) 
 
6.5.1 
Source and Pharmacology:  Filgrastim is a human granulocyte colony-stimulating factor (G-CSF), 
produced by recombinant DNA technology.  Colony-stimulating factors are glycoproteins which act on 
hematopoietic cells by binding to specific cell surface receptors and stimulating proliferation‚ 
differentiation commitment‚ and some end-cell functional activation.  
 
Endogenous G-CSF is a lineage specific colony-stimulating factor which is produced by monocytes‚ 
fibroblasts, and endothelial cells.  G-CSF regulates the production of neutrophils within the bone marrow 
and affects neutrophil progenitor proliferation, differentiation  and selected end-cell functional activation 
(including enhanced phagocytic ability, priming of the cellular metabolism associated with respiratory 
burst, antibody dependent killing, and the increased expression of some functions associated with cell 
surface antigens).  G-CSF is not species-specific and has been shown to have minimal direct in vivo or in 
vitro effects on the production of hematopoietic cell types other than the neutrophil lineage. 
 
Filgrastim is a 175 amino acid protein manufactured by recombinant DNA technology. It is produced by 
Escherichia coli (E coli) bacteria into which has been inserted the human granulocyte colony-stimulating 
factor gene.  Filgrastim has a molecular weight of 18‚800 daltons.  The protein has an amino acid 
sequence that is identical to the natural sequence predicted from human DNA sequence analysis‚ except 
for the addition of an N-terminal methionine necessary for expression in E coli. Because Filgrastim is 
produced in E coli‚ the product is nonglycosylated and thus differs from G-CSF isolated from a human 
cell. 
 
6.5.2 
Toxicity/Adverse Events:  In clinical trials involving patients receiving Filgrastim following 
chemotherapy, most adverse experiences were the sequelae of the underlying malignancy or cytotoxic 
chemotherapy.  Medullary bone pain is the most common adverse reaction attributed to Filgrastim 
therapy.  Spontaneously reversible elevation in uric acid, LDH, and alkaline phosphatase also observed in 
patients receiving Filgrastim. 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
Original  version date: 1-20-2017  
Amendment 1 version date: 09-06-2017 
 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
Amendment 4 version date: 07-01-2019 
 
 
 
 
 
Original Protocol version 1-20-2017 
Amendment 1 version date: 09-06-2017 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
 
Amendment 4 version date: 07-01-2019 
42 
CONFIDENTIAL 
 
 
TACL Internal Distribution Only 
 
Filgrastim (G-CSF, Neupogen) 
 
Common 
Happens to 21-100 children 
out of every 100 
Occasional 
Happens to 5-20 children 
out of every 100 
Rare 
Happens to < 5 children out of 
every 100 
Immediate: 
Within 1-2 days of 
receiving drug 
 
Local irritation at the 
injection site, headache 
Allergic reactions (more 
common with IV 
administration than subq):skin 
(rash, urticaria, facial edema), 
respiratory (wheezing, 
dyspnea) and cardiovascular 
(hypotension, tachycardia), 
low grade fever 
Prompt: 
Within 2-3 weeks, 
prior to the next 
course 
Mild to moderate 
medullary bone pain 
Increased: alkaline 
phosphatase, lactate 
dehydrogenase and uric 
acid, 
thrombocytopenia 
Splenomegaly, splenic 
rupture, exacerbation of pre-
existing skin rashes, sickle cell 
crises in patients 
with SCD, excessive 
leukocytosis 
Delayed: 
Any time later 
during therapy, 
excluding the 
above conditions 
 
 
Cutaneous vasculitis, ARDS 
Late: 
Any time after 
completion of 
treatment 
 
 
MDS or AML (confined to 
patients with severe chronic 
neutropenia and 
long term administration) 
Unknown Frequency and Timing:  
Fetal toxicities and teratogenic effects of filgrastim in humans are unknown. Conflicting data exist in animal 
studies and filgrastim is known to pass the placental barrier. It is unknown whether the drug is excreted in 
breast milk. 
 
6.5.3 
Preparation and Administration:  Use only one dose per vial; do not re-enter the vial.  Discard unused 
portions.  Do not save unused drug for later administration.  Use only one dose per prefilled syringe.  
Discard unused portions.  Do not save unused drug for later administration. 
 
Vials:  Single-dose‚ preservative-free vials containing 300 mcg (1 mL) of Filgrastim (300 mcg/mL).  
Dispensing packs of 10 (NDC 55513-530-10). 
 
Single-dose‚ preservative-free vials containing 480 mcg (1.6 mL) of Filgrastim (300 mcg/mL). Dispensing 
packs of 10 (NDC 55513-546-10). 
 
Prefilled Syringes (SingleJect®):  Single-dose‚ preservative-free, prefilled syringes with 27 gauge, ½ 
inch needles with a needle guard, containing 300 mcg (0.5 mL) of filgrastim (600 mcg/mL) Dispensing 
packs of 10 (NDC 55513-924-10). 
 
Single-dose‚ preservative-free, prefilled syringes with 27 gauge, ½ inch needles with a needle guard, 
containing 480 mcg (0.8 mL) of filgrastim (600 mcg/mL). Dispensing packs of 10 (NDC 55513-209-10). 

 
 
 
 
Original  version date: 1-20-2017  
Amendment 1 version date: 09-06-2017 
 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
Amendment 4 version date: 07-01-2019 
 
 
 
 
 
Original Protocol version 1-20-2017 
Amendment 1 version date: 09-06-2017 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
 
Amendment 4 version date: 07-01-2019 
43 
CONFIDENTIAL 
 
 
TACL Internal Distribution Only 
 
 
The needle cover of the prefilled syringe contains dry natural rubber (a derivative of latex). 
 
6.5.4 
Storage and Dilution:  NEUPOGEN® should be stored in the refrigerator at 2 °C to 8 °C (36 °F to 46 °F).  
Avoid shaking. Prior to injection‚ NEUPOGEN® may be allowed to reach room temperature for a 
maximum of 24 hours.  Any vial or prefilled syringe left at room temperature for greater than 24 hours 
should be discarded.  Parenteral drug products  should be inspected visually for particulate matter and 
discoloration prior to administration‚ whenever solution and container permit; if particulates or 
discoloration are observed‚ the container should not be used. 
 
Dilution:  If required‚ NEUPOGEN® may be diluted in 5% dextrose.  NEUPOGEN® diluted to 
concentrations between 5 and 15 mcg/mL should be protected from adsorption to plastic materials by the 
addition of Albumin (Human) to a final concentration of 2 mg/mL.  When diluted in 5% dextrose or 5% 
dextrose plus Albumin (Human)‚ NEUPOGEN® is compatible with glass bottles‚ PVC and polyolefin IV 
bags‚ and polypropylene syringes. Dilution of NEUPOGEN® to a final concentration of less than 5 
mcg/mL is not recommended at any time.  Do not dilute with saline at any time; product may precipitate. 
 
6.5.5 
Supplier:  Filgrastim is commercially available.  See package insert and  prescriber information for further 
information. 
 
 
7.0 
REQUIRED OBSERVATIONS/MATERIAL AND DATA TO BE ASSESSIONED 
 
All protocol-specified hematology, blood chemistries, and bone marrow aspirations and/or biopsies are to be 
performed in the local laboratory at each investigational site. 
 
 
7.1 
Clinical and Laboratory Studies 
 
All entry/eligibility studies must be performed within 1 week prior to study enrollment. Additional assessments may 
be obtained as needed for good patient care. 
 
 
Studies to be Obtained 
Pre-Study 
Course 1 & 2 
Final Visit 
 
Follow-Up 
History 
X 
Twice Weekly 
X 
X 
Physical Exam (Ht, Wt, BSA, VS) 
X1 
Twice Weekly* 
X 
X 
CBC, differential, platelets 
X1 
Twice Weekly* 
X 
X 
Chemistry Panel2 
X1 
Weekly* 
X 
X 
Liver Panel3 
X1 
 
 
 
Urine pregnancy or Serum β-HCG 
(females of childbearing potential) 
X1 
 
 
 
Echocardiogram or MUGA 
X1 
Prior to Course 2 
X 
 

 
 
 
 
Original  version date: 1-20-2017  
Amendment 1 version date: 09-06-2017 
 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
Amendment 4 version date: 07-01-2019 
 
 
 
 
 
Original Protocol version 1-20-2017 
Amendment 1 version date: 09-06-2017 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
 
Amendment 4 version date: 07-01-2019 
44 
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TACL Internal Distribution Only 
 
Studies to be Obtained 
Pre-Study 
Course 1 & 2 
Final Visit 
 
Follow-Up 
EKG 
X1 
Prior to Course 2 
X 
 
Bone marrow aspirate and/or biopsy for 
routine morphology 
X1, ,5 
Day 35-42 or when counts 
recover4 
 
 
CSF Cell Count and Differential 
X1 
Around Day 35-42 or when 
counts recover 
 
 
Bone marrow sample for MRD 
 
Around Day 35-42 or when 
counts recover 
 
 
Bone marrow for Required Correlative 
Studies  
X1 
Day 35-42 or when counts 
recover 
 
 
Peripheral blood for Required 
Correlative Studies  
X1,4 
Days 5, 14, and 35-42 or when 
counts recover 
 
 
 
* Any Grade 3 or 4 lab tests or other adverse experiences found should be reviewed and repeated within 48 hours 
to determine if the grade and duration meet the definition for DLT (section 6.6) 
1 Required for verification of eligibility. If a patient has labs done prior to study entry that establish eligibility, then 
abnormal Day 1 labs do not deem them ineligible. Height only needs to be recorded at study entry to determine 
BSA and not repeated with subsequent visits. Bone marrow evaluations done prior to study enrollment that 
establish patient’s eligibility, can be waived for pre-study entry marrow if leukemia blasts are present in the 
peripheral blood and can be sent for biology correlative studies. Bone marrow does not have to be repeated 
purely for the purposes of obtaining correlative study samples. In this case, peripheral blood samples for 
correlative biology studies are acceptable. 
2 Chemistry panel should include: Creatinine, calcium, glucose, electrolytes (chloride, sodium, potassium, and 
bicarbonate) and uric acid (uric acid is required at baseline and during 1st week of therapy, otherwise only if 
clinically indicated),  
3 Liver panel should include: AST, ALT, total bilirubin, direct bilirubin, alkaline phosphatase, total protein, albumin 
4 Day 35-42 peripheral blood correlative studies should be done on the same day as the bone marrow aspirate 
and/or biopsy 
5 Relapse bone marrow sample must be sent for FLT3-ITD molecular testing pre-study. 
 
 
7.2 
Disease Evaluation During Therapy 
 
All patients are required to have a bone marrow aspirate and/or biopsy and CBC to assess response around day 
35-42 or when blood counts recover (ANC >500/µL AND platelet >50,000/µL), whichever occurs first.  
 
 
A bone marrow aspiration/biopsy to assess remission status should be performed approximately on day 
35-42 when blood counts recover and discontinuation of G-CSF for at least 24 hours. Bone marrow 
aspirate may be delayed beyond day 42 if adequate peripheral count recovery has not yet occurred. See 
section 11 for response criteria.  
 
 
If the marrow is hypoplastic and/or there is little or no evidence of normal hematopoiesis, a repeat marrow 
should be performed after a further 7-21 days (based upon peripheral blood count recovery and the 

 
 
 
 
Original  version date: 1-20-2017  
Amendment 1 version date: 09-06-2017 
 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
Amendment 4 version date: 07-01-2019 
 
 
 
 
 
Original Protocol version 1-20-2017 
Amendment 1 version date: 09-06-2017 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
 
Amendment 4 version date: 07-01-2019 
45 
CONFIDENTIAL 
 
 
TACL Internal Distribution Only 
 
clinician’s judgment) and remission status assessed at this later time point. Patients who continue to have 
hypoplastic bone marrow aspiration beyond day 56 will be considered to have experienced a DLT. Bone 
marrow hypoplasia is defined as overall marrow cellularity less than 10%. 
 
 
Administration of course 2 intrathecal therapy at the time of the end of course 1 bone marrow evaluations 
is permitted to avoid additional sedation procedures.  
 
 
Patients who achieve CR, CRi, PR, or SD should receive a second course of chemotherapy as soon as 
clinically acceptable to the treating institution but no earlier than 33 days after the start of course 1, and 
the following criteria are met:  
 
– 
All grade 3 and 4 non-hematologic toxicities have resolved to grade 2 or less 
 
– 
Patients in CR or CRi must have an ANC > 500/ul and PLT > 50,000/ul. It is recommended 
but not required that ANC>750/ul and platelet count > 50,000/ul to be achieved before 
proceeding with a second course of therapy EXCEPT patients with PR, or SD. These 
patients, if in good enough clinical condition (based on treating physician’s clinical judgment), 
may continue begin Course 2 irrespective of blood counts.  
 
– 
Patients who do not meet these criteria by day 56 will be considered to have a DLT  
 
– 
Administration of course 2 intrathecal therapy at the time of the end of course 1 bone marrow 
evaluations is permitted to avoid additional sedation procedures.  
 
 
7.3 
Bone Marrow Sample for MRD  
 
(ALL MRD RESULTS MUST BE SENT TO TACL OPERATIONS AT TACL@CHLA.USC.EDU ONCE THEY 
HAVE BEEN RECEIVED FROM SEATTLE) 
 
Participation in the collection of these specimens is required  
 
Samples requested: 
Bone Marrow Sample for MRD  
 
At the end of course 1 and 2 around day 35-42 when counts recover 
 
The sample should also be submitted if the bone marrow procedure is 
repeated after day 42 to document marrow and count recovery. 
 
Bone marrow Collection 
procedure: 
a. Collect minimum of 2 mL of marrow into a syringe and place marrow into a 
large purple EDTA tube that are commonly used in all hospitals. Mix well 
b. Use multiple syringes and tubes as needed. Reposition marrow aspirates 
needle at least once during procedure to ensure the maximum quality of 
marrow 
Specimen Labeling: 
Each tube must be labeled with the study ID number, along with the date the 
sample was obtained.  No personal identifying patient information should be 
included in the specimen or transmittal form. 
Specimen Packaging and 
Samples are to be sent at room temperature except for international samples that 

 
 
 
 
Original  version date: 1-20-2017  
Amendment 1 version date: 09-06-2017 
 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
Amendment 4 version date: 07-01-2019 
 
 
 
 
 
Original Protocol version 1-20-2017 
Amendment 1 version date: 09-06-2017 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
 
Amendment 4 version date: 07-01-2019 
46 
CONFIDENTIAL 
 
 
TACL Internal Distribution Only 
 
Shipping: 
 
 
 
are expected to be delayed for more than 48 hours, place a cold pack (not ice 
pack) in shipment. 
 
Include the completed Specimen Shipping Form with shipment and  email a copy 
to TACL Operations Center at tacl@chla.usc.edu.  For specimen shipping, 
contact TACL Operations for a FED-EX label 24 hrs in advance of shipment. 
Please call the TACL Operations Center for any questions. 
 
Samples can be shipped to arrive Monday-Friday. For Saturday arrivals, please 
call the lab ahead of time: Phone: 206-288-7060 
 
Brent Wood, MD, PhD 
SCCA 
Hematopathology Laboratory 
Room G7-800 
825 Eastlake Ave. E. 
Seattle WA 98109-1028 
Phone: 206-288-7060 
Fax: 206-288-7127 
 
 
All MRD results MUST be sent to TACL operations once they are received from Seattle. 
 
7.4 
Required Observations Following Completion of Protocol Therapy 
 
Upon completing protocol therapy or exiting the study, all patients will be followed for life or until otherwise notified 
by the study committee that the study is closed. Sites should submit follow-up a minimum of every 6 months. 
Events such as patient death, relapse or development of toxicity related to this therapy should be reported right 
away. The purpose is to assess safety, remission status, administration of alternative therapies, and survival. The 
following data will be collected: 
 
1) Disease status information 
2) Anti-cancer therapy received after exiting the protocol 
3) All adverse events thought to be related to this study’s treatment 
4) Date and cause of death 
 
8.0 
CORRELATIVE STUDIES 
 
8.1 
Determination of Baseline  
 
Determination of Baseline “functional epigenetic profile” on leukemic blasts isolated at study entry using 
the following triad of assays:   
 
8.1.1 
Reduced representation bisulfite sequencing (RRBS) will be used to analyze the genome-wide 
methylation profiles on a single nucleotide level; To quantitatively assess global changes in DNA 
methylation, a LINE-methylation assay will be utilized and specific genes monitored through 
advanced Infinium MethylationEPIC BeadChip from Illumina. 
 

 
 
 
 
Original  version date: 1-20-2017  
Amendment 1 version date: 09-06-2017 
 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
Amendment 4 version date: 07-01-2019 
 
 
 
 
 
Original Protocol version 1-20-2017 
Amendment 1 version date: 09-06-2017 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
 
Amendment 4 version date: 07-01-2019 
47 
CONFIDENTIAL 
 
 
TACL Internal Distribution Only 
 
8.1.2 
Chromatin immunoprecipitation (ChIP) with antibodies specific for histone modifications 
associated with transcriptional activation (H3K4me3 and H3K27ac) and repression (H3K9me3 
and H3K27me3) and isotype controls, followed by DNA sequencing (ChIP-seq); 
 
8.1.3 
RNA sequencing analysis will be used to measure global transcriptome changes. The power of 
this approach derives from the integration of complimentary, cross-referenced genome-wide data 
to generate lists of candidate genes for which it is likely that over- or under-expression is truly 
driven by epigenetic regulation. Profiles of CD33+ umbilical cord blood cells, whole bone marrow, 
or Peripheral Blood Stem Cells (PBSCs) will be used as normal controls for each sample.  
 
8.1.4 
Immune assessment: Peripheral blood immune cell phenotyping and serum cytokine analysis.  
 
8.2 Assessment of the in Vivo Effects  
 
Assessment of the in vivo effects of combined DNMTi/HDACi on the functional epigenetic profile by 
comparing the following in paired pre- (Day 0) and post-exposure (Day 5, Day 14 and Day 35) leukemic 
blasts: 
 
8.2.1 Reversal of DNA promoter hypermethylation of “repressed” genes of interest using RRBS, validated 
with Pyrosequencing-based methylation assay; 
 
8.2.2 Increase in H3K9/14 acetylation in association with “repressed” genes of interest using H3K9/14 
ChIP-seq, validated with ChIP-qPCR;  
 
8.2.3 Reversal of transcriptional silencing of “repressed” genes of interest using RNA seq, validated by 
qRT-PCR.  Since significant acute cell kill is unlikely during the 5-day “window” of DNMTi/HDACi, we will 
have a unique opportunity to assess the in vivo effects of epigenetic therapy with the Day 5 sample.  The 
Day 14 peripheral blood and Day 35 marrow samples will also contribute in patients whose leukemic 
blasts persist at these time points.  
 
8.2.4 Changes in peripheral blood immune cell subsets and serum cytokines. 
 
      8.3 Correlations of Baseline  
 
Correlations of Baseline functional epigenetic phenotype and pharmacodynamic modulation of repressed 
genes of interest with clinical responses:  While the ability to definitively correlate either baseline 
epigenetic phenotypes or successful reversal of epigenetic phenotypes with clinical response will be 
limited by small patient numbers, the descriptive data we generate will be invaluable in developing 
biomarkers to be validated in future trials.  
 
     8.4 Chemo-Sensitivity Profiling 
 
We hypothesize that vorinostat and decitabine may influence sensitivity of leukemic cells to the standard 
re-induction chemotherapy.  We will test blasts isolated at baseline (pre-treatment) vs. those isolated at 
Day 5 (post-exposure to DNMTi/HDACi) and compare cytotoxic IC50 for fludarabine and cytarabine using 
enzyme-based proliferation assays (WST-1, e.g.) and flow-based apoptosis assays (annexin V and 7-
AAD). 
 

 
 
 
 
Original  version date: 1-20-2017  
Amendment 1 version date: 09-06-2017 
 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
Amendment 4 version date: 07-01-2019 
 
 
 
 
 
Original Protocol version 1-20-2017 
Amendment 1 version date: 09-06-2017 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
 
Amendment 4 version date: 07-01-2019 
48 
CONFIDENTIAL 
 
 
TACL Internal Distribution Only 
 
     8.5 Immune monitoring 
 
It is now clear that the immune system can have an important role in controlling cancer progression.  
Epigenetic modifying drugs and many chemotherapeutic agents are known to have both positive and 
negative effects on the immune system.  The combination of agents being used here could have either 
beneficial or detrimental effects on immune cell function and composition.  We hypothesize that immune 
cell subsets and serum cytokines levels will be impacted by the treatment regimen.  Plasma will be 
quantitatively analyzed for 65 different cytokines and chemokines in multi-plex assays.  We will also 
immunophenotype peripheral blood mononuclear cells using multi-color (8 parameters) flow cytometry.  
Cell subsets to be analyzed will include T cells (naïve, effector and regulatory), B cells, NK cells, dendritic 
cells and myeloid cells. 
 
Samples requested: 
Bone Marrow 
Courses 1 and 2 
 
Pre-study  
 
Day 35* 
Peripheral Blood 
Courses 1 and 2 
 
Pre-study  
 
Days 5, 14, 35* 
Blood Sample Procedure: 
 
Draw 5-10 mL of blood into a sodium-heparin (BD Vacutainer Green top) 
 
Bone Marrow Draw 
Procedure: 
 
Draw 5-10 mL of bone marrow into a sodium-heparin (BD Vacutainer 
Green top) 
 
Specimen Processing: 
 
Include the completed Correlative Sample Transmittal Form with shipment 
and  email a copy to TACL Operations Center at tacl@chla.usc.edu.  For 
specimen shipping, contact TACL Operations for a FED-EX label 24 hrs 
in advance of shipment. Please call the TACL Operations Center for any 
questions. 
 
 
No processing. Please ship immediately at room temperature using 
overnight FedEx shipping on Monday-Thursday (excluding holidays).  
 
If the samples cannot be shipped immediately, please store at Room 
Temperature until they can be shipped.  
 
Specimen Labeling: 
Each tube must be labeled with the patient study ID number, type of 
specimen (blood or bone marrow) and the date and time the specimen 
was drawn.  No identifying patient information should be included on the 
specimen or transmittal form. 
Specimen Packaging and 
Shipping: 
 
Green Top Tubes with sample: 
Attn:  Cary Stelloh (Rao Lab) 
Phone: 414-937-3878 (cell 617-504-2984) 
Sid Rao, MD 

 
 
 
 
Original  version date: 1-20-2017  
Amendment 1 version date: 09-06-2017 
 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
Amendment 4 version date: 07-01-2019 
 
 
 
 
 
Original Protocol version 1-20-2017 
Amendment 1 version date: 09-06-2017 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
 
Amendment 4 version date: 07-01-2019 
49 
CONFIDENTIAL 
 
 
TACL Internal Distribution Only 
 
Blood Research Institute 
Medical College of Wisconsin 
8727 Watertown Plank Rd. 
Milwaukee, WI 53226-3548 
FedEx # 053204660   
 
*Can be performed between day 35 and 42 
 
9.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY, OFF STUDY CRITERIA AND STUDY 
TERMINATION 
 
9.1 
Criteria for Removal from Protocol Therapy 
 
a. Progressive disease 
b. Patients remains CNS positive after the first course of therapy 
c. Relapse in any site following remission 
d. Second malignant neoplasm 
e. Completion of protocol therapy 
f. 
Patient/parent withdrawal or refusal after beginning protocol therapy 
g. Patient/parent withdrawal or refusal before beginning protocol therapy 
h. Patient off treatment for other complicating disease 
i. 
Non-compliance with protocol regimen and procedures 
j. 
Unacceptable toxicity  
k. Female patient becomes pregnant or begins breast-feeding 
 
 
9.2 
Off Study Criteria 
 
1. Death 
2. Patient lost to follow-up 
3. Patient withdraws consent, refuses follow-up 
 
 
9.3 
Termination of Study by TACL 
 
The TACL Consortium may terminate this study prematurely, either in its entirety or at an investigative site, for 
reasonable cause provided that written notice is submitted in advance of the intended termination.  Advance 
notice is not required if the study is stopped due to safety concerns.   
 
 
10.0 
STATISTICAL CONSIDERATIONS 
 
The primary objectives of this study, and thus of the statistical design and analysis, are to determine the 
maximum tolerated dose (MTD) of decitabine when used in combination with vorinostat, fludarabine, high dose 
cytarabine and G-CSF (FLAG), and to evaluate the ability to safely deliver this combination in children and young 

 
 
 
 
Original  version date: 1-20-2017  
Amendment 1 version date: 09-06-2017 
 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
Amendment 4 version date: 07-01-2019 
 
 
 
 
 
Original Protocol version 1-20-2017 
Amendment 1 version date: 09-06-2017 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
 
Amendment 4 version date: 07-01-2019 
50 
CONFIDENTIAL 
 
 
TACL Internal Distribution Only 
 
adults with relapsed or refractory AML.  Both of these objectives are addressed by the Phase I dose-escalation 
design. Secondary objectives include evaluating pharmacodynamic endpoints and their possible association with 
tumor response in the context of a Phase I study, and evaluating the ability to safely deliver this treatment 
combination in Down syndrome patients with relapse/refractory AML.   
 
The study will enroll patients in two strata – a primary stratum of eligible patients without Down syndrome, and a 
secondary stratum of eligible patients with Down syndrome.   
 
10.1 
Statistical Considerations for Dose Escalation Criteria 
 
The primary endpoint for dose escalation is the occurrence of a dose-limiting toxicity (DLT – Section 4.4) 
observed during the first couse of therapy. Within each of the two strata, a standard 3+3 patient cohort 
escalation design33, as described below, will be used, starting at dose level 1 (Table 6): 
 
1. Up to three evaluable patients are entered initially at the current dose level. 
2. If 0/3 patients experience a DLT at the current dose level, then the dose is escalated to the next 
higher level, if one exists, and three patients are enrolled. 
3. If 1/3 patients experience a DLT at current dose, then up to three additional patients are accrued at 
the same dose level. 
4. If 2 or or more patients experience a DLTs in a three-patient or six-patient cohort at the current dose 
level, then the MTD has been exceeded, and dose escalation will be stopped. Up to three additional 
patients will be enrolled at the next lower dose level if one exists and fewer than six patients have 
already been treated at that dose level. 
 
10.2 
Study Stopping Rules 
 
Study duration will be based on enrollment and outcome in the primary stratum.  Enrollment to the study 
will be halted when, in the primary stratum, a provisional RP2D as defined in 10.3.1 is established and the 
optional expansion phase (see below) is complete, or when at least two evaluable patients treated at 
dose level 0 experiences DLT. In the latter case no MTD is established and we will conclude that this 
combination cannot be safely delivered at any of the dose levels tested. 
 
If a provisional RP2D is established in the primary stratum, accrual can continue until a maximum of 33 
DLT- and response-evaluable patients overall in the primary stratum has been enrolled, with the number 
of additional patients at the discretion of the study committee based on considerations of numbers of 
patients evaluable for secondary endpoints, accrual rate, occurrence of toxicity or severe adverse events, 
and existence of other competing studies.  Patients who are not DLT- or response-evaluable will be 
replaced but will be included in statistical analysis as appropriate. 
 
Patients with Down syndrome will be enrolled according to a 3+3 design as described, but with the 
additional restriction that the dose level in Down syndrome patients may never exceed the current dose 
level in the primary stratum.  Given the rarity of Down syndrome patients, this stratum is not expected to 
accrue many patients.  Hence the analysis of this stratum will be primarily descriptive. 
 
10.3 
Definitions  
 
10.3.1 Maximum Tolerated Dose (MTD)/Highest Tested Dose (HTD)/Recommended Phase 2 Dose 
(RP2D):  The MTD is the highest dose level tested at which 0/6 or 1/6 patients experience DLT 

 
 
 
 
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with at least 2/3 or 2/6 patients encountering DLT at the next higher dose.  If the highest specified 
dose level in this study is reached with 0/6 or 1/6 patients experiencing DLT, i.e., the MTD has not 
been reached, this dose level will be referred to as the Highest Tested Dose (HTD). The MTD or 
HTD will be the provisional recommended phase 2 dose (RP2D).  If 2 or more DLTs are observed 
at the lowest specified dose, an MTD, and therefore an RP2D, does not exist.  The decision about 
the final RP2D, or whether an RP2D exists, will be made after the completion of the expansion 
phase based on the additional toxicity, SAE, and other data that is generated during the expansion 
phase. 
 
10.3.2 Definition of a Patient Evaluable for DLT:  Any patient not experiencing a DLT who receives 
less than 80% of the prescribed total dose of any of the systemic anticancer agents (i.e., fewer 
than 4 of the 5 prescribed doses of Decitabine, Vorinostat, Fludarabine, or IV Cytarabine) for 
reasons unequivocally unrelated to Decitabine toxicity, or who starts subsequent anti-cancer 
therapy before the required observation times specified in the DLT definition, will be considered 
NOT EVALUABLE for DLT and will be replaced. All other patients who receive any portion of 
treatment will be considered EVALUABLE for DLT. 
 
10.3.3 Definition of a Patient Evaluable for Response:  A patient will be considered evaluable for 
response if the patient receives all or part of protocol therapy and the patient is under follow-up for 
a sufficient period to evaluate the disease or to meet the definition of progressive disease. A 
patient who is removed from therapy for problems possibly related to disease progression will be 
considered a non responder. 
 
10.4 
Patient Accrual and Study Duration 
 
10.4.1 Patient Accrual:  This study will enroll a minimum of 4 and a maximum of 33 non-Down syndrome 
patients who are evaluable for dose-limiting toxicity (DLT) to complete the dose escalation and 
expansion at the RP2D. A small number of Down syndrome patients will also be enrolled.  
 
10.4.2 Study Duration:  The study will require approximately 18 to 24 months of accrual. 
 
 
10.5 
Interim Monitoring of Toxic Death 
 
The occurrence of toxic death (TD) at any time during protocol therapy will be a primary endpoint for safety 
monitoring. A population toxic death rate that exceeds p0=0.10 will be considered unacceptable. A Bayesian 
monitoring rule based on a pessimistic Beta (1,3) prior distribution on the parameter p0 will be used to judge the 
evidence that the population toxic death rate exceeds this quantity. This prior has mean 0.25, median 0.21, and 
90% of support under 0.54.  A posterior probability of greater than 80% that p0>0.10 will be considered statistical 
evidence that the population toxic death rates may exceed 0.10.  Operationally, this criterion will be satisfied if the 
following fractions of TDs out of total patients treated are exceeded: ≥1/5, ≥2/12, ≥3/20, ≥4/28, and so on as 
dictated by this rule.  If this criterion is satisfied at any time the cause and circumstances of these deaths will be 
reviewed with the study committee and with the Data and Safety Monitoring Committee to determine whether 
modifications to or termination of the study is warranted.  The monitoring rule will apply across both study strata 
combined. 
 
10.6     Analysis of Correlative Studies  
 

 
 
 
 
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The analysis of genome wide and specific gene methylation, histone modification, RNA expression, peripheral 
blood immune cell parameters, and chemosensitivity  pre- and post-exposure and, where applicable, their 
possible assocation with tumor response and achievement of MRD- status, will be performed using standard 
statistical methods (e.g. linear regression, logistic regression). These analyses will be primarily descriptive, as the 
sample size will not provide sufficient power to detect any but extremely large effects, but they nevertheless will 
provide useful prelminary information that will inform planning of successor studies or investigations. 
 
 
10.7 
Inclusion of Women and Minorities 
 
The study is open to all participants regardless of gender or ethnicity.  Review of accrual to past studies of new 
agents demonstrates the accrual of both genders and all NIH-identified ethnicities to such studies. The small number 
of patients entered into this trial will obviate any analysis of variation in response rate with gender or ethnicity. 
 
 
 

 
 
 
 
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11.0 
RESPONSE CRITERIA 
 
11.1 
Bone Marrow Response Criteria  
 
11.1.1 Complete Remission, MRD negative (CR MRD-) 
 
A bone marrow with <5% blasts by morphology; and  
 
MRD <0.1% by flow or molecular testing (e.g. PCR); and 
 
No evidence of circulating blasts or extramedullary disease; and 
 
Recovery of peripheral counts (ANC > 500/µL and PLT count > 50,000 µL).  
 
Qualifying marrow and peripheral counts should be performed within 1 week of each other 
 
11.1.2 Complete Remission (CR) 
 
A bone marrow with <5% blasts by morphology; and  
 
No evidence of circulating blasts or extramedullary disease; and 
 
Recovery of peripheral counts (ANC > 500/µL and PLT count > 50,000 µL).  
 
Qualifying marrow and peripheral counts should be performed within 1 week of each other. 
 
11.1.3 Complete Response with Incomplete Count Recovery (CRi) 
 
A bone marrow with <5% blasts by morphology; and  
 
No evidence of circulating blasts or extramedullary disease; and  
 
Insufficient recovery of absolute neutrophil counts (ANC <500/µL), and or insufficient 
recovery of platelets (PLT counts <50,000/ul),  
 
11.1.4  Partial Remission (PR) 
 
Complete disappearance of circulating blasts and one of the following:  
 
A decrease of at least 50% of blasts in the bone marrow with >5% and < 20% blasts by 
morphology with recovery of peripheral counts (ANC > 500/µL and PLT count > 50,000 µL) 
Note: only patients who entered the study with > 20% blasts in the marrow may be assessed as 
PR 
 
11.1.5 Stable Disease (SD) 
Patient does not satisfy the criterion for either CR, CRi, PR or disease progression. 
 
11.1.6 Progressive Disease (PD) 
An increase of at least 25% in the absolute number of bone marrow or circulating leukemic cells, 
development of new sites of extramedullary disease, or other laboratory or clinical evidence of 
progression of disease. 
 
11.1.7 Not evaluable (NE) 
Aplastic or severely hypoplastic marrow with any blast percentage. Bone marrow 
aplasia/hypoplasia is defined as overall marrow cellularity less than 10-20%. In this instance, 
marrow evaluation should be repeated every 1-2 weeks until response determination can be 
made or patient meets criteria for a DLT of prolonged myelosuppression (as defined in section 
4.3.b). 
 
11.1.8 Relapse 

 
 
 
 
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After documentation of remission, one bone marrow aspirate and/or biopsy showing ≥5% 
leukemic blasts or pathological evidence of extramedullary disease. 
 
 
11.1.9 MRD Response Criteria 
Patient who achieves CR or CRi will additionally be classified according to their minimum residual 
disease (MRD) status as follows, based on the results of an MRD assay of contemporaneously 
obtained BM sample: 
 
 
MRD-: MRD is undetectable – i.e. below the level of quantifiability of the assay 
 
MRD+: MRD is detectable (the quantified level of MRD will also be recorded) 
 
MRD unknown: MRD assay result is not available” 
 
11.2 
CNS Response Criteria 
 
11.2.1 CNS Disease Definition for patients with AML 
 
AML patients with CNS disease is defined as:  
 
 
Any number of blasts on a cytospin prep in an atraumatic (< 100 RBCs) lumbar puncture, OR  
 
 
Blasts in a traumatic tap in which the WBC/RBC ratio in the CSF is twice that in the peripheral 
blood OR  
 
 
Clinical signs of CNS leukemia (such as facial nerve palsy, brain/eye involvement or 
hypothalamic syndrome). Extra-ocular orbital masses are not considered CNS leukemia, OR  
 
 
Radiographic evidence of an intracranial, intradural mass consistent with a chloroma.  
 
 
 
 
 
11.2.2 Method of Evaluating Initial Traumatic Lumbar Punctures: 
If the patient has leukemic cells in the peripheral blood and the lumbar puncture is traumatic and 
contains ≥ 5 WBC/µL and blasts, the following Steinherz/Bleyer algorithm should be used 
 
CSF WBC > 2X  Blood WBC 
CSF RBC           Blood RBC 
 
A patient with CSF blasts, whose CSF WBC/RBC is 2X greater than the blood WBC/RBC ratio, 
has CNS disease at diagnosis.  
 
Example: CSF WBC = 60/μL; CSF RBC = 1500/μL; blood WBC = 46000/μL; blood RBC = 3 X 
106/μL: 
60/1500 = 0.04 > 2X 4600/3x106 = 0.015 
 
 
 
Therefore this patient has CNS disease because 0.04 > 2x 0.015 

 
 
 
 
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12.0 
ADVERSE EVENT REPORTING REQUIREMENTS  
 
12.1 
Definitions 
 
Adverse Event: An adverse event means any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related. 
 
Suspected Adverse Reaction: Any adverse event for which there is a reasonable possibility that the drug 
caused the adverse event.  Reasonable possibility means there is evidence to suggest a causal relationship 
between the drug and the adverse event. 
 
Unexpected Adverse Event or Unexpected Suspected Adverse Reaction: An adverse event or suspected 
adverse reaction is considered “unexpected” if it is not listed in the investigator brochure or is not listed at the 
specificity or severity that has been observed; or, if an investigator brochure is not available, is not consistent with 
the risk information described in the general investigational plan. 
 
Serious Adverse Events or Serious Suspected Adverse Reactions: An adverse event or suspected adverse 
reaction is considered serious if, in the view of either the investigator or sponsor, it results in any of the following 
outcomes: 
 
Death of Patient 
An event that results in the death of a patient. 
Life-Threatening 
An event that, in the opinion of the investigator, would have resulted in immediate 
fatality if medical intervention had not been taken.  This does not include an event 
that would have been fatal if it had occurred in a more severe form. 
Hospitalization 
An event that results in an admission to the hospital for any length of time.  This 
does not include an emergency room visit or admission to an outpatient facility. 
Prolongation of 
Hospitalization 
An event that occurs while the study patient is hospitalized and prolongs the 
patient’s hospital stay. 
Congenital 
Anomaly 
An anomaly detected at or after birth or any anomaly that results in fetal loss. 
Persistent or 
Significant 
Disability/ 
Incapacity 
An event that results in a condition that substantially interferes with the activities of 
daily living of a study patient.  Disability is not intended to include experiences of 
relatively minor medical significance such as headache, nausea, vomiting, diarrhea, 
influenza, or accidental trauma (e.g., sprained ankle). 
Important Medical 
Event Requiring 
Medical or Surgical 
Intervention to 
Prevent Serious 
Outcome 
An important medical event that may not be immediately life-threatening or result in 
death or hospitalization, but based on medical judgment may jeopardize the patient 
and may require medical or surgical intervention to prevent any of the outcomes 
listed above (i.e., death of patient, life-threatening, hospitalization, prolongation of 
hospitalization, congenital anomaly, or persistent or significant disability/incapacity). 
Examples of such events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or convulsions that do 
not result in inpatient hospitalization, or the development of drug dependency or drug 
abuse. 

 
 
 
 
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12.2 
Data Collection 
 
Adverse events and suspected adverse reactions will be collected and reported on the electronic CRFs beginning 
with the first dose of study therapy until 30 days following the last dose of study therapy. All toxicities both 
hematologic and non-hematologic should be reported in the eCRF. This includes toxicities of all grades (i.e. 1 
through 5) and all grade fluctuations. The investigator will evaluate all adverse events and suspected adverse 
reactions as to their severity and relationship to  decitabine and vorinostat as well as the regimen as a whole. 
Serious adverse events and suspected adverse reactions will require expedited reporting to the TACL Operations 
Center as described below.  
 
12.3 
Reporting Serious Adverse Events or Serious Suspected Adverse Reactions 
 
12.3.1 The following serious adverse events or serious suspected adverse reactions requires 
expedited reporting: 
 
 
All Grade 5 events regardless of causality. 
 
All Grade 4 non-hematologic events that are possibly, probably or definitely related to 
decitabine and vorinostat or the regimen as a whole. 
 
All unexpected Grade 3 events that are possibly, probably or definitely related to decitabine 
and vorinostat or the regimen as a whole. 
 
12.3.2 Steps for Reporting 
 
Step 1: Identify the adverse event or suspected adverse reaction using the NCI Common 
Toxicity Criteria (CTC), version 4.0.    
 
The CTC provides descriptive terminology and a grading scale for each adverse event listed.  A 
copy of the CTC can be downloaded at  
http://evs.nci.nih.gov/ftp1/CTCAE/About.html.   
 
Step 2: Grade the event using the NCI CTCAE version 4.0. 
 
Step 3: Determine if the adverse event or suspected adverse reaction meets the criteria of 
being “serious”. 
 
Step 4: Determine the relationship of DRUG and the regimen as a whole to the event 
The investigator will assess the causal relationship between the investigational product and the 
regimen as a whole and the adverse event.  The investigator will use his/her clinical expertise and 
judgment to select the attribution category below that best fits the circumstances of the AE. 
 
 
 
 
 
 
Attribution categories are as follows: Unrelated, Unlikely, Possible, Probable, and Definite. 

 
 
 
 
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Unrelated: 
 
The adverse event is clearly unrelated to the investigational agent(s). 
 
Does not follow a known response pattern to the suspect investigational product (if response pattern 
is previously known). 
 
Can be explained by the known characteristics of the patient’s clinical state or therapy administered 
to the patient. 
 
Unlikely: 
 
The adverse event is doubtfully related to the investigational agent(s). 
 
May or may not follow a reasonable temporal sequence from administration of the investigational 
product. 
 
Likely explained by the known characteristics of the patient’s clinical state or other therapy 
administered to the patient. 
 
Possibly Related: 
 
The adverse event may be related to the investigational agent(s). 
 
Follows a reasonable temporal sequence from administration of the investigational product. 
 
May also be reasonably explained by the patient’s clinical state or therapy administered to the patient. 
 
May follow a known response pattern to the investigational product (if response pattern is previously 
known) 
 
Probably Related: 
 
The adverse event is likely related to the investigational agent(s). 
 
Follows a reasonable temporal sequence from administration of the investigational product. 
 
May follow a known response pattern to the investigational product (if response pattern is previously 
known) 
 
Could not be reasonably explained by the known characteristics of the patient’s clinical state or other 
modes of therapy administered to the patient, if applicable; 
 
Definitely Related: 
 
The adverse event is clearly related to the investigational agent(s). 
 
Follows the temporal sequence from administration of the investigational product. 
 
Follows a known response pattern to the investigational product. 
 
Cannot be explained by the known characteristics of the patient’s clinical state or other therapy 
administered to the patient. 
 
Is confirmed by improvement of symptoms on stopping or slowing administration of the investigational 
product and re-emergence of symptoms on restarting administration of the investigational product, (if 
applicable). 
 
 
Step 5: Determine if the adverse event or suspected adverse reaction is “unexpected”.  
 
Step 6: Notify the TACL Operations Center by telephone or email 
 
The following information should be submitted within 24 hours of event notification by either phone 
(323)361-3022, or Email tacl@chla.usc.edu. 
 

 
 
 
 
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1. Patient TACL study ID and initials 
2. Event description 
3. Severity (NCI Grade) 
4. Onset date 
5. Reason event is considered serious 
6. Dose of study drug and dates of administration 
7. Investigator opinion of relationship to DRUG and the regimen as a whole 
8. Name and phone number of physician in charge of the case 
9. Name and phone number of CRA or Research nurse working with the case 
 
Step 7: Submit a written report to the TACL Operations Center 
 
Complete the TACL SAE Notification Form within 72 hours of learning of the event.  The 
completed form should be emailed to tacl@chla.usc.edu. The form may also be faxed to (877) 
904-2166. A follow-up SAE Notification Form must be submitted upon resolution of the event or at 
the request of the study chair or study vice-chair. Please confirm via email or phone that the TACL 
Operations Center has received this notification.   
 
12.4 
Institutional Reporting to the IRB 
 
All SAE’s should be reported to the treating institutions IRB or Ethics board. The TACL Operations Center will 
also report all SAE’s to the TACL IRB. The TACL Operations Center will distribute SAE’s to all TACL sites as 
appropriate for submission to their own IRB’s.  
 
 
 

 
 
 
 
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13.0 
DATA AND SAFETY MONITORING 
 
13.1 
Data Submission 
 
All study data will be submitted via electronic data capture forms using the Rave-Medidata/TACL Website.  
Please refer to the TACL web site (https://tacl.chla.usc.edu) for the Rave user manual or contact the TACL 
Operations Center at (323) 361-3022 if you need assistance.   
 
The following are required to be submitted to the Operations Center for all patients entered: 
Scanned copy of following:  Roadmaps and Bone Marrow Reports (include both aspirate and biopsy reports). 
These forms are to be emailed to the TACL Operations Office at tacl@chla.usc.edu at the end of each course 
during which the bone marrows are done. 
 
13.2 
Weekly Safety Review 
 
The TACL Operations Center (TOC) conducts weekly (as needed) patient safety and review meetings with the 
protocol chair, protocol vice-chair, research coordinators and other administrative TACL team members to review 
all data submitted, non-serious adverse events and other correspondence pertaining to patients.  Serious adverse 
events will be immediately evaluated by the study team and determination regarding notification of participating 
sites will be made.  All serious adverse events will be sent to the CHLA CCI and DSMC if required.  Any interim 
results that would affect patient safety would be immediately communicated to all participating TACL sites. All 
correspondence with sites will be done via email, with all information also being posted on a member’s only 
section of the TACL website. 
 
13.3     Data Safety and Monitory Committee 
 
DSMC meetings will occur every 6 months. Every 6 months, a DSMC report for each protocol will be prepared by 
the study statistician and study PI detailing patient accrual, toxicities, deaths on study, current study status, 
responses (responses will be blinded until study completes accrual), summary of amendments to 
protocol/consent, lists of any publications from study, and plans for study in coming year.  Any publications from 
the study (abstract or manuscript) will be attached to the DSMC report.  After DSMC review, the DSMC will issue 
a confidential report for each study to the study PI and TACL Operations Center. 
 
Not more than 8 weeks after the DSMC meeting, a DSMC public review report will also be created for each 
protocol after approval of the confidential report and resolution of any issues by the PI The public report will then 
be emailed to the participating sites for each study.  These can be filed at the IRB at each site if required per local 
IRB guidelines. 
 
 
 

 
 
 
 
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14.0 
SAMPLE INFORMED CONSENT 
 
SAMPLE INFORMED ASSENT*/CONSENT DOCUMENT / PARENTAL PERMISSION FOR PARTICIPATION IN 
RESEARCH 
*Assent for patients >13 years of age 
*Assent for patients <13 years of age should be written per institutional guidelines 
 
TACL Protocol  
 
Subject Name: 
 
Medical Record #  
 
Physician: 
 
 
When we say “you” in this consent form, we mean you or your child; “we” means the doctors and other 
staff. 
 
This is a clinical trial, a type of research study. Your study doctor will explain the clinical trial to you. Clinical trials 
include only people who choose to take part. Please take your time to make your decision about taking part.  You 
may discuss your decision with your friends and family.  You can also discuss it with your health care team.  If you 
have any questions, you can ask your study doctor for more explanation.  
 
This study is being carried out by the Therapeutic Advances in Childhood Leukemia & Lymphoma (TACL) 
Consortium. TACL is a group of Universities and Children’s Hospitals that are working together to find treatments 
for children with leukemia and lymphoma.  
 
You are being asked to take part in this research study because your acute myelogenous leukemia (AML) has 
relapsed. Relapse means your leukemia has come back after treatment. DECITABINE (DEC) and VORINOSTAT 
(VOR) are drugs approved by the FDA (Food and Drug Administration) for the treatment of myelodysplastic 
syndrome, and T-Cell Lymphoma, respectively, which are cancers similar to leukemia. These drugs are thought to 
work by turning on genes that limit the growth of cancer cells. DEC and VOR have been given to children and 
adults with AML, and has been given together with other chemotherapy. This study is being done to find out if 
DEC and VOR can be given safely together before treatment with standard chemotherapy drugs in patients with 
AML. 
 
It is important for you to know why this study is being done before you decide to take part in this research study. 
This consent will tell you about the study. This consent will also tell you about risks and side effects that might 
happen to you if you take part in this study. You also need to know you do not have to take part in this study. You 
can talk to your doctor about other cancer treatments. Because all of the drugs used in this study are each 
available to doctors, it is possible for you to receive these drugs without taking part in this study. Taking part in 
this study is voluntary. 
Local IRB changes to this document are allowed. Changes within the document should not substantially 
alter the meaning or intent of the consent document. If the institution or IRB insists on making deletions 
or more substantive modifications to the consent, especially in the risks sections, they should be 
reviewed and approved by the TACL Operations Center.  

 
 
 
 
Original  version date: 1-20-2017  
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Amendment 3 version date: 06-29-2018 
Amendment 4 version date: 07-01-2019 
 
 
 
 
 
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Why is this study being done? 
 
The goals of this study are to improve survival rates in children and young adults with relapsed AML through the 
combination of DEC and VOR. We believe the addition of DEC and VOR in combination with standard AML 
chemotherapy will provide greater treatment response rates than without these drugs but the effectiveness and 
safety of this approach is not known. 
 
 
How many people will take part in this study? 
 
It is expected that approximately 12 to 33 children and young adults will take part in this study. 
 
 
What will happen if I take part in this research study? 
 
Before you begin the study… 
 
You will need to have the following exams, tests or procedures to find out if you can be in the study. These exams, 
tests or procedures are part of your regular cancer care and may be done even if you do not join the study.  If you 
have had some of them recently, they may not need to be repeated. The results of these tests will be reviewed.  It 
is possible that after these tests are reviewed, you will not be able to take part in the study.  If you are not able to 
take part in the study, your doctor will discuss with you the reasons why. 
 
 
A medical history 
 
Physical exam with vital signs 
 
Bone marrow test to check your cancer (see Tests on the Bone Marrow, below) 
 
Lumbar puncture to test the fluid in your spinal cord (see Lumbar Punctures, below) 
 
Blood tests to check your organ function 
 
Tests to make sure you are not pregnant (if you are a female and old enough to become pregnant) 
 
Tests of liver function 
 
Echocardiogram (ECHO) which uses sound waves to test heart function 
 
EKG to check your heart rhythm  
 
Tests on the Bone Marrow 
Examinations of the bone marrow will be performed routinely and may be done at the discretion of your study 
doctor. You have already had many tests of your bone marrow for your previous treatment of AML.                    
Many children receive some form of sedation or anesthesia during this procedure. A small area over your hip 
bone on the back will be cleaned and numbed with lidocaine and/or with an anesthetic cream. Approximately 2 
teaspoons of bone marrow will be withdrawn through a needle inserted into the bone. The test is painful, 
especially when the bone marrow is withdrawn. There is also a small risk of bleeding or infection from this 
procedure.   
 
Lumbar Punctures (“L.P.s”, “spinal taps”) 
You are familiar with spinal taps since they were done during your initial therapy for AML. Whether you decide to 
participate or not in this study, additional spinal taps will need to be done to give medicines, which are necessary 

 
 
 
 
Original  version date: 1-20-2017  
Amendment 1 version date: 09-06-2017 
 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
Amendment 4 version date: 07-01-2019 
 
 
 
 
 
Original Protocol version 1-20-2017 
Amendment 1 version date: 09-06-2017 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
 
Amendment 4 version date: 07-01-2019 
62 
CONFIDENTIAL 
 
 
TACL Internal Distribution Only 
 
to prevent the leukemia from spreading to the spinal fluid. The drugs cytarabine, hydrocortisone and methotrexate 
will be injected into your spine while you are having a lumbar puncture. If you are found to have leukemia in your 
spinal fluid you may receive cytarabine, hydrocortisone and methotrexate otherwise all patients will receive only 
cytarabine. This way of giving medicine is called “intrathecal” or IT. Many children receive some form of sedation 
or anesthesia during this procedure. Spinal taps are painful and may cause headaches. The skin at the site of 
needle insertion is usually numbed with an anesthetic cream or lidocaine before the procedure is performed. 
Approximately 1 teaspoon of spinal fluid will be withdrawn prior to injection of the medicine. 
 
 
During the study… 
 
Dose Escalation Schedule 
 
 
 
 
 
 
 
 
 
 
Treatment 
You will receive a total of 2 planned courses  
 
Days (Courses 1 and 2) 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
… 
35 
Decitabine 
 
• 
• 
• 
• 
• 
 
 
Vorinostat 
 
• 
• 
• 
• 
• 
 
 
 
 
 
 
 
 
 
Fludarabine 
 
• 
• 
• 
• 
• 
 
 
Cytarabine 
 
• 
• 
• 
• 
• 
 
Filgrastim (G-CSF) 
 
• 
• 
• 
• 
• 
• 
• 
• 
•# 
IT Cytarabine 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ITT Therapy 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bone Marrow Asp/Bx 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Treatment will last about 5 to 7 weeks. At the end of each treatment course, you will have an evaluation to see 
how your leukemia is responding to therapy. Additional therapy is recommended after completion of this treatment 
and your doctor will discuss those options with you.  
 
Medical Tests During Treatment 
Decitabine Dose Level 
Dose 
Days Given 
0 
5 mg/m2 
1-5 
 
 
 
1 
7.5 mg/m2 
1-5 
2 
10 mg/m2 
1-5 
3 
15 mg/m2 
1-5 

 
 
 
 
Original  version date: 1-20-2017  
Amendment 1 version date: 09-06-2017 
 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
Amendment 4 version date: 07-01-2019 
 
 
 
 
 
Original Protocol version 1-20-2017 
Amendment 1 version date: 09-06-2017 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
 
Amendment 4 version date: 07-01-2019 
63 
CONFIDENTIAL 
 
 
TACL Internal Distribution Only 
 
Whether you are on this study or not the following medical tests will be done to monitor for response to treatment 
as well as side effects related to treatment. You will have regular medical appointments throughout treatment. The 
timing of the appointments will be the same regardless if you participate in the research study. These include: 
 
Physical exams with vital signs 
 
Blood tests to check your organ function including 
– 
CBC to look at your blood cells 
– 
Chemistries to look at elements and minerals in your blood 
– 
Blood tests to look at your kidney function 
 
Bone Marrow Tests 
 
Lumbar Punctures 
 
ECHO and EKG before course 2 
 
Tests for Research Purposes: 
In addition to the routine tests listed above, we would like to do other tests while you are enrolled on the study.   
Bone marrow for Required Correlative Studies 
Peripheral blood for Required Correlative Studies 
 
Minimal Residual Disease (MRD)  
 
Doctors have developed tests to detect whether very small amounts of cancer cells can be found in blood 
or bone marrow.  During treatment  1/2 teaspoon (2mL) of bone marrow will be taken. Samples will be 
taken at the end of course 1 and 2.  This testing is done at the time of scheduled bone marrow 
procedures to determine response and disease status so it does not require any additional procedures. 
Any leftover bone marrow that is not used for this test will be destroyed. 
 
Final Study Visit 
Within 30 days after you finish the last dose of study drugs, your doctor will need to check to see how you are 
doing. The doctor will ask you how you feel, if you have trouble doing your daily routine, and what drugs you are 
taking. You will also have the following tests done:  
 
Physical exam, weight and vital signs 
 
CBC and chemistry blood tests 
 
Echocardiogram if required 
 
EKG 
 
Follow-up Tests 
After completing the treatment on this study we would like to continue to collect some medical information about 
how you are doing for as long as you are willing to let us or until the study is completely closed. We will collect 
information on how your AML is doing, what kind of therapy you may be getting and if you have any long term 
side effects.   
 
 
What are my responsibilities? 
 
 
During the study you will be asked to take all your chemotherapy drugs as prescribed. It is very important that 
you follow your doctor’s instructions regarding when and how to take your study medications.  Be sure to ask 
your study doctor or nurse if you have any questions about taking your study medications.   

 
 
 
 
Original  version date: 1-20-2017  
Amendment 1 version date: 09-06-2017 
 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
Amendment 4 version date: 07-01-2019 
 
 
 
 
 
Original Protocol version 1-20-2017 
Amendment 1 version date: 09-06-2017 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
 
Amendment 4 version date: 07-01-2019 
64 
CONFIDENTIAL 
 
 
TACL Internal Distribution Only 
 
 
 
If you experience any unusual side effects as explained by your study doctor, you should contact the study 
center immediately. You should also contact your study doctor if you are hospitalized for any reason during 
the study or within 30 days after completion of therapy. 
 
  
How long will I be in the study?   
 
You will be in the study for two courses of therapy which will last approximately 2 months. After completing the 
study therapy, your doctor will discuss with you the options for additional treatment.These options will vary 
depending on whether or not your leukemia responded to the therapy.  
 
 
Can I stop being in the study? 
 
Yes. You can decide to stop at any time. Your clinical care will not be affected by your decision to withdraw. Tell 
your doctor if you are thinking about stopping or decide to stop.  He or she will tell you how to stop safely. You will 
be asked to visit the hospital or clinic for some follow-up tests to make sure all the side effects you may have 
experienced have gone away. 
 
It is important to tell your doctor if you are thinking about stopping so any risks of the study treatment and 
chemotherapy drugs can be evaluated by your doctor. Another reason to tell your doctor that you are thinking 
about stopping is to discuss what follow-up care and testing could be most helpful for you. 
 
Your doctor may stop you from taking part in this study at any time without your permission if he/she believes it is 
in your best interest; if you do not follow the study rules; if you become pregnant or begin to breast feed; or if the 
study is stopped. 
 
 
What side effects or risks can I expect from being in the study?  
 
All people who receive cancer treatment are at risk of having side effects.  In addition to killing leukemia cells, 
chemotherapy drugs can damage normal tissues and produce side effects.  Side effects are usually reversible 
when the medication is stopped, but occasionally can persist and cause serious complications or death. The 
therapy used in this clinical trial is intensified so that it can kill cancer cells quickly before they can become 
resistant to treatment. Protocols used to treat relapsed leukemia are more intense than are those to treat newly 
diagnosed disease. It is not possible to predict whether the side effects listed below, or other rare side effects may 
occur.  Side effects can be increased when chemotherapy drugs are combined.  
 
Common side effects include nausea, vomiting, hair loss and fatigue. Chemotherapy causes temporary bone 
marrow depression. Bone marrow depression results in a decreased production of red cells causing anemia; 
decreased platelet production causing bruising and an increased chance of bleeding; and decreased white cell 
production, causing a risk of serious and potentially life threatening infections. Red blood cell and platelet 
transfusions may be required 
 

 
 
 
 
Original  version date: 1-20-2017  
Amendment 1 version date: 09-06-2017 
 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
Amendment 4 version date: 07-01-2019 
 
 
 
 
 
Original Protocol version 1-20-2017 
Amendment 1 version date: 09-06-2017 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
 
Amendment 4 version date: 07-01-2019 
65 
CONFIDENTIAL 
 
 
TACL Internal Distribution Only 
 
Risks of having the bone marrow procedure include bleeding, chance of an infection and long lasting pain at the 
place where the needle is inserted into the bone.  
 
Each drug will have a unique set of side effects.  Side effects related to drugs occur in people at different rates or 
frequencies.    
 
 
DRUG 
 
. 
Decitabine 
System Organ Class 
Adverse Events Reported more 
than 10 of 100 adult patients who 
received decitabine in a Phase 3 
MDS trial 
Adverse Events Reported in 5-10 of 
100 adult patients who received 
decitabine in a Phase 3 MDS trial 
Blood and Lymphatic 
System 
 
Neutropenia (condition in 
which the number of white 
blood cells called neutrophils 
is abnormally low) 
 
Thrombocytopenia (low 
number of cells called 
platelets which may cause 
bleeding and brusing) 
 
Anemia (Low number of red 
blood cells) 
 
Febrile neutropenia (condition 
in which the number of white 
blood cells called neutrophils 
is abnormally low along with 
fever 
 
Leukopenia (low number of 
white blood cells) 
 
Lymphadenopathy (disease 
where lymph nodes are 
abnormal) 
 
Thrombocythemia (disease 
where a large amount of cells in 
clotting called platelets are 
produced) 

 
 
 
 
Original  version date: 1-20-2017  
Amendment 1 version date: 09-06-2017 
 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
Amendment 4 version date: 07-01-2019 
 
 
 
 
 
Original Protocol version 1-20-2017 
Amendment 1 version date: 09-06-2017 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
 
Amendment 4 version date: 07-01-2019 
66 
CONFIDENTIAL 
 
 
TACL Internal Distribution Only 
 
Decitabine 
System Organ Class 
Adverse Events Reported more 
than 10 of 100 adult patients who 
received decitabine in a Phase 3 
MDS trial 
Adverse Events Reported in 5-10 of 
100 adult patients who received 
decitabine in a Phase 3 MDS trial 
Gastrointestinal  
 
 
Nausea (feeling sick to the 
stomach) 
 
Constipation (difficulty passing 
stools) 
 
Diarrhea  
 
Vomiting 
 
Abdominal pain (pain in the 
belly) 
 
Decreased appetite (less 
hungry than normal) 
 
Anorexia (illness where 
person does not want to eat) 
 
Oral Mucosal petechia (Small 
red dots in the mouth caused 
by problems with clotting) 
 
Stomatitis (sores in the mouth) 
 
Dyspepsia (indigestion) 
 
Ascites (build up of fluid in the 
belly which causes bloating 
and discomfort) 
 
Gum bleeding 
 
Hemorrhoids (swollen veins in 
the lower part of the rectum and 
anus) 
 
Tongue ulceration (small parts 
of the tongue are eroded away) 
 
Difficulty swallowing 
 
Oral soft tissue disorders 
(disorders of the skin in the 
mouth) 
 
Lip ulceration (small parts of the 
lip are eroded away) 
 
Abdominal distention (bloating) 
 
Upper abdominal pain (pain in 
the upper part of the belly) 
 
Gastro-esophogeal reflux 
disease (acid reflux) 
 
Pain in tongue 
General Disorders 
 
Pyrexia (fever) 
 
Peripheral edema (swelling of 
the limbs) 
 
Rigors (chills and shivering) 
 
Edema NOS (swelling) 
 
Pain NOS  
 
Lethargy (tiredness) 
 
Falls 
 
Chest discomfort 
 
Intermittent pyrexia (fevers that 
come and go) 
 
Malaise (general feeling of 
unwellness) 
 
Crepitations (a crackling or 
rattling sound made in 
breathing) 
 
Catheter site redness (reddness 
around the site where a tube is 
entered into the body) 
 
Catheter site pain (pain around 
the site where a tube is entered 
into the tbody) 
 
Injection site swelling  

 
 
 
 
Original  version date: 1-20-2017  
Amendment 1 version date: 09-06-2017 
 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
Amendment 4 version date: 07-01-2019 
 
 
 
 
 
Original Protocol version 1-20-2017 
Amendment 1 version date: 09-06-2017 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
 
Amendment 4 version date: 07-01-2019 
67 
CONFIDENTIAL 
 
 
TACL Internal Distribution Only 
 
Decitabine 
System Organ Class 
Adverse Events Reported more 
than 10 of 100 adult patients who 
received decitabine in a Phase 3 
MDS trial 
Adverse Events Reported in 5-10 of 
100 adult patients who received 
decitabine in a Phase 3 MDS trial 
Infection 
 
Pneumonia NOS (condition 
with severe coughing, fever 
and chest pain that has no 
known cause) 
 
Cellulitis (infection of th skin) 
 
Candidal infection NOS 
(infection caused by a yeast 
called candida) 
 
Catheter related infection 
 
Urinary tract infection (infection 
of the part of the body that urine 
comes out of) 
 
Staphylococcal infection 
(infection caused by a bacteria 
called staphylococci) 
 
Oral candidiasis (infection of the 
mouth by a yeast called 
candida) 
 
Sinusitis (infection of the 
sinuses) 
 
Bacteremia (infection in the 
blood) 

 
 
 
 
Original  version date: 1-20-2017  
Amendment 1 version date: 09-06-2017 
 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
Amendment 4 version date: 07-01-2019 
 
 
 
 
 
Original Protocol version 1-20-2017 
Amendment 1 version date: 09-06-2017 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
 
Amendment 4 version date: 07-01-2019 
68 
CONFIDENTIAL 
 
 
TACL Internal Distribution Only 
 
Decitabine 
System Organ Class 
Adverse Events Reported more 
than 10 of 100 adult patients who 
received decitabine in a Phase 3 
MDS trial 
Adverse Events Reported in 5-10 of 
100 adult patients who received 
decitabine in a Phase 3 MDS trial 
Metabolic/Laboratory 
 
Hyperbilirubinemia (a build up 
of a substance called bilirubin 
in the blood) 
 
Elevated alkaline phophatase 
(abnormally high levels in a 
liver test of a protein called 
alkaline phosphatase) 
 
Elevated AST (abnormally 
high levels in a liver test of a 
protein called aspartate 
aminotransaminase) 
 
Elevated BUN (High levels in 
a kidney test of a molecule  
 
Hyperglycemia (high levels of 
sugar in the blood) 
 
Hypoalbuminemia (low levels 
of a protein called albumin in 
the blood) 
 
Hypomagnesemia (low levels 
of an ion called magnesium in 
the blood) 
 
Hypokalemia (low levels of an 
ion called potassium in the 
blood) 
 
Hyponatremia (low levels of 
an ion called sodium in the 
blood) 
 
Hyperkalemia (high levels of 
an ion called potassium in the 
blood) 
 
 
 
Dehydration (sickness resulting 
from not have enough fluids) 
 
Lactate dehydrogenase 
increased (high levels of a 
molecule called lactate 
dehydrogenase in the blood) 
 
Increased blood bicarbonate  
 
Decreased blood bicarobonate 
 
Decreased blood chloride 
 
Blood protein decreased 
 
Blood bilirubin decreased  
Musculoskeletal 
 
Arthralgia (pain in the joins) 
 
Limb pain (pain in the arms or 
legs) 
 
Back pain 
 
Chest wall pain 
 
Musculoskeletal discomfort 
(pain in the muscles or bones) 
 
Muscle pain 
Neurological 
 
Headache 
 
Dizziness 
 
Hypoesthesia (reduced sense 
of touch) 
 
Insomnia (difficulty sleeping) 
 
Confusional state 
 
Anxiety 
 

 
 
 
 
Original  version date: 1-20-2017  
Amendment 1 version date: 09-06-2017 
 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
Amendment 4 version date: 07-01-2019 
 
 
 
 
 
Original Protocol version 1-20-2017 
Amendment 1 version date: 09-06-2017 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
 
Amendment 4 version date: 07-01-2019 
69 
CONFIDENTIAL 
 
 
TACL Internal Distribution Only 
 
Decitabine 
System Organ Class 
Adverse Events Reported more 
than 10 of 100 adult patients who 
received decitabine in a Phase 3 
MDS trial 
Adverse Events Reported in 5-10 of 
100 adult patients who received 
decitabine in a Phase 3 MDS trial 
Pulmonary 
 
Cough 
 
Pharyngitis (infection in the 
throat) 
 
Crackles lung (lungs with a 
build up of fluid in them) 
 
Breath sounds decreased 
 
Hypoxia (low levels of oxygen 
reaching the body) 
 
Rales (abnormal rattling sound 
when listening to unhealthy 
lungs with a stethoscope) 
 
Postnasal drip (when fluid from 
the sinuses drain into the throat) 
Renal  
 
 
Dysuria (pain when urinating) 
 
Urinary frequency (urinating 
frequently 
Skin 
 
Ecchymosis (discoloration of 
the skin caused by bleeding 
underneath, for example by 
bruising) 
 
Rash 
 
Erythema (reddness of the 
skin) 
 
Skin lesions NOS (general 
wounds of the skin) 
 
Pruritus (itching) 
 
Petechiae (small points of 
discoloration of the skin 
caused by bleeding 
underneath) 
 
Pallor (paleness) 
 
Alopecia (Baldness) 
 
Urticaria (a type of skin rash) 
 
Facial swelling (enlargening of 
the face caused by fluid) 
Cardiac 
 
Cardiac murmur NOS (sound 
the heart makes when the 
valves inside of it generally 
don’t work properly) 
 
Hypotension (low blood 
pressure) 
 
Hematoma (bruise) 
 
 

 
 
 
 
Original  version date: 1-20-2017  
Amendment 1 version date: 09-06-2017 
 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
Amendment 4 version date: 07-01-2019 
 
 
 
 
 
Original Protocol version 1-20-2017 
Amendment 1 version date: 09-06-2017 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
 
Amendment 4 version date: 07-01-2019 
70 
CONFIDENTIAL 
 
 
TACL Internal Distribution Only 
 
Vorinostat 
Adverse Events Reported in more than 10 of 100 adult patients 
With Cutaneous T-cell Lymphoma Who Were Receiving Vorinostat (Regardless of Causality) 
 
Fatigue (tiredness) 
 
Diarrhea (loose stools) 
 
Nausea (feeling of wanthing to throw up) 
 
Dysguesia (change in sense of taste) 
 
Thrombocytopenia (low number of cells 
caused platelets resulting in blood clotting 
problems) 
 
Anorexia (disease of an abnormally low 
appetite that often causes extreme weight 
loss) 
 
Weight decrease 
 
Muscle spasms (when muscles contract 
uncontrollably) 
 
Alopecia (baldness) 
 
Dry mouth 
 
Blood creatinine increased (test of the 
kidneys where there is a high level of a 
protein called creatinine in the blood) 
 
Chills (shivering) 
 
Vomiting 
 
Constipation (difficulty passing stools) 
 
Dizziness 
 
Anemia (Low number of red blood cells that 
causes tiredness) 
 
Decreased appetite (less desire to eat) 
 
Peripheral edema (swelling of the arms or 
legs) 
 
Headache  
 
Pruritus (itchiness) 
 
Cough 
 
Upper respiratory infection (infection of the 
nose, throat and upper parts of the lungs) 
 
Pyrexia (fever) 
Adverse Events Reported in 5-10 of 100 adult patients 
With Cutaneous T-cell Lymphoma Who Were Receiving Vorinostat (Regardless of Causality) 
 
Pulmonary embolism (clot in the lungs) 
 
Hyperglycemia (high levels of sugar in the 
blood) 
Rare Adverse Events Reported in Other Patients Who Were Receiving Vorinostat (Regardless of 
Causality) 
 
Deep vein thrombosis (clot in the deep blood 
vessels of the leg) 
 
Abnormal electrolytes (including blood 
creatinine, magnesium, potassium and 
calcium) (abnormal levels of ions in the 
blood) 
 
Ischemic stroke (blocking of blood vessels in 
the brain causing a lower level of oxygen 
reaching the brain) 
 
Pelviureteric obstruction (when part of the 
kidney is blocked) 
 
Spinal cord injury (damage to part of the 
spine) 
 
Syncope (temporary loss of consciousness 
caused by a fall in blood pressure) 
 
Ureteric obstruction (blockage of tube that 
carries urine from the kidney to the bladder) 
 
Squamous cell carcinoma (cancer of the skin) 
 
Cholecystitis (inflammation of the gallbladder) 
 
Death 
 
Blood stream infections (including specifically, 
for example: enterococcal, streptococcal) 
 
Exfoliative dermatitis (redness and peeling of 
the skin in large parts of the body) 
 
Gastrointestinal hemorrhage (bleeding within 
the belly) 
 
Lobar pneumonia (severe infection of a section 
of the lung often causing fever and cough) 
 
Myocardial infarction (heart attack) 
 
T-cell lymphoma (a type of cancer of the 
immune system) 
 
Prolonged QT interval (heart rhythm disorder) 
 

 
 
 
 
Original  version date: 1-20-2017  
Amendment 1 version date: 09-06-2017 
 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
Amendment 4 version date: 07-01-2019 
 
 
 
 
 
Original Protocol version 1-20-2017 
Amendment 1 version date: 09-06-2017 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
 
Amendment 4 version date: 07-01-2019 
71 
CONFIDENTIAL 
 
 
TACL Internal Distribution Only 
 
 
Fludarabine 
Frequency of Adverse 
Event: 
Common: Happens to 21-100 children out of every 100 
Timing of AE Onset in 
Relation to Drug 
Administration: 
Adverse Events 
Immediate:  Within 1-2 
days of receiving drug 
 
Fever  
 
Fatigue (tiredness)  
 
weakness  
 
pain 
 
nausea (Feeling of wanting to vomit) 
 
vomiting  
 
anorexia (disease of severely decreased appetite often causing a 
large amount of weight loss) 
 
cough  
 
dyspnea (difficulty breathing) 
Prompt:  Within 2-3 weeks, 
prior to the next course 
 
Myelosuppression including: 
o 
anemia (decrease in red blood cells) 
o 
Neutropenia (decrease in cells of the immune system 
called neutrophils) 
o 
thrombocytopenia (decrease in cells called platelets in the 
blood which causes problems in clotting) 
 
Infection including: 
o 
urinary tract infection (infection causing pain when peeing) 
o 
herpes simplex infection (infection caused by a virus 
called herpes simplex virus) 
o 
pneumonia (severe infection of the chest causing fever 
and coughing) 
o 
upper respiratory infection (infection of the nose, airways 
and upper parts of the lungs) 
Delayed:  Any time later 
during therapy, excluding 
the above conditions 
 
Late:  Any time after 
completion of treatment 
 
 
 
 
Frequency of Adverse 
Event: 
Occasional:  Happens to 5-20 children out of every 100 
Timing of AE Onset in 
Relation to Drug 
Administration: 
Adverse Events 
Immediate:  Within 1-2 
days of receiving drug 
 
Edema including peripheral edema (swelling including swelling in 
the limbs) 

 
 
 
 
Original  version date: 1-20-2017  
Amendment 1 version date: 09-06-2017 
 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
Amendment 4 version date: 07-01-2019 
 
 
 
 
 
Original Protocol version 1-20-2017 
Amendment 1 version date: 09-06-2017 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
 
Amendment 4 version date: 07-01-2019 
72 
CONFIDENTIAL 
 
 
TACL Internal Distribution Only 
 
 
Chills (shivering) 
 
rash  
 
diarrhea (loose stools) 
 
rhinitis (stuffy and runny nose) 
 
diaphoresis (heavy sweating) 
 
malaise (general feeling of being unwell) 
 
abdominal pain (pain in the belly) 
 
headache 
 
back pain 
 
myalgia (muscle pains) 
 
stomatitis (inflamed and sore mouth) 
 
flu-like syndrome 
Prompt:  Within 2-3 weeks, 
prior to the next course 
 
Weight loss,  
 
gastrointestinal bleeding (bleeding in the belly) 
 
hemoptysis (coughing with blood) 
 
paresthesia (burning or prickling sensation in the skin) 
 
allergic pneumonitis (inflammation within the lungs due to irritation 
from a substance breathed in)  
 
bronchitis (inflammation of air passages) 
 
pharyngitis (inflammation of the throat) 
 
visual disturbance (problems in seeing) 
 
hearing loss  
 
hyperglycemia (high levels of sugar in the blood) 
Delayed:  Any time later 
during therapy, excluding 
the above conditions 
 
Late:  Any time after 
completion of treatment 
 
Frequency of Adverse 
Event: 
Rare:  Happens to < 5 children out of every 100 
Timing of AE Onset in 
Relation to Drug 
Administration: 
Adverse Events 
Immediate:  Within 1-2 
days of receiving drug 
 
Anaphylaxis (severe allergic reaction) 
 
tumor lysis syndrome (disease caused by a large amount of tumor 
cells being killed off at the same time) 
 
dehydration (lack of fluid in the body) 
Prompt:  Within 2-3 weeks, 
prior to the next course 
 
 
 
 
 
Sinusitis (inflammation of the sinus) 
 
dysuria (painful or difficulty urinating) 
 
opportunistic infections and reactivation of latent viral infections 
like (infections caused by weakened immune system) 
o 
Epstein-Barr virus (EBV) 
o 
herpes zoster  
o 
John Cunningham (JC) virus (progressive multifocal 
leukoencephalopathy [PML])  
 
EBV associated lymphoproliferative disorder (large production of a 
cell in the immune system called lymphocytes due to an infection 

 
 
 
 
Original  version date: 1-20-2017  
Amendment 1 version date: 09-06-2017 
 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
Amendment 4 version date: 07-01-2019 
 
 
 
 
 
Original Protocol version 1-20-2017 
Amendment 1 version date: 09-06-2017 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
 
Amendment 4 version date: 07-01-2019 
73 
CONFIDENTIAL 
 
 
TACL Internal Distribution Only 
 
with a virus called Epstein Barr virus) 
 
panycytopenia (can be prolonged) (low levels of red blood cells, 
white blood cells and platelets) 
 
pulmonary hypersensitivity  
o 
dyspnea (difficulty breathing) 
o 
cough 
o 
hypoxia (low levels of oxygen in the body) 
o 
interstitial pulmonary infiltrate (build up of fluid in the walls 
around the air sacs in the lungs) 
 
pulmonary toxicity (acute respiratory distress syndrome [ARDS]  
 
pulmonary fibrosis (scarring within the lungs) 
 
pulmonary hemorrhage (bleeding within the lungs) 
 
respiratory distress  
 
respiratory failure (failure of respiratory system) 
 
pericardial effusion (fluid build up in the space around the heart) 
 
skin toxicity including: 
o 
erythema multiforme (a severe allergic reaction associated 
with certain infections and medications) 
o 
Stevens-Johnson syndrome (severe skin reaction 
associated with fever and flu like symptoms) 
o 
toxic epidermal necrolysis (widespread redness and 
peeling off of the skin) 
o 
pemphigus (skin disease with watery blisters) 
 
liver failure 
 
renal failure  
 
hemorrhage (bleeding) 
 
transfusion-associated graft-versus-host disease following 
transfusion of non-irradiated blood products (Immune system 
attack of the cells that were transfused) 
 
phlebitis (inflammation of a vein) 
 
sleep disorder  
 
cerebellar syndrome (dysfunction of a part of the brain called the 
cerebellum) 
 
depression  
 
mentation impaired (memory lapses) 
 
alopecia (hair loss) 
 
pruritus (itchiness) 
 
seborrhea (chronic dandruff) 
 
esophagitis (inflammation of the tube between the mouth and 
stomach that may cause difficulty swallowing and chest pain) 
 
constipation 
 
mucositis  
 
dysphagia 
 
hesitancy 
 
cholelithiasis 
 
abnormal liver function tests  
 
osteoporosis 
 
arthralgia 

 
 
 
 
Original  version date: 1-20-2017  
Amendment 1 version date: 09-06-2017 
 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
Amendment 4 version date: 07-01-2019 
 
 
 
 
 
Original Protocol version 1-20-2017 
Amendment 1 version date: 09-06-2017 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
 
Amendment 4 version date: 07-01-2019 
74 
CONFIDENTIAL 
 
 
TACL Internal Distribution Only 
 
 
 
 
Cytarabine Intravenous 
 
Common 
Happens to 21-100 
children out of every 
100 
Occasional 
Happens to 5-20 
children out of every 
100 
Rare 
Happens to < 5 children out of 
every 100 
Immediate:  Within 1-
2 days of receiving 
drug  
Nausea, vomiting, 
anorexia (weight 
loss)  
Flu-like symptoms 
with fever, rash  
Ara-C syndrome (fever, myalgia, 
bone pain, occasionally chest pain, 
maculopapular rash, malaise, 
conjunctivitis), anaphylaxis (severe 
allergic reaction) 
Prompt:  Within 2-3 
weeks, prior to the 
next course  
Myelosuppression 
(anemia, 
thrombocytopenia, 
leukopenia, 
megaloblastosis, 
reticulocytopenia)(low 
levels of red blood 
cells, platelets, white 
blodd cells, several 
large immature red 
blood cells, marrow 
failure)    
Stomatitis 
(inflammation of the 
mouth and lips) 
alopecia (hairloss) 
Diarrhea (loose 
stools), hypokalemia 
(low levels of 
potassium in the 
blood), hypocalcemia 
(low levels of calcium 
in the blood) 
hyperuricemia (high 
levels of uric acid in 
the blood) 
Hepatotoxicity (damage to the 
liver),  
sinusoidal obstruction syndrome 
(SOS, formerly VOD),  
urinary retention (inability to 
completely empty the bladder),  
renal dysfunction (kidney 
problems),  
pain and erythema (redness) of the 
palms and soles  
Delayed:  Any time 
later during therapy, 
excluding the above 
conditions 
 
 
Asymptomatic nonoliguric 
rhabdomyolysis (kidney failure as a 
consequence of muscle 
breakdown) 
Unknown Frequency 
and Timing:  
Fetal toxicities (toxicities of a baby while mother is still pregnant) and teratogenic 
effects (birth defects) of cytarabine have been noted in humans. It is unknown 
whether the drug is excreted in breast milk. 
 
 
 
 
 
 
 
abnormal renal function test  
 
proteinuria 
 
epistaxis 
 
hemorrhagic cystitis  
 
eosinophilia 

 
 
 
 
Original  version date: 1-20-2017  
Amendment 1 version date: 09-06-2017 
 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
Amendment 4 version date: 07-01-2019 
 
 
 
 
 
Original Protocol version 1-20-2017 
Amendment 1 version date: 09-06-2017 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
 
Amendment 4 version date: 07-01-2019 
75 
CONFIDENTIAL 
 
 
TACL Internal Distribution Only 
 
Cytarabine Intrathecal 
 
Common 
Happens to 21-100 
children out of every 
100 
Occasional 
Happens to 5-20 
children out of every 100 
Rare 
Happens to < 5 children out of 
every 100 
Immediate:  Within 
1-2 days of 
receiving drug  
 
Nausea 
(feeling of 
wanting to 
vomit) 
 
vomiting 
 
fever  
 
headache 
 
Arachnoiditis 
(inflammation of 
tissues that 
surround the 
brain called the 
arachnoid) 
 
 
Rash 
 
Somnolence (sleepiness) 
 
meningismus (irritation of 
the tissue around the brain 
called meninges) 
 
convulsions (a sudden, 
violent irregular movement 
of a limb) 
 
paresis (muscular damage 
caused by weakness) 
Prompt:  Within 2-3 
weeks, prior to the 
next course  
 
 
 
Myelosuppression (bone 
marrow activitiy is 
decreased which result in 
cells called red blood cells, 
white blood cells and 
platelets being decreased) 
 
Ataxia (the loss of full 
control of body 
movements) 
Delayed:  Any time 
later during therapy, 
excluding the above 
conditions 
 
 
 
Necrotizing 
leukoencephalopathy 
(changes in the brain that 
result from chemotherapy) 
 
Paraplegia (paralysis of 
the legs)  
 
blindness (in combination 
with XRT & systemic 
therapy) 
 
 
 
Cytarabine, Methotrexate and Hydrocortisone Intrathecal 
 
Common 
Happens to 21-100 
children out of every 
100 
Occasional 
Happens to 5-20 
children out of every 
100 
Rare 
Happens to < 5 children out of 
every 100 
 
 
Nausea 
 
Vomiting 
 
Fever 
 
Headache 
 
Swelling of 
the brain 
which may 
cause stiff 
neck, 
sensitivity to 
light, 
 
Rash 
 
Bleeding in the brain 
 
Paralysis, weakness 
 
Dizziness 
 
Damage to the brain which 
may cause changes in 
thinking, blindness 

 
 
 
 
Original  version date: 1-20-2017  
Amendment 1 version date: 09-06-2017 
 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
Amendment 4 version date: 07-01-2019 
 
 
 
 
 
Original Protocol version 1-20-2017 
Amendment 1 version date: 09-06-2017 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
 
Amendment 4 version date: 07-01-2019 
76 
CONFIDENTIAL 
 
 
TACL Internal Distribution Only 
 
Cytarabine, Methotrexate and Hydrocortisone Intrathecal 
 
Common 
Happens to 21-100 
children out of every 
100 
Occasional 
Happens to 5-20 
children out of every 
100 
Rare 
Happens to < 5 children out of 
every 100 
headache, 
vomiting 
 
Major change 
in thinking 
patterns 
 
Difficulty 
learning 
 
Confusion 
 
Tiredness 
 
Seizure 
  
 
Infection 
 
A low number of red blood 
cells can make you feel 
tired and weak 
 
A low number of white 
blood cells can make it 
easier to get infections 
 
Allow number of platelets 
causes you to bruise and 
bleed more easily 
 
 
 
Filgrastim (G-CSF, Neupogen) 
 
Common 
Happens to 21-100 
children out of every 100 
Occasional 
Happens to 5-20 children 
out of every 100 
Rare 
Happens to < 5 children out of 
every 100 
Immediate: 
Within 1-2 days of 
receiving drug 
 
 
Local irritation at 
the injection site,  
 
headache 
 
Allergic reactions (more 
common with IV 
administration than subq): 
 
skin  
o 
rash  
o 
urticaria (hives) 
o 
facial edema (facial 
swelling) 
 
respiratory  
o 
wheezing 
o 
dyspnea (difficulty 
breathing) 
 
cardiovascular  
o 
hypotension (low 
blood pressure) 
o 
Tachycardia (rapid 
heart rate) 
 
low grade fever 

 
 
 
 
Original  version date: 1-20-2017  
Amendment 1 version date: 09-06-2017 
 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
Amendment 4 version date: 07-01-2019 
 
 
 
 
 
Original Protocol version 1-20-2017 
Amendment 1 version date: 09-06-2017 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
 
Amendment 4 version date: 07-01-2019 
77 
CONFIDENTIAL 
 
 
TACL Internal Distribution Only 
 
Filgrastim (G-CSF, Neupogen) 
 
Common 
Happens to 21-100 
children out of every 100 
Occasional 
Happens to 5-20 children 
out of every 100 
Rare 
Happens to < 5 children out of 
every 100 
Prompt: 
Within 2-3 weeks, 
prior to the next 
course 
Mild to moderate 
medullary bone pain 
(pain inside the bone) 
 
Increased: alkaline 
phosphatase, 
lactate 
dehydrogenase 
and uric acid, 
(increased levels 
of molecules called 
alkaline 
phosphatase, 
lactate 
dedhyrogenase 
and uric acid in the 
blood) 
 
Thrombocytopenia 
(low levels of cells 
called platelets that 
causes problems 
with clotting) 
 
Splenomegaly 
(enlargement of the spleen)  
 
splenic rupture (major injury 
to the spleen)  
 
exacerbation of pre-existing 
skin rashes (Worsening of 
skin rashes that were 
already present)  
 
sickle cell crises in patients 
with SCD (severe pain in 
patients with a disease 
called sickle cell disease) 
 
excessive leukocytosis 
(high levels of white blood 
cells in the blood) 
Delayed: 
Any time later during 
therapy, excluding the 
above conditions 
 
 
 
Cutaneous 
vasculitis (inflamed 
blood vessels of 
the skin)  
 
ARDS (fluid build 
up of the tiny, 
elastic air cells of 
the lungs) 
Late: 
Any time after 
completion of 
treatment 
 
 
 
MDS or AML 
(confined to 
patients with 
severe chronic 
neutropenia and 
long term 
administration) 
(types of cancer 
that develop when 
patients have either 
a low amount of 
cells in the blood 
called neutrophils 
or are given anti-
cancer medications 
for a long priod of 
time) 

 
 
 
 
Original  version date: 1-20-2017  
Amendment 1 version date: 09-06-2017 
 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
Amendment 4 version date: 07-01-2019 
 
 
 
 
 
Original Protocol version 1-20-2017 
Amendment 1 version date: 09-06-2017 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
 
Amendment 4 version date: 07-01-2019 
78 
CONFIDENTIAL 
 
 
TACL Internal Distribution Only 
 
Filgrastim (G-CSF, Neupogen) 
 
Common 
Happens to 21-100 
children out of every 100 
Occasional 
Happens to 5-20 children 
out of every 100 
Rare 
Happens to < 5 children out of 
every 100 
Unknown Frequency and Timing:  
Fetal toxicities (toxicities in a baby while the mother is still pregnant) and teratogenic effects (effects that cause 
birth defects)of filgrastim in humans are unknown. Conflicting data exist in animal studies and filgrastim is known 
to pass the placental barrier. It is unknown whether the drug is excreted in breast milk. 
 
Fungal Risks 
With high doses of chemotherapy and decitabine there has been some evidence of greater risks of fungal 
infections. You will be required to take medication to prevent these infections. 
 
Reproductive risks  
 
Because the drugs in this study can affect an unborn baby, you should not become pregnant or father a baby 
while on this study.  You should not breast-feed a baby while on this study.  It is a condition of this study that 
adequate birth control methods be used by all participants while enrolled in the study. Examples of these include 
total abstinence (no sex), oral contraceptives (“the pill”), an intrauterine device (IUD), Levonorgestrol implants 
(Norplant), or medroxyprogesterone acetate injections (Depo-provera shots).  If one of these methods of birth 
control cannot be used, contraceptive foam with a condom is recommended.  Ask your doctor about counseling 
and more information about preventing pregnancy. 
 
If you become pregnant or father a child during this study, contact your doctor immediately to discuss the 
requirements for pregnancy outcome follow-up. Female subjects will be given instructions for discontinuation of 
study medication. 
 
Confidential Information  
 
There is the potential risk of accidental disclosure (release) of confidential information when you participate in 
research.  Please see the “Will my medical information be kept private?” section of this document for more details. 
 
Developing a Second Cancer 
 
It is possible that you may develop a second form of cancer as a result of this treatment.  Experience so far 
suggests that the chance of this happening is very small. Not enough information has been gathered in children to 
be able to give an accurate prediction, although it may be in the range of one in every 50 to 800 children treated.   
 
Are there benefits to subjects taking part in the study? 
Participation in this study may or may not benefit you. Participating in this study will not cure your relapsed 
leukemia.  Based on experience with the drugs used in the treatment plan, researchers believe this therapy may 
cause your leukemia to stop growing or go into remission for a period of time.  Your cancer may not have any 
response to the therapy received while participating in this study.   
 
It is hoped that the information learned from this study may help future children or young adults with relapsed 
AML. 

 
 
 
 
Original  version date: 1-20-2017  
Amendment 1 version date: 09-06-2017 
 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
Amendment 4 version date: 07-01-2019 
 
 
 
 
 
Original Protocol version 1-20-2017 
Amendment 1 version date: 09-06-2017 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
 
Amendment 4 version date: 07-01-2019 
79 
CONFIDENTIAL 
 
 
TACL Internal Distribution Only 
 
 
 
 
 
What other choices do I have if I do not take part in this study? 
 
You do not have to participate in this study to receive treatment for recurrent leukemia. There is no “standard” 
therapy for recurrent leukemia. Most treatment plans have used drugs similar to those used in this protocol, 
although these drugs may be given in different combinations, and at different times.  You can receive other 
combinations of chemotherapy without participating in this study.   
 
As an alternative to this study, you may decide you don’t want additional treatment for your relapsed leukemia.  
You will always receive medicines to help you feel more comfortable and deal with problems caused by your 
cancer or treatment whether you participate in this study or not. 
 
Talk to your doctor about your choices before you decide if you will take part in this study. 
 
 
Will my medical information be kept private?  
 
We will do our best to make sure that the personal information in your medical record will be kept private. 
However, we cannot guarantee total privacy. Your personal information may be given out if required by law. 
 
Members of the research team and, if appropriate, your primary care physicians and nurses will know that you are 
a research subject. All results will be kept confidential, but may be made available to you, and/or your physician if 
you wish.  Because this study involves the treatment of a medical condition, a copy of this consent form will be 
placed in your medical record. This will allow the doctors that are caring for you to obtain information about what 
medications or procedures you are receiving in the study and treat you appropriately. You may read your medical 
record. The records are available to those caring for you at this hospital. 
 
Organizations that may inspect/or copy your research records for quality assurance and data analysis include: 
 
Therapeutic Advances in Childhood Leukemia Consortium (TACL) 
 
The United States Food and Drug Administration (FDA) 
 
Health Canada 
 
Therapeutic Goods Administration, Australia 
 
The Department of Health and Human Services (DHHS) 
 
The Institutional Review Board (IRB) of CHLA  - Committee on Clinical Investigations 
 
As a result, these organizations may see your name; but they are bound by rules of confidentiality not to reveal 
your identity to others. These organizations will also have access to study data in a form that does not mention 
your name in order to complete the research including processing, analyzing (studying), using, and storing data. 
Reasonable steps will be taken to protect your right to privacy. No information about you, or provided by you 
during the research, will be shared with others without your written permission, except as explained below: 
 
 
If necessary to protect your rights or welfare (for example, if you are injured and need emergency care); 
or 

 
 
 
 
Original  version date: 1-20-2017  
Amendment 1 version date: 09-06-2017 
 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
Amendment 4 version date: 07-01-2019 
 
 
 
 
 
Original Protocol version 1-20-2017 
Amendment 1 version date: 09-06-2017 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
 
Amendment 4 version date: 07-01-2019 
80 
CONFIDENTIAL 
 
 
TACL Internal Distribution Only 
 
 
If required by law (i.e., child abuse, reports of certain infectious diseases) 
 
The information collected will be used to meet the purpose of this clinical study. In addition, this information may 
be used to support applications to market the studied drug in the United States and in other countries. It may also 
be used in reports of the study or for scientific publications and presentations that will not identify study 
participants by name.   
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. Law.  This 
website will not include information that can identify you.  At most, the website will include a summary of the 
results.  You can search this website at anytime. 
 
What are the costs of taking part in this study? 
 
The health care costs during your participation in this study that are considered part of the standard treatment of 
your disease will be billed to your insurance or other third-party payer.  This includes blood tests, hospitalizations, 
procedures that will be done and medications.  
 
You will not have to pay for the following tests that will be done for research purposes only. 
 
Tests for MRD 
 
Tests for how the DEC and VOR are affecting your leukemia cells 
 
Your family is responsible for other costs which may result from your participation in the study, such as, but not 
limited to, time off of work, car fare, baby sitter fees, food purchased while at the hospital, etc.  You will not 
receive any type of payment for participating in this study.  Taking part in this study may lead to added costs to 
your insurance company. Please ask about any expected added costs or insurance problems. 
 
For more information on clinical trials and insurance coverage, you can visit the National Cancer Institute’s Web 
site at http://cancer.gov/clinicaltrials/understanding/insurance-coverage . You can print a copy of the “Clinical 
Trials and Insurance Coverage” information from this Web site. 
 
Another way to get the information is to call 1-800-4-CANCER (1-800-422-6237) and ask them to send you a free 
copy. 
 
What happens if I am injured because I took part in this study? 
 
It is important that you tell your study doctor, __________________ [investigator’s name(s)], if you feel that you 
have been injured because of taking part in this study.  You can tell the doctor in person or call him/her at 
__________________ [telephone number]. 
 
You will get medical treatment if you are injured as a result of taking part in this study.  You and/or your health 
plan will be charged for this treatment. The study will not pay for medical treatment.   
 
What are my rights if I take part in this study? 
 
Taking part in this study is voluntary. You may choose not to participate in this study. If you decide not to 
participate, you will not be penalized and you will still receive the standard treatment. 

 
 
 
 
Original  version date: 1-20-2017  
Amendment 1 version date: 09-06-2017 
 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
Amendment 4 version date: 07-01-2019 
 
 
 
 
 
Original Protocol version 1-20-2017 
Amendment 1 version date: 09-06-2017 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
 
Amendment 4 version date: 07-01-2019 
81 
CONFIDENTIAL 
 
 
TACL Internal Distribution Only 
 
 
If you choose to participate, you may discontinue your participation in the study at any time. If you discontinue 
participation in the study, physicians and hospital personnel will still take care of you. 
 
You also have the right to know about new information that may affect your health, welfare, or your willingness to 
participate in the study. You will be provided with this information as soon as it becomes available. 
 
Whether you participate or not, you will continue to get the best medical care this hospital can provide. 
 
 
Who can answer my questions about the study? 
 
You can talk to your study doctor about any questions or concerns you have about this study.  Contact your study 
doctor __________________ [name(s)] at __________________ [telephone number]. 
 
For questions about your rights while taking part in this study, call the ________________________ [name of 
center] Institutional Review Board (a group of people who review the research to protect your rights) at 
__________________ [telephone number].  [Note to Local Investigator: Contact information for patient 
representatives or other individuals in a local institution who are not on the IRB or research team but take calls 
regarding clinical trial questions can be listed here.]    
 
Where can I get more information? 
 
Call the National Cancer Institute’s Cancer Information Service: 
1-800-4-CANCER (1-800-422-6237) OR 1-800-332-8615 (for the hearing impaired) 
 
 
You will be given a copy of this consent form. 
 
You will be given a copy of this treatment plan upon request. 
 
CancerNetTM: http:/cancernet.nci.nih.gov This site provides accurate cancer information including the 
Physicians Data Query (PDQ). The PDQ is the National Cancer Institute’s comprehensive cancer database. It 
contains peer-reviewed summaries on cancer treatment, screening, prevention, and supportive care; a 
registry of about 1,700 open and 10,300 closed cancer clinical trials from around the world; and directories of 
physicians, genetic counselors, and organizations that provide cancer care. 
 
Visit the TACL Consortium Website at https://tacl.chla.usc.edu 
 
 
 

 
 
 
 
Original  version date: 1-20-2017  
Amendment 1 version date: 09-06-2017 
 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
Amendment 4 version date: 07-01-2019 
 
 
 
 
 
Original Protocol version 1-20-2017 
Amendment 1 version date: 09-06-2017 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
 
Amendment 4 version date: 07-01-2019 
82 
CONFIDENTIAL 
 
 
TACL Internal Distribution Only 
 
SIGNATURE OF RESEARCH SUBJECT 
Your signature below indicates:  
 
You have read this document and understand its meaning;  
 
You have had a chance to ask questions and have had these questions answered to your satisfaction;  
 
You agree to participate in this research study; and 
 
You will be given a copy of the signed permission form.  
 
______________________________________ 
Name of Subject 
 
 
 
 
  
 
______________________________________        
 ______________________ 
Signature of Subject 
 
 
 
 
  Date 
 
 
SIGNATURE OF PARENT(S)/GUARDIAN (if the subject is a minor) 
Your signature below indicates that you have read this document; understand its meaning; have had a chance to 
ask questions; have had these questions answered to your satisfaction; and agree to your child’s participation in 
this research study. You have been given a signed copy of this assent/permission form. 
 
________________________________    
 
_______________________________  
Name(s) of Parent(s)/Guardian  
 
Name(s) of Parent(s)/Guardian 
 
________________________________                  
 ___________________________________ 
Signature of Parent (Guardian)        
 
 
  Date 
 
 
________________________________                  
 ___________________________________ 
Signature of Parent (Guardian)        
 
 
  Date 
 
 
SIGNATURE OF INVESTIGATOR 
I have explained the research to the subject and/or the subject’s parent(s)/guardian(s) and have answered all of 
their questions.  I believe that they understand the information described in this document and freely give 
consent/permission/assent to participate. 
 
________________________________________ 
Name of Investigator/Person obtaining consent 
 
_________________________________________ 
 
______________________________ 
Signature of Investigator/Person obtaining consent 
             Date 
 
SIGNATURE OF WITNESS (if applicable) 
My signature as witness certified that the subject and/or the subject’s parent(s)/guardian(s) signed this permission 
form in my presence as their voluntary act and deed. 
 

 
 
 
 
Original  version date: 1-20-2017  
Amendment 1 version date: 09-06-2017 
 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
Amendment 4 version date: 07-01-2019 
 
 
 
 
 
Original Protocol version 1-20-2017 
Amendment 1 version date: 09-06-2017 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
 
Amendment 4 version date: 07-01-2019 
83 
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__________________________________ 
Name of Witness 
 
____________________________________ 
 
___________________________ 
Signature of Witness 
 
 
 
 
Date 
 
 

 
 
 
 
Original  version date: 1-20-2017  
Amendment 1 version date: 09-06-2017 
 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
Amendment 4 version date: 07-01-2019 
 
 
 
 
 
Original Protocol version 1-20-2017 
Amendment 1 version date: 09-06-2017 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
 
Amendment 4 version date: 07-01-2019 
84 
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APPENDIX I: DISEASE CLASSIFICATION 
 
WHO CLASSIFICATION OF ACUTE MYELOID LEUKEMIA [Blood, October 1, 2002 vol 100(7)] 
 
Acute myeloid leukemia with recurrent genetic abnormalities 
Acute myeloid leukemia with t(8;21)(q22;q22), AML1/ETO) 
Acute myeloid leukemia with abnormal bone marrow eosinophils and inv(16)(p13q22) 
t(16;16)(p13;q22), (CBFβ/MYH11) 
Acute promyelocytic leukemia with t(15;17)(q22;q12), (PML/RARα) and variants 
Acute myeloid leukemia with 11q23 (MLL) abnormalities 
 
Acute myeloid leukemia with multilineage dysplasia 
Following MDS or MDS/MPD 
Without antecedent MDS or MDS/MPD, but with dysplasia in at least 50% of cells in 2 or more 
myeloid lineages 
 
Acute myeloid leukemia and myelodysplastic syndromes, therapy related 
Alkylating agent/radiation-related type 
Topoisomerase II inhibitor-related type (some may be lymphoid) 
Others 
 
Acute myeloid leukemia, not otherwise categorized 
Acute myeloid leukemia, minimally differentiated 
Acute myeloid leukemia without maturation 
Acute myeloid leukemia with maturation 
Acute myelomonocytic leukemia 
Acute monoblastic/acute monocytic leukemia 
Acute erythroid leukemia (erythroid/myeloid and pure erythroleukemia) 
Acute megakaryoblastic leukemia 
Acute basophilic leukemia 
Acute panmyelosis with myelofibrosis 
Myeloid sarcoma 
 
 
 

 
 
 
 
Original  version date: 1-20-2017  
Amendment 1 version date: 09-06-2017 
 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
Amendment 4 version date: 07-01-2019 
 
 
 
 
 
Original Protocol version 1-20-2017 
Amendment 1 version date: 09-06-2017 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
 
Amendment 4 version date: 07-01-2019 
85 
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APPENDIX II: PERFORMANCE STATUS SCALES/SCORES 
 
Performance Status Criteria 
Karnofsky and Lansky performance scores are intended to be multiples of 10 
ECOG (Zubrod) 
Karnofsky 
Lansky 
Scor
e 
Description 
Score 
Description 
Score 
Description 
0 
Fully active, able to carry 
on all pre-disease 
performance without 
restriction. 
100 
Normal, no complaints, 
no evidence of disease 
100 
Fully active, normal. 
90 
Able to carry on normal 
activity, minor signs or 
symptoms of disease. 
90 
Minor restrictions in 
physically strenuous 
activity. 
1 
Restricted in physically 
strenuous activity but 
ambulatory and able to 
carry out work of a light 
or sedentary nature, e.g., 
light housework, office 
work. 
80 
Normal activity with 
effort; some signs or 
symptoms of disease. 
80 
Active, but tires more 
quickly 
70 
Cares for self, unable to 
carry on normal activity 
or do active work. 
70 
Both greater restriction of 
and less time spent in play 
activity. 
2 
Ambulatory and capable 
of all self-care but unable 
to carry out any work 
activities.  Up and about 
more than 50% of 
waking hours 
60 
Required occasional 
assistance, but is able 
to care for most of 
his/her needs. 
60 
Up and around, but 
minimal active play; keeps 
busy with quieter activities. 
50 
Requires considerable 
assistance and frequent 
medical care. 
50 
Gets dressed, but lies 
around much of the day; 
no active play, able to 
participate in all quiet play 
and activities. 
3 
Capable of only limited 
self-care, confined to 
bed or chair more than 
50% of waking hours.  
40 
Disabled, requires 
special care and 
assistance. 
40 
Mostly in bed; participates 
in quiet activities. 
30 
Severely disabled, 
hospitalization indicated.  
Death not imminent. 
30 
In bed; needs assistance 
even for quiet play. 
4 
Completely disabled.  
Cannot carry on any 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. 
 
 
 

 
 
 
 
Original  version date: 1-20-2017  
Amendment 1 version date: 09-06-2017 
 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
Amendment 4 version date: 07-01-2019 
 
 
 
 
 
Original Protocol version 1-20-2017 
Amendment 1 version date: 09-06-2017 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
 
Amendment 4 version date: 07-01-2019 
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APPENDIX III: ORAL SUSPENSION RECIPE 
 
DO NOT PHOTOCOPY THIS FORM 
***Use compounding equipment designated for hazardous drugs & wear gloves and mask while 
preparing*** 
Product Description 
Recipe 
References 
Name: Vorinostat 
Strength: 50 mg/ml 
Dosage Form: Suspension 
Route: PO 
Stability: expires 14 days 
after preparation 
Packaging: Package in tight 
light-resistant *GLASS* 
bottles 
Storage: Room Temperature 
Items Needed 
 
#20 Vorinostat 100mg capsules 
20ml Ora-Plus 
20ml Ora-Sweet 
Preparation Instructions 
 
1.Place 20ml of Ora-Plus (Paddock 
Labs brand) in glass bottle 
 
2.Place contents of 20 vorinostat 
100mg capsules in same bottle and 
shake to disperse.  Note shaking 
could take upwards of 3 minutes. 
 
3.Add 20ml of Ora-Sweet  (Paddock 
Labs brand) and shake to disperse. 
REF: unpublished 
information from CTEP 
pediatric clinical trials 
provided by Merck. 
 
 
 
 
Ref: Reviewed Date: 
04/2011 
 
Date Updated: 04/2009 
***Please use the Chemo Hood*** 
Date 
CMH 
Total Qty 
Prepared 
Manufacturer 
Initals 
Control 
Number 
Exp 
Date 
Name 
Manufacturer 
NDC 
Lot 
Number 
Exp 
Date 
Qty 
Prep 
Check 
Final 
Check 
 
 
 
 
Vorinostat 
100mg 
capsules 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ora-Plus 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ora-
Sweet 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vorinostat 
100mg 
capsules 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ora-Plus 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ora-
Sweet 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vorinostat 
100mg 
capsules 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ora-Plus 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ora-
Sweet 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vorinostat 
100mg 
capsules 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ora-Plus 
 
 
 
 
 
 
 
 

 
 
 
 
Original  version date: 1-20-2017  
Amendment 1 version date: 09-06-2017 
 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
Amendment 4 version date: 07-01-2019 
 
 
 
 
 
Original Protocol version 1-20-2017 
Amendment 1 version date: 09-06-2017 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
 
Amendment 4 version date: 07-01-2019 
87 
CONFIDENTIAL 
 
 
TACL Internal Distribution Only 
 
 
 
 
 
 
Ora-
Sweet 
 
 
 
 
 
 
 
 
 
APPENDIX IV: DOSING SCHEDULE 
 
Vorinostat is only available in 100 mg capsules. Vorinostat is given for 5 days.  The dose of vorinostat is 180 
mg/m2/day on days1 through 5.  For patients whose body surface area falls between those noted on the table, 
round up or down to the closest BSA value on the table and treat patient at that level.  If your patient’s BSA is less 
than 0.35 m2 or above 2 m2, call the TACL Operations Center (323) 361-5429 for the correct dose. 
 
Vorinostat Dose 180 mg/m2/day 
Given days 1 to 5 
BSA (m2) 
Calculated 
daily dose 
Calculated dose 
Over 5 days 
Actual dose 
Over 5 days 
Daily Dosing Schedule 
0.35 
63 mg 
315 mg 
300 mg 
1 capsule given on days 1, 2, 3,  no vorinostat 
on days 4 and 5 
 
0.4 
72 mg 
360 mg 
400 mg 
1 capsule given on days 1, 2, 3, 4,  no 
vorinostat on day 5 
 
0.45 
81 mg 
405 mg 
400 mg 
1 capsule given on days 1, 2, 3, 4,  no 
vorinostat on day 5 
 
0.5 
90 mg 
450 mg 
500 mg 
1 capsule given on days 1 through 5 
 
0.55 
99 mg 
495 mg 
500 mg 
1 capsule given on days 1 through 5 
 
0.6 
108 mg 
540 mg 
500 mg 
1 capsule given on days 1 through 5 
 
0.65 
117 mg 
585 mg 
600 mg 
1 capsule given on days 1 through 4, (2) 
capsules given on day 5  
 
0.7 
126 mg 
630 mg 
600 mg 
1 capsule given on days 1 through 4, (2) 
capsules given on day 5  
 
0.75 
135 mg 
675 mg 
700 mg 
1 capsule given on days 1 through 3, (2) 
capsules given on days 4, 5 
 
0.8 
144 mg 
720 mg 
700 mg 
1 capsule given on days 1 through 3, (2) 
capsules given on days 4, 5 
 

 
 
 
 
Original  version date: 1-20-2017  
Amendment 1 version date: 09-06-2017 
 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
Amendment 4 version date: 07-01-2019 
 
 
 
 
 
Original Protocol version 1-20-2017 
Amendment 1 version date: 09-06-2017 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
 
Amendment 4 version date: 07-01-2019 
88 
CONFIDENTIAL 
 
 
TACL Internal Distribution Only 
 
Vorinostat Dose 180 mg/m2/day 
Given days 1 to 5 
BSA (m2) 
Calculated 
daily dose 
Calculated dose 
Over 5 days 
Actual dose 
Over 5 days 
Daily Dosing Schedule 
0.85 
153 mg 
765 mg 
800 mg 
(2) capsules given on days 1 through 4  
 
0.9 
162 mg 
810 mg 
800 mg 
(2) capsules given on days 1 through 4  
0.95 
171 mg 
855 mg 
900 mg 
1 capsule given on days 1, (2) capsules given 
on days 2 through 5 ** 
1 
180 mg 
900 mg 
900 mg 
1 capsule given on days 1, (2) capsules given 
on days 2 through 4 ** 
1.05 
189 mg 
945 mg 
900 mg 
1 capsule given on days 1, (2) capsules given 
on days 2 through 4 ** 
1.1 
198 mg 
990 mg 
1000 mg 
(2) capsules given on days 1 through 5  
1.15 
207 mg 
1035 mg 
1000 mg 
(2) capsules given on days 1 through 5  
1.2 
216 mg 
1080 mg 
1100 mg 
(2) capsules given on days 1 through 4, (3) 
capsules given on day 5  
1.25 
225 mg 
1125 mg 
1100 mg 
(2) capsules given on days 1 through 4, (3) 
capsules given on day 5  
1.3 
234 mg 
1170 mg 
1200 mg 
(2) capsules given on days 1 through 3, (3) 
capsules given on days 4 and 5 
1.35 
243 mg 
1215 mg 
1200 mg 
(2) capsules given on days 1 through 3, (3) 
capsules given on days 4 and 5 
1.4 
252 mg 
1260 mg 
1300 mg 
(2) capsules given on days 1 and 2, (3) 
capsules given on days 3 through 5  
1.45 
261 mg 
1305 mg 
1300 mg 
(2) capsules given on days 1 and 2, (3) 
capsules given on days 3 through 5 
1.5 
270 mg 
1350 mg 
1400 mg 
(2) capsules given on day 1 (3) capsules given 
on days 2 through 5  
1.55 
279 mg 
1395 mg 
1400 mg 
(2) capsules given on day 1 (3) capsules given 
on days 2 through 5  
1.6 
288 mg 
1440 mg  
1400 mg 
(2) capsules given on day 1 (3) capsules given 
on days 2 through 5  
1.65 
297 mg 
1485 mg 
1500 mg 
(3) capsules given on days 1 through 5  
1.7 
306 mg 
1530 mg 
       1500 mg 
(3) capsules given on days 1 through 5  
1.75 
315 mg 
1575 mg 
1600 mg 
(3) capsules given on days 1 through 4, (4) 
capsules given on day 5  
1.8 
324 mg 
1620 mg 
1600 mg 
(3) capsules given on days 1 through 4, (4) 
capsules given on day 5  

 
 
 
 
Original  version date: 1-20-2017  
Amendment 1 version date: 09-06-2017 
 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
Amendment 4 version date: 07-01-2019 
 
 
 
 
 
Original Protocol version 1-20-2017 
Amendment 1 version date: 09-06-2017 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
 
Amendment 4 version date: 07-01-2019 
89 
CONFIDENTIAL 
 
 
TACL Internal Distribution Only 
 
Vorinostat Dose 180 mg/m2/day 
Given days 1 to 5 
BSA (m2) 
Calculated 
daily dose 
Calculated dose 
Over 5 days 
Actual dose 
Over 5 days 
Daily Dosing Schedule 
1.85 
333 mg 
1665 mg 
1700 mg 
(3) capsules given on days 1 through 3, (4) 
capsules given on days 4 and 5  
1.9 
342 mg 
1710 mg 
1700 mg 
(3) capsules given on days 1 through 3, (4) 
capsules given on days 4 and 5  
2 
360 mg 
1800 mg 
1800 mg 
(2) capsules given on day 1, (4) capsules given 
on days 2 through 5  
 
 
15.0 
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Original  version date: 1-20-2017  
Amendment 1 version date: 09-06-2017 
 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
Amendment 4 version date: 07-01-2019 
 
 
 
 
 
Original Protocol version 1-20-2017 
Amendment 1 version date: 09-06-2017 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
 
Amendment 4 version date: 07-01-2019 
90 
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Original  version date: 1-20-2017  
Amendment 1 version date: 09-06-2017 
 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
Amendment 4 version date: 07-01-2019 
 
 
 
 
 
Original Protocol version 1-20-2017 
Amendment 1 version date: 09-06-2017 
Amendment 2 version date: 09-27-2017 
Amendment 3 version date: 06-29-2018 
 
Amendment 4 version date: 07-01-2019 
91 
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