Clinical trial NCT01802333
Conditions: Acute Myeloid Leukemia Untreated Adult Acute Myeloid Leukemia
Sponsor: National Cancer Institute (NCI)
Start date: 2013-02-12; Completion date: 2017-06-15
Enrollment: 754 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This randomized phase III trial studies cytarabine and daunorubicin hydrochloride or idarubicin and cytarabine with or without vorinostat to see how well they work in treating younger patients with previously untreated acute myeloid leukemia. Drugs used in chemotherapy, such as cytarabine, daunorubicin hydrochloride, idarubicin, and vorinostat, work in different ways to stop the growth of cancer cells, either by killing the cells, stopping them from dividing, or by stopping from spreading. Giving more than one drug (combination chemotherapy) and giving the drugs in different doses and in different combinations may kill more cancer cells. It is not yet known which combination chemotherapy is more effective in treating acute myeloid leukemia.

Detailed description:
PRIMARY OBJECTIVES:

I. To compare event-free survival (EFS) between patients with acute myeloid leukemia (AML) who receive standard 7+3 (cytarabine and daunorubicin hydrochloride) or idarubicin and high-dose cytarabine (IA) to patients who receive IA + vorinostat. (Chemotherapy) II. To determine whether it is possible to get 60% or more of adults with high-risk AML (by cytogenetics) in first complete remission (CR1) to allogeneic hematopoietic cell transplantation (HCT). (Transplant)

SECONDARY OBJECTIVES:

I. To estimate the frequency and severity of toxicities of the three regimens in this patient population. (Chemotherapy) II. To estimate disease-free survival (DFS) among patients who receive transplant. (Transplant) III. To compare event-free survival (EFS) between patients who receive standard 7 + 3 to patients who receive IA. (Chemotherapy) IV. To estimate the prevalence of the mutations nucleophosmin (nucleolar phosphoprotein B23, numatrin) (NPM1), isocitrate dehydrogenase 1 (NADP+), soluble (IDH1), isocitrate dehydrogenase 2 (NADP+), mitochondrial (IDH2), tet methylcytosine dioxygenase 2 (TET2) and deoxyribonucleic acid (DNA) (cytosine-5-)-methyltransferase 3 alpha (DNMT3A) and the cytogenetic risk distribution of patients on this study and to evaluate the association between these and overall survival (OS), event-free survival (EFS), disease-free survival (DFS), and complete remission rate. (Chemotherapy/Translational Medicine) V. To compare the complete response rate, disease-free survival (DFS), and overall survival (OS) between patients who receive standard 7+3 therapy or IA to patients who receive IA + vorinostat. (Chemotherapy)

TERTIARY OBJECTIVES:

I. Future planned studies will include testing of histone H3 acetylation, induction of gamma H2A histone family, member X (H2AX), analysis of reactive oxygen species (ROS) resistance and DNA methylation profiles. (Chemotherapy/Translational Medicine)

OUTLINE: Patients are randomized to 1 of 3 treatment arms.

INDUCTION/RE-INDUCTION:

ARM I: Patients receive standard dose cytarabine intravenously (IV) continuously on days 1-7 and daunorubicin hydrochloride IV on days 1-3. Patients with residual blasts may receive re-induction treatment beginning on day 15. Patients achieving complete remission (CR) or complete remission with incomplete platelet recover (CRi) may proceed to allogeneic hematopoietic stem cell transplant (HSCT) or to consolidation therapy.

ARM II: Patients receive high dose cytarabine IV continuously on days 1-4 and idarubicin IV over 15 minutes on days 1-3. Patients with residual blasts may receive re-induction treatment beginning on day 28. Patients achieving CR or CRi may proceed to allogeneic HSCT or to consolidation therapy.

ARM III: Patients receive vorinostat orally (PO) thrice daily (TID) on days 1-3, high-dose cytarabine IV continuously on days 4-7, and idarubicin IV over 15 minutes on days 4-6. Patients with residual blasts may receive re-induction treatment beginning on day 28. Patients achieving CR or CRi may proceed to allogeneic HSCT or to consolidation therapy. (Permanently closed to accrual, effective 6/2/2015) Patient previously randomized to Arm III may continue treatment without vorinostat.

CONSOLIDATION:

ARM I: Patients receive cytarabine IV over 3 hours every 12 hours on days 1, 3, and 5.

ARM II: Patients receive cytarabine IV continuously on days 1-3 and idarubicin IV over 15 minutes on days 1-2.

ARM III: Patients receive vorinostat PO TID on days 1-3, cytarabine IV continuously on days 4-6, and idarubicin IV over 15 minutes on days 4-5. (Permanently closed to accrual, effective 6/2/2015) Patient previously randomized to Arm III may continue treatment with or without vorinostat.

In all arms, treatment repeats every 28 days for 4 courses or until transplant in the absence of disease progression or unacceptable toxicity.

TRANSPLANT: Patients may undergo an allogeneic transplant after induction therapy or consolidation therapy.

After completion of study treatment, patients are followed up every 3 months for 1 year, every 6 months for 2 years, and then annually for 2 years.

Arms: arm 1: INDUCTION/RE-INDUCTION: Patients receive standard dose cytarabine IV continuously on days 1-7 and daunorubicin hydrochloride IV on days 1-3. Patients with residual blasts may receive re-induction treatment beginning on day 15. Patients achieving CR or CRi may proceed to allogeneic HSCT or to consolidation therapy.

CONSOLIDATION: Patients receive cytarabine IV over 3 hours every 12 hours on days 1, 3, and 5.

TRANSPLANT: Patients may undergo an allogeneic transplant after induction therapy or consolidation therapy. arm 2: INDUCTION/RE-INDUCTION: Patients receive high dose cytarabine IV continuously on days 1-4 and idarubicin IV over 15 minutes on days 1-3. Patients with residual blasts may receive re-induction treatment beginning on day 28. Patients achieving CR or CRi may proceed to allogeneic HSCT or to consolidation therapy.

CONSOLIDATION: Patients receive cytarabine IV continuously on days 1-3 and idarubicin IV over 15 minutes on days 1-2.

TRANSPLANT: Patients may undergo an allogeneic transplant after induction therapy or consolidation therapy. arm 3: INDUCTION/RE-INDUCTIONI: Patients receive vorinostat PO TID on days 1-3, high-dose cytarabine IV continuously on days 4-7, and idarubicin IV over 15 minutes on days 4-6. Patients with residual blasts may receive re-induction treatment beginning on day 28. Patients achieving CR or CRi may proceed to allogeneic HSCT or to consolidation therapy.

CONSOLIDATION: Patients receive vorinostat PO TID on days 1-3, cytarabine IV continuously on days 4-6, and idarubicin IV over 15 minutes on days 4-5.

TRANSPLANT: Patients may undergo an allogeneic transplant after induction therapy or consolidation therapy. (Permanently closed to accrual, effective 6/2/2015) Patients previously randomized to Arm III may continue treatment with or without vorinostat.
Interventions: intervention 1: Allogeneic Hematopoietic Stem Cell Transplantation intervention 2: Cytarabine intervention 3: Daunorubicin Hydrochloride intervention 4: Idarubicin intervention 5: Laboratory Biomarker Analysis intervention 6: Vorinostat
Intervention descriptions: intervention 1: Undergo allogeneic transplant intervention 2: Given IV intervention 3: Given IV intervention 4: Given IV intervention 5: Correlative studies intervention 6: Given PO

Protocol documents:
Prot_SAP_000.pdf: 
 
 
Page 1 
 
 
 
Distribution Date: 
TBD 
E-mailed Date: 
TBD 
CTEP Submission Date: 
June 2, 2015 
 
 
TO: 
ALL NATIONAL CLINICAL TRIALS NETWORK (NCTN) MEMBERS; CTSU 
 
 
FROM: 
Cara Laubach, MIIM, Protocol Coordinator (E-mail:  claubach@swog.org) 
 
 
RE: 
S1203, “A Randomized Phase III Study of Standard Cytarabine plus Daunorubicin (7+3) 
Therapy or Idarubicin with High Dose Cytarabine (IA) versus IA with Vorinostat (IA+V) in 
Younger Patients with Previously Untreated Acute Myeloid Leukemia (AML)”.  Study 
Chairs:  Drs. G. Garcia-Manero, J.M. Pagel, J.P. Radich and M. Fang. 
 
REVISION #7 
 
Study Chair: Guillermo Garcia-Manero, M.D. 
Phone number:  281/380-7813 
E-mail: ggarciam@mdanderson.org 
 
IRB Review Requirements 
 
(   ) 
Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign  
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
( √ ) Expedited review allowed 
 
(   ) 
No review required 
 
 
REVISION #7 
 
Due to the outcome of the interim analysis conducted by the SWOG Data and Safety Monitoring 
Committee on May 1, 2015, Arm 3 (Idarubicin +AraC +Vorinostat) will be permanently closed to 
accrual, effective immediately.  A minor study re-design is also being implemented to allow more 
precise estimates of the outcomes of the transplant objective and to clarify the treatment schedule for 
patients that opt to remain on Arm 3 with or without vorinostat. 
 
IRB Review Requirements:   
 
Institutions must update their local consent forms to include the changes to the Model Consent Form 
at the time of distribution of this notice.   
 
Patients currently receiving Arm 3 protocol treatment and patients randomized to Arm 3 who 
signed a consent form prior to this notice must be informed of the closure of Arm 3 at their 
next scheduled visit. Please reference the Investigator Letter and Patient Letter distributed 
with the May 26, 2015 Memorandum. 
 
SWOG considers that the closure of Arm 3 and associated Model Consent Form changes represent 
an alteration in risk/benefit ratio.  Therefore, for all sites utilizing a local IRB, accrual of all new 
patients (to all study arms) remains suspended until this amendment is approved by your local 
Institutional Review Board (IRB) and proof of that IRB approval is received by the Coalition for 
National Cancer Cooperative Groups/CTSU.  Submit proof of IRB approval to the following location: 
 
 


 
 
Page 2 
 
 
Coalition for National Cancer Cooperative Groups 
1818 Market Street 
Suite 1100 
Philadelphia, PA 19103 
FAX:  215/569-0206 
E-mail:  CTSURegulatory@ctsu.coccg.org 
 
The above-referenced protocol has been modified as follows: 
 
1. 
The Version Date of the protocol and Model Consent Form have been updated.  
 
2. 
Page 1, Title Page:  Hongli Li, M.S. has replaced Shannon McDonough, M.S. as a 
Biostatistician on this study. 
 
3. 
Pages 3-4, Table of Contents:  Content has been inserted in Section 7.2 on Page 34 which 
caused a shift in the page numbers for Section 7.3 and all subsequent sections. The titles for 
Sections 9.5 and 9.6 have also been updated. 
 
4. 
Page 6, Schema: The following note has been included under Arm 3 (IA +V): “Permanently 
closed to accrual, effective TBD” 
 
5. 
Pages 33 and 34, Section 7.2c:  
 
• 
The following paragraph has been inserted at the beginning of the section: 
"Arm 3 was permanently closed to accrual effective TBD. Effective TBD, patients 
previously randomized to Arm 3 have the option to remain on Arm 3 as a medical 
intervention and must follow the applicable treatment schedule below." 
• 
Footnote (3) has been added to Arm 3- IA + Vorinostat, "Patients previously 
randomized to Arm 3 that opt to continue medical treatment with IA + Vorinostat must 
follow protocol and protocol data submission requirements." 
• 
"Arm 3-IA" treatment schedule has been added for induction and re-induction for 
patients previously randomized to Arm 3 wanting to remain on Arm 3 without 
vorinostat.  
 
6. 
Page 36, Section 7.4c:  "Arm 3-IA" treatment has been added for consolidation for patients 
previously randomized to Arm 3 wanting to remain on Arm 3 without vorinostat. 
 
7. 
Pages 39-41, Section 8.2:  For clarification, the phrase "during treatment" has been added 
after "For bilirubin > 5.0 mg/dL" in Sections 8.2c.1, 8.2c.2, 8.2d.1 and 8.2d.2.  Similarly, the 
phrase "during treatment" has been added after "For bilirubin > 3.0 mg/dL" in Sections 8.2d.1 
and 8.2d.2. 
 
8. 
Pages 43-44, and 46-48:  Section 9.0:   
 
• 
"X"s have been added for "History & Physical Exam" at Weeks 2-4 for both Induction 
and Re-Induction in Section 9.1.  Similarly, "X"s have been added for "History & 
Physical Exam" in the Wk 2, Wk 3, and Wk 4 columns for Consolidation in Sections 
9.2, 9.4, and 9.6. 
• 
Page 47:  The title of the table has been revised to reflect the option for IA treatment 
alone for patients already registered to Arm 3. "IA + V" has been added to the title of 
the treatment line and a separate treatment line for "IA" therapy has been added. 
Footnote "√" has also been inserted to clarify that, " Arm 3 was permanently closed 
to accrual, effective TBD. Patients previously randomized to Arm 3 may opt to 
continue medical treatment with IA or IA + V, and if so, must follow protocol and 
protocol data submission requirements.". The same changes have also been made 
to Page 48, for Consolidation therapy for patients previously randomized to Arm 3. 
 


 
 
Page 3 
 
 
9. 
Page 50, Section 11.1:  The following text has been added to the end of the second 
paragraph of this section to allow for additional accrual to, and more precise estimates of the 
outcomes of, the transplant objective:   
 
In contrast to S0106, S1203 allows patients with complete remission with incomplete blood count 
recovery (CRi) to register to consolidation (S0106 required patients to be in complete remission 
[CR] to register for consolidation).  Due to this difference, the accrual rate of high-risk patients in 
CR has been slower than expected based on S0106 data.  Rather than 13% of patients being 
eligible for the transplant objective (53/418), the observed rate has been approximately 9%.  
Given the slower than expected accrual to this objective and the desire to have more precise 
estimates of outcomes after transplant, accrual to this objective will be open for all patients 
registered to the trial. 
 
The Model Consent Form has been modified as follows:   
 
1. 
Page 3, “Why is the study being done?”: This section has been revised to remove reference 
to three treatment combinations and comparison of those combinations, and to include 
additional information on the transplant objective of the study. 
 
2. 
Page 5, Schema: The study schema has been updated to remove reference to Arm 3 
(IA+Vorinostat) of the study. 
 
3. 
Page 6, “Induction and Consolidation”: The first sentence of this paragraph has been revised 
to refer to “2” instead of “3” types of induction/consolidation treatments, and the last sentence 
of this paragraph (which previously referred to Group 3 Induction and Consolidation) has 
been deleted in its entirety. 
 
4. 
Page 8, The “Group 3 (often called Arm 3) – IA + Vorinostat” section has been removed in its 
entirety, and subsequent content/page numbers have been shifted. 
 
5. 
Pages 11-12:  The Group 3 (Vorinostat) risks have been removed in their entirety, and 
subsequent content/page numbers have been shifted. 
 
6. 
Page 12: “Are there benefits to taking part in the study?”: The second sentence of this 
paragraph has been removed, and the following text has been included at the end of the third 
sentence of this paragraph, “and any benefits of matching high-risk AML patients with 
unrelated stem cell transplant donors.” 
 
7. 
Page 13, “What are the costs of taking part in this study?”: The second and third paragraphs 
of this section (which referred to provision of vorinostat) have been removed in their entirety. 
 
8. 
Page 14:  The website link for more information on clinical trials and insurance coverage at 
the end of the first sentence of the second paragraph has been updated. 
 
This memorandum serves to notify the NCI and the SWOG Statistical Center. 
 
This study has been approved by the NCI's Central Institutional Review Board. 
 
cc: 
PROTOCOL & INFORMATION OFFICE  
Megan Othus, Ph.D. 
 
Hongli Li, M.S. 
 
Louise Highleyman 
 
Laura Kingsbury, M.R.T. 
 
Tracy Maher, C.C.R.P. 
 
Samantha Sublett – Alliance 
 
Laura Gagnon – ECOG-ACRIN 
Becky Fillingham – ECOG-ACRIN 
Gail McDonald – NCIC CTG 


 
 
Page 4 
 
 
Kate Whelan – NCIC CTG 
Louisa Zak – NCIC CTG 
Maria Brown, M.T. - CIBMTR 
Stephen Spellman, M.D., M.S.C.I. – CIBMTR 
Mindy Goldman – OneMatch 
 
 
 
 


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Version Date 6/2/15 
 
 
 
PRIVILEGED COMMUNICATION 
Activation Date December 15, 2012 
FOR INVESTIGATIONAL USE ONLY 
 
SWOG 
 
A RANDOMIZED PHASE III STUDY OF STANDARD CYTARABINE PLUS DAUNORUBICIN (7+3) 
THERAPY OR IDARUBICIN WITH HIGH DOSE CYTARABINE (IA) VERSUS IA WITH VORINOSTAT 
(NSC-701852) (IA + V)  IN YOUNGER PATIENTS WITH PREVIOUSLY UNTREATED ACUTE MYELOID 
LEUKEMIA (AML) 
 
NCT #0180233 
 
STUDY CHAIRS: 
AGENTS: 
 
Guillermo Garcia-Manero, M.D. (Medical Oncology) 
IND Exempt Agents: 
M.D. Anderson Cancer Center 
Cytosine Arabinoside (AraC, Cytarabine)  
1515 Holcombe Blvd. 
 
(NSC-63878) 
Houston, TX 77030 
Daunorubicin Hydrochloride (Cerubidine)  
Phone:  281/380-7813 
 
(NSC-82151) 
FAX:  713/563-0289 
Idarubicin (Idamycin®) (NSC-256439) 
E-mail:  ggarciam@mdanderson.org  
 
 
NCI Supplied Investigational Agents:                 
John M. Pagel, M.D., Ph.D. (Transplant) 
Vorinostat (Zolinza®, Suberoylanilide Hyroxamic 
Swedish Medical Center First Hill 
 
Acid, SAHA) (NSC-701852) (IND-117406) 
Swedish Cancer Institute 
1221 Madison St, Suite 1020 
 
 
 
 
Seattle, WA 98104 
BIOSTATISTICIANS: 
Phone:  206/215-3245 
 
FAX:  206/991-2041 
Megan Othus, Ph.D. (Biostatistics) 
E-mail:  john.pagel@swedish.org 
Hongli Li, M.S. (Biostatistics) 
 
SWOG Statistical Center 
Jerald P. Radich, M.D. (Translational Medicine) 
Fred Hutchinson Cancer Research Center  
Fred Hutchinson Cancer Research Center  
1100 Fairview Avenue N, M3-C102 
 
1100 Fairview Avenue N, D4-100 
P.O. Box 19024 
P.O. Box 19024 
Seattle, WA 98109-1024 
Seattle, WA 98109-1024 
Phone:  206/667-4623 
Phone:  206/667-4118 
FAX:  206/667-4408 
FAX:  206/667-2917 
E-mail:  mothus@fhcrc.org  
E-mail:  jradich@fhcrc.org  
E-mail:  hongli@fredhutch.org  
 
 
Min Fang, M.D., Ph.D. (Cytogenetics) 
NCIC-ACRIN CTG STUDY CHAIR: 
Fred Hutchison Cancer Research Center 
 
825 Eastlake Ave E 
M. Lynn Savoie, M.D. (Medical Oncology) 
M/S G7-500 
Alberta Health Services 
Seattle, WA 98109 
E-mail:  lynn.savoie@albertahealthservices.ca 
Phone:  206/288-1385 
 
FAX:  206/288-7567 
ECOG-ACRIN STUDY CHAIRS: 
E-mail:  mfang@fhcrc.org  
 
 
Stephen Strickland, M.D., M.S.C.I. 
ALLIANCE STUDY CHAIRS: 
   (Medical Oncology) 
 
Vanderbilt University Medical Center 
David A. Rizzieri, M.D. (Medical Oncology) 
E-mail: stephen.strickland@vanderbilt.edu  
Duke University Medical Center 
 
E-mail:  rizzi003@mc.duke.edu  
Elisabeth Paietta, Ph.D. (Translational Medicine) 
 
Montenfiore Medical Center – North campus 
Guido Marcucci, M.D. (Correlative Science) 
 
Ohio State University 
E-mail:  guido.marcucci@osumc.edu  
 


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PARTICIPANTS 
 
ALLIANCE/Alliance for Clinical Trials in Oncology 
ECOG-ACRIN/ECOG-ACRIN Cancer Research Group 
NRG/NRG Oncology 
NCIC-CTG/NCIC Clinical Trials Group 
SWOG/SWOG 
 
 
 
 
 
 
 


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TABLE OF CONTENTS 
 
 
Page 
PARTICIPANTS ............................................................................................................................................ 2 
CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION ....................... 5 
SCHEMA ....................................................................................................................................................... 6 
1.0 
OBJECTIVES .................................................................................................................................. 7 
1.1 
Primary Objectives ........................................................................................................................... 7 
1.2 
Secondary Objectives ...................................................................................................................... 7 
1.3 
Additional Objectives ........................................................................................................................ 7 
2.0 
BACKGROUND ............................................................................................................................... 7 
3.0 
DRUG INFORMATION .................................................................................................................. 14 
3.1 
Cytosine Arabinoside (AraC, Cytarabine) (NSC-63878) ................................................................ 14 
3.2 
Daunorubicin Hydrochloride (Cerubidine) (NSC-82151) ............................................................... 16 
3.3 
Idarubicin HCL (Idamycin®) (NSC-256439) ................................................................................... 17 
3.4 
Vorinostat (Zolinza®, Suberoylanilide hydroxamic acid; SAHA)(NSC-701852)(IND-117406) ...... 18 
4.0 
STAGING CRITERIA ..................................................................................................................... 26 
4.1  
Diagnostic Criteria .......................................................................................................................... 26 
4.2  
Staging Criteria .............................................................................................................................. 26 
5.0 
ELIGIBILITY CRITERIA ................................................................................................................ 27 
5.1 
Registration Step 1 – Induction/Re-Induction ................................................................................ 27 
5.2 
Registration Step 2 – Consolidation ............................................................................................... 29 
6.0 
STRATIFICATION FACTORS ....................................................................................................... 30 
7.0 
TREATMENT PLAN ...................................................................................................................... 30 
7.1 
General Considerations ................................................................................................................. 30 
7.2 
Induction/Re-Induction ................................................................................................................... 31 
7.3 
Allogeneic Stem Cell Transplant .................................................................................................... 35 
7.4 
Consolidation ................................................................................................................................. 35 
7.5 
Criteria for Removal from Protocol Treatment ............................................................................... 36 
7.6 
Discontinuation of Treatment ......................................................................................................... 37 
7.7 
Follow-Up Period ............................................................................................................................ 37 
8.0 
TOXICITIES TO BE MONITORED AND DOSAGE MODIFICATIONS ........................................ 38 
8.1 
NCI Common Terminology Criteria for Adverse Events ................................................................ 38 
8.2 
Dose Modifications ......................................................................................................................... 38 
8.3 
Dose Modification Contacts ........................................................................................................... 41 
8.4 
Adverse Event Reporting ............................................................................................................... 42 
9.0 
STUDY CALENDARS ................................................................................................................... 42 
9.1 
Arm 1 (7+3) – Induction ................................................................................................................. 43 
9.2 
Arm 1 (7+3) – Consolidation .......................................................................................................... 44 
9.3 
Arm 2 (IA) – Induction .................................................................................................................... 45 
9.4 
Arm 2 (IA) – Consolidation ............................................................................................................. 46 
9.5 
Arm 3 (IA+V or IA) – Induction ....................................................................................................... 47 
9.6 
Arm 3 (IA+V or IA) - Consolidation ................................................................................................ 48 
10.0 
CRITERIA FOR EVALUATION AND ENDPOINT DEFINITIONS................................................. 49 
10.1  
Remission Definitions ..................................................................................................................... 49 
10.2  
Treatment Failures ......................................................................................................................... 49 
10.3  
Relapse from CR or CRi ................................................................................................................ 49 
10.4  
Event Free Survival (EFS) ............................................................................................................. 49 
10.5 
Disease Free Survival (DFS) ......................................................................................................... 50 
10.6  
Time to Death ................................................................................................................................. 50 
10.7  
Performance Status ....................................................................................................................... 50 
11.0 
STATISTICAL CONSIDERATIONS .............................................................................................. 50 
11.1 
Accrual Goals ................................................................................................................................. 50 
11.2 
Primary Chemotherapy Objective .................................................................................................. 51 


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11.3 
Transplant Objective ...................................................................................................................... 54 
11.4 
Translational Medicine Objective ................................................................................................... 54 
11.5 
Data and Safety Monitoring Committee ......................................................................................... 56 
12.0 
DISCIPLINE REVIEW .................................................................................................................... 57 
13.0 
REGISTRATION GUIDELINES ..................................................................................................... 57 
13.1 
Registration Timing ........................................................................................................................ 57 
13.2 
Investigator/Site Registration ......................................................................................................... 57 
13.3 
OPEN Registration Requirements ................................................................................................. 59 
13.4 
Registration Procedures................................................................................................................. 60 
13.5 
Exceptions to SWOG Registration Policies will Not be Permitted ................................................. 61 
14.0 
DATA SUBMISSION SCHEDULE ................................................................................................ 61 
14.1 
Data Submission Requirement ...................................................................................................... 61 
14.2 
Master Forms ................................................................................................................................. 62 
14.3 
Data Submission Procedures ........................................................................................................ 62 
14.4 
Data Submission Overview and Timepoints .................................................................................. 63 
15.0 
SPECIAL INSTRUCTIONS............................................................................................................ 65 
15.1 
Correlative Studies and Banking (REQUIRED FOR ALL GROUPS) ............................................ 65 
15.2 
Cytogenetics and FISH (REQUIRED FOR ALL PATIENTS) ......................................................... 66 
15.3 
Buccal Swab for Transplant Donor Identification (REQUIRED FOR ALL PATIENTS) ................. 68 
16.0 
ETHICAL AND REGULATORY CONSIDERATIONS ................................................................... 69 
16.1 
Adverse Event Reporting Requirements........................................................................................ 71 
17.0 
BIBLIOGRAPHY ............................................................................................................................ 77 
18.0 
APPENDIX ..................................................................................................................................... 79 
18.1  
Determination of Expedited Adverse Event Reporting Requirements ........................................... 80 
18.2 
New York Heart Association Classifications .................................................................................. 82 
18.3 
Intake Calendar .............................................................................................................................. 83 
18.4 
Hematopoietic Cell Transplant-Comorbidity Index (HCT-CI) ......................................................... 84 
18.5 
AML Transplant Study Flowchart ................................................................................................... 85 
18.6 
Transplant Donor Search Process ................................................................................................. 86 
18.7 
ECOG-ACRIN Ancillary Study – NO SUBMISSIONS AFTER 1/29/14 .......................................... 88 
18.8 
Alliance Ancillary Studies – NO SUBMISSIONS AFTER 2/28/14 ................................................. 91 
18.9 
Specimen Submission Consent ..................................................................................................... 95 
 
 


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CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION 
To submit site registration 
documents: 
For patient enrollments:  
Submit study data  
directly to the Lead 
Cooperative Group 
unless otherwise 
specified in the 
protocol:  
CTSU Regulatory Office 
1818 Market Street, Suite 1100 
Philadelphia, PA 19103 
Phone – 1-866-651-CTSU 
Fax – 215-569-0206 
Please refer to the patient enrollment 
section for instructions on using the 
OPEN system. 
Data collection for this 
study will be done 
exclusively through 
Medidata Rave.  Please 
see the data submission 
section of the protocol for 
further instructions.  
 
Do not submit study data 
or forms to the CTSU 
Data Operations.  Do not 
copy the CTSU on data 
submission. 
 
 
The study protocol and all related forms and documents must be downloaded from the protocol-
specific Web page of the CTSU Member Web site located at https://www.ctsu.org.  Sites must use the 
current form version and adhere to the instructions and submission schedule outlined in the protocol. 
 
CTSU sites should follow procedures outlined in the protocol for Site registration, Patient Enrollment, 
Adverse Event Reporting, Data Submission (including ancillary studies), and Drug Procurement. 
For patient eligibility questions contact the SWOG Data Operations Center by phone at 206/652- 
2267. For treatment or toxicity related questions contact the Study PI of the Coordinating Group. 
For questions unrelated to patient eligibility, treatment, or data submission contact the CTSU Help 
Desk by phone or e-mail: 
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com. All calls and 
correspondence will be triaged to the appropriate CTSU representative.  
For detailed information on the regulatory and monitoring procedures for CTSU sites please 
review the CTSU Regulatory and Monitoring Procedures policy located on the CTSU members’ website   
https://www.ctsu.org 
The CTSU Web site is located at https://www.ctsu.org 
 
 
 


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SCHEMA 
 
INDUCTION/RE-INDUCTION 
(Registration Step 1) 
 
 
 
 
Arm 1 (7+3) 
 
           Arm 2 (IA) 
 
          Arm 3 (IA+V or IA) 
     Daunorubicin + AraC 
      Idarubicin + AraC 
                   Idarubicin + AraC+ 
 
 
 
 
 
 
                          Vorinostat OR 
 
Idarubicin + AraC 
 
(Permanently closed to accrual, 
 
effective [TBD; date of distribution of  
 
this notice] 
 
 
 
 
 
 
 
 
           Off protocol 
 
 
 
 
 
 
 
                            therapy 
 
 
 
 
 
 
 
 
 
 
 
 
 
CONSOLIDATION 
 
(Registration Step 2)  
 
 
 
 
 
(up to 4 cycles) 
 
Arm 1 (7+3) 
 Arm 2 (IA) 
Arm 3 (IA+V) 
       AraC 
Idarubicin + AraC   Idarubicin + AraC+ 
 
 
 
        Vorinostat 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
      ALLOGENEIC  
      STEM CELL TRANSPLANT 
                Transplant details are at  
                     the discretion of the  
                 specific transplant center 
 
 
 
 
 
 
Off protocol therapy 
RANDOMIZATION 
Is patient in remission? 
NO 
Is patient high-risk by 
cytogenetics? 
YES 
NO 
YES 
Is transplant ready? 
NO 
YES 
Is patient 
high risk  
AND 
in remission 
AND 
transplant is 
ready? 
NO 
YES 


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1.0 
OBJECTIVES 
 
1.1 
Primary Objectives 
 
a. 
(Chemotherapy): To compare event-free survival (EFS) between patients with 
AML who receive standard 7+3 or idarubicin and high-dose cytarabine (IA) to 
patients who receive IA + vorinostat. 
 
b. 
(Transplant): To determine whether it is possible to get 60% or more of adults 
with high-risk AML (by cytogenetics) in first complete remission (CR1) to 
allogeneic hematopoietic cell transplantation (HCT). 
 
1.2 
Secondary Objectives 
 
c. 
(Chemotherapy): To estimate the frequency and severity of toxicities of the three 
regimens in this patient population. 
 
d. 
(Transplant): To estimate disease-free survival (DFS) among patients who 
receive transplant. 
 
e. 
(Chemotherapy):  To compare event-free survival (EFS) between patients who 
receive standard 7+3 to patients who receive IA. 
 
f. 
(Chemotherapy/Translational Medicine): To estimate the prevalence of the 
mutations NPM1, IDH1, IDH2, TET2 and DMT3A and the cytogenetic risk 
distribution of patients on this study and to evaluate the association between 
these and overall survival (OS), event-free survival (EFS), disease-free survival 
(DFS), and complete remission rate . 
 
g. 
(Chemotherapy): To compare the complete response rate, disease-free survival 
(DFS), and overall survival (OS) between patients who receive standard 7+3 
therapy or IA to patients who receive IA + vorinostat. 
 
1.3 
Additional Objectives 
 
h. 
(Chemotherapy/Translational Medicine):  Future planned studies will include 
testing of histone H3 acetylation, induction of gammaH2AX, analysis of ROS 
resistance and DNA methylation profiles. 
 
 
2.0 
BACKGROUND 
 
Standard induction therapy for patients with acute myeloid leukemia (AML) consists of the 
combination of cytarabine (AraC) plus an anthracycline, the so called “7+3” schema. Different 
doses and schedules of this combination have been used over the last two decades. Recently a 
combination of AraC 100 mg/m2 as a daily continuous infusion for seven days with daunorubicin 
90 mg/m2 daily for 3 days has been established to be superior to a combination with lower doses 
of daunorubicin. (1) In that study, complete remission (CR) rates were as follows: favorable 
cytogenetics 79.5%, intermediate 69.3%, unfavorable 59.3%, FLT-3 wild type (wt) 70.9% and 
FLT3 mutated (mut) 66.7%. An additional recent study compared induction therapy consisting of 
idarubicin and cytarabine at a dose of either 200 mg/m2 by continuous infusion for 7 days or 
1,000 mg/m2 over 3 hours twice daily on Days 1-5. They saw no difference in CR rates, relapse, 
event free survival (EFS) or overall survival (OS). (2)  While other regimens have yielded similar 
results, a combination of daunorubicin at 90 mg/m2 for 3 days and cytarabine at either 100 or 
200 mg/m2 for 7 days is generally considered to be “standard.”  


 
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There is less of a consensus as to what constitutes standard post-remission therapy. The 
National Comprehensive Cancer Network (NCCN) guidelines and expert reviews generally 
recommend allogeneic transplant from a matched sibling or alternative donor for patients with 
poor-risk disease (as determined by cytogenetics), and several cycles of consolidation 
containing intermediate or high dose cytarabine for patients with good risk disease. Therapy for 
patients with intermediate risk disease is generally driven by further molecular testing. For 
patients with a normal karyotype (NK) but FLT3 mutations or without mutations in NPM1, an 
allogeneic transplant is generally recommended if a matched sibling is available, but it is less 
certain if alternative donors should be used. For NK patients without FLT3 mutations but with 
mutations in NPM1, high-dose cytarabine containing regimens are generally recommended, with 
transplantation reserved until relapse. The optimal cytarabine regimen has recently been 
revisited, and although 3 gm/m2 given over 3 hours every 12 hours on Days 1, 3 and 5 is most 
popular, regimens of 1 or 2 gm/m2 over 3 hours every 12 hours on Days 1-5 may be equivalent. 
(2)  With standard induction and consolidation chemotherapy, approximately 35% of patients can 
be expected to be alive and disease-free at 3 years.  
 
In addition to a better understanding of optimal dosing of daunorubicin and cytarabine, the last 
decade has witnessed a remarkable increase in the understanding of the disease, but current 
therapies still need improvement. A subgroup of the National Cancer Institute (NCI) Leukemia 
Steering Committee (NCI AML Working Group Subgroup 3) consisting of Harry Erba, Stephen 
Couban, Deborah Banker, Richard Larson, Wendy Stock, Richard Stone, Steven Gore, Martin 
Tallman, Eli Estey, Megan Othus, Richard Little and Frederick Appelbaum was charged with 
developing a strategy for developing the next intergroup clinical trials of upfront therapy for 
younger patients with AML. This study is one product of this group’s work. 
 
Following a series of face-to-face and conference call meetings, the subgroup suggested a 
general strategy for protocol development. First, it was concluded that it would be optimal if there 
were a single intergroup protocol that allowed uniform diagnosis, protocol assignment and 
specimen collection. Such a protocol is currently under discussion. Next, the group concluded 
that there were several subgroups of AML where targeted therapies were sufficiently developed 
to be tested as part of up front therapy. These include core binding factor (CBF) AMLs and those 
associated with FLT3 mutations. Thus, separate protocols dealing with these subgroups are 
already active or are being developed. However, for the majority of patients, while many 
potential targets and therapies exist, it was less clear which, if any, were sufficiently mature for a 
large upfront trial.  
 
In an effort to determine which questions might be addressed, the subgroup felt that a 
reasonable approach would be to review the literature and invite researchers with clinical data to 
submit their results for further analysis. The group was particularly interested in Phase II trials of 
upfront therapy for AML, with the idea that the results of these studies would be compared to 
those seen with standard therapy. If the results of the comparisons suggested a possible 
improvement, the regimen might be considered for a Phase III trial, whereas if no advantage 
was suggested, enthusiasm for further study of the regimen would be considerably less. Data 
from five regimens were reviewed, including 7+3 with pravastatin, a combination of flavopiridol, 
cytarabine and mitoxantrone (FLAM), 7+3 with bortezomib, idarubicin with cytarabine (IA), and 
vorinostat with IA. Data for standard 7+3 came from the recently completed SWOG study 
S0106. The initial analysis focused on CR rates, since analyses of disease-free survival (DFS) 
and overall survival (OS) were hampered by limited follow-up and variations in post-induction 
therapies. The CR rate for each of the five regimens was compared to historical data of 7+3 
controlling for the risk factors age, performance status, cytogenetic risk, and secondary AML 
status.  Only two of the five regimens had CR rates that were significantly better than the CR 
rates (controlling for risk factors) from patients treated with 7+3 on S0106. Those two regimens 
were IA (p=0.009) and IA + vorinostat (p < 0.001). These studies will be presented in more detail 
below.  


 
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Discussions then turned to the structure of the next upfront study. The general consensus 
favored a randomized Phase III trial with early stopping rules for futility.  While some favored a 
randomized Phase II approach, others noted that such a trial had the disadvantage of not 
providing definitive conclusions, of requiring considerable delay from the time of its completion 
until a subsequent definitive trial could be initiated, and that data from the Phase II components 
would be lost. Thus, a more attractive approach was felt to be a randomized Phase III trial with 
early interim analysis and strict rules for early stoppage for futility. Admittedly, such an approach 
carries a risk that a potentially positive study could be stopped early, but this risk was felt to be 
acceptable and preferable to the shortcomings of a randomized Phase II approach. It was also 
debated whether to compare 7+3 with IA + vorinostat or include IA as a third arm. The decision 
to include IA was based on the argument that if IA + vorinostat was positive, there would be no 
way to determine if vorinostat was the contributing agent. While some felt that a 2 armed study 
of IA versus IA + vorinostat might be acceptable, others felt that it would be important to include 
standard 7+3. Ultimately, a three-armed study was decided upon.  
 
Standard induction therapy at MD Anderson (MDA) includes idarubicin 12 mg/m2 daily for 3 days 
with continuous infusion AraC at doses of 1.5 gm/m2 daily for 3 or 4 days depending on age. 
This approach results in CR rates in excess of 75% in patients with AML younger than 65 years 
of age. At MDA, patients with favorable karyotypes (i.e. APL and CBF) are treated on other 
protocols. Over the years there has been a debate as to whether standard 7+3 or MDA IA is a 
better approach. This has never been formally tested in a randomized clinical trial.  
 
The MDA group has been interested in improving the results of IA by adding a third agent. 
Examples have included combinations with tipifarnib and more recently sorafenib. (3,4)  A third 
combination consisted of the addition of the histone deacetylase inhibitor (HDACI) vorinostat. 
This work has evolved over the last 5 years from initial Phase I single agent trials and preclinical 
models to a Phase II study of the combination of IA with vorinostat.  In the initial Phase I trial, the 
maximum tolerated dose (MTD) of vorinostat was defined as 200 mg orally three times a day for 
14 days every 21 days. Using this schedule, the drug was well tolerated and associated with an 
overall response rate (ORR) of 15% in patients with advanced AML. (5)  Because of the effects 
of vorinostat on chromatin, it was hypothesized that a combination of vorinostat with a DNA 
topoisomerase II inhibitor, such as the anthracycline idarubicin, could lead to synergistic anti-
leukemia effects. This was confirmed in a series of preclinical models. (6)  Based on these data, 
a CTEP sponsored randomized two arm Phase I trial of the combination of idarubicin with 
vorinostat was conducted. In this trial, two schedules of vorinostat were studied: a 3 day 
schedule and a classic 14 day schedule based on the initial Phase I trial. In this study, 14 days 
of vorinostat with idarubicin was too toxic and the dose of idarubicin had to be reduced. In 
contrast, it was observed that when using vorinostat for 3 days with standard dose idarubicin, 
the dose of vorinostat could be increased safely to 500 mg orally three times a day for 3 days. 
(7) In parallel with this work, the group at the University of Maryland reported their experience 
combining AraC, anthracycline and vorinostat. (8)  These investigators found that the 
anthracyclines and vorinostat appeared to be synergistic in a sequence independent fashion but 
demonstrated that for optimal activity vorinostat had to be administered prior to AraC. All this 
information led to the development of a Phase II study of the combination of vorinostat with IA 
(IA + vorinostat). The dose of vorinostat was 500 mg orally three times a day for 3 days (Days 1-
3) followed on Day 4 by standard IA. In that study (ASH 2010), 75 patients were treated. (9) The 
overall response rate was 86% (including ORR of 93% in diploid patients, 80% in others and 
100% in FLT3 mutated patients). The study had a Bayesian design with stopping rules for lack of 
response rate, excess toxicity/mortality and PFS at 7 months. IA vorinostat was superior in all 3 
rules to standard experience with IA. Table 1 summarizes the comparison of IA + vorinostat 
(IA+V) and IA at MDA (Garcia-Manero, in preparation). Therefore the body of information 
provided above indicates that IA + vorinostat is safe and very active in patients with newly 
diagnosed AML and potentially superior to standard IA at MDA. 


 
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Table 1:  IA + Vorinostat vs. IA at MDA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Role of Allogeneic Stem Cell Transplant in Front Line AML 
The prognosis of adults with AML can be estimated using a variety of methods, but cytogenetics 
remains the most common and reproducible.  Using cytogenetics, patients can be categorized as 
having favorable, intermediate or unfavorable (high) risk, the latter group including those with 
del(5q)/-5, del(7q)/-7, abn3q26 [inv (3)/t(3:3)], abn11q23 rearrangement [except t(9;11)], 17p-, t(6;9), 
t(9;22), complex (at least 3 unrelated abn), and monosomal karyotype (either a loss of two different 
chromosomes or loss of one chromosome along with a structural chromosome abnormality other than 
add, ring and mar).  In a previous intergroup trial for adult AML patients age < 61 (S9034), the 
unfavorable risk group made up 30% of all patients, and had a complete response (CR) rate of 54% 
and an estimated survival at 5 years of 11%, figures that were significantly worse than seen in 
intermediate or favorable risk patients. (10)  In this trial, patients with matched siblings were assigned 
to receive an allogeneic hematopoietic cell transplant in first CR, while those without donors were 
randomized to autologous transplantation or further chemotherapy.  Forty percent of patients 
randomized to transplant in this trial were actually transplanted.  Based on an intent-to-treat analysis, 
the estimated survival at 5 years from achieving CR was 52% for allogeneic transplantation, 42% for 
autologous transplantation and 39% for chemotherapy.  The advantage of allogeneic transplantation 
was most obvious for patients with high risk disease, with a 44% survival at 5 years with allogeneic  
 
 
Response Rates 
IA+V (N) 
IA+V (%) 
IA (N) 
IA (%) 
P-value 
All Patients 
75 
  
347 
  
0.015 
  CR/CRp 
64 
85% 
249 
72% 
 
  Otherwise 
11 
15% 
98 
28% 
 
Total 
75 
 
347 
 
 
 
Response Rates 
IA+V (N) 
IA+V (%) 
IA (N) 
IA (%) 
P-value 
Diploid Only 
29 
  
147 
  
0.055 
  CR/CRp 
27 
93% 
114 
78% 
 
  Otherwise 
2 
7% 
33 
22% 
 
Total 
29 
 
147 
 
 
 
Response Rates 
IA+V (N) 
IA+V (%) 
IA (N) 
IA (%) 
P-value 
Miscellaneous Only 
29 
  
137 
  
0.039 
  CR/CRp 
27 
93% 
104 
76% 
 
  Otherwise 
2 
7% 
33 
24% 
 
Total 
29 
 
137 
 
 
 
Response Rates 
IA+V (N) 
IA+V (%) 
IA (N) 
IA (%) 
P-value 
Only -5/-7 
17 
  
63 
  
0.484 
  CR/CRp 
10 
59% 
31 
49% 
 
  Otherwise 
7 
41% 
32 
51% 
 
Total 
17 
 
63 
 
 
 
Response Rates 
IA+V (N) 
IA+V (%) 
IA (N) 
IA (%) 
P-value 
FLT3 + 
11 
  
32 
  
0.066 
  CR/CRp  
11 
100% 
24 
75% 
 
  Otherwise 
0 
0% 
8 
25% 
 
Total 
11 
 
32 
 
 


 
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transplantation versus 15% with chemotherapy. (11)  Based on these results, as well as those of 
other single institution studies and large meta-analyses, the recommendation of most experts, 
including that of the recently published European LeukemiaNet, is that allogeneic transplantation from 
a matched related donor is recommended for adults age < 61 with high-risk AML in CR1. (12-15) 
 
Unfortunately, fewer than 30% of adults will have HLA-matched relatives able to donate.  Recent data 
from the Fred Hutchinson Cancer Research Center (FHCRC) and other centers suggest outcomes 
after allogeneic HCT from fully matched unrelated donors appear to be similar to that following 
matched related donor transplantation. (16)  Depending on ethnicity, matched unrelated donors can 
be found for anywhere from 25-50% of patients who do not have a matched related donor. 
Additionally, data recently presented by the groups from Minnesota and the FHCRC show that for 
patients age < 45, outcomes following double cord transplantation are similar to those seen with 
either matched related donors or matched unrelated donors. (17,18)  Given the current criteria for 
cord blood transplants based on cell dose and degree of mismatch, double cord blood should be 
available for almost 95% of patients lacking a matched related or matched unrelated donor.  
Theoretically then, alternative donors should be available for the large majority of high risk AML 
patients, and outcomes of transplantation should approximate those seen with matched related 
donors.   
However, it takes time, effort and resources to identify potential donors, and there are no prospective 
data addressing how often this can actually be done.  In the prior North American intergroup trial, only 
70% of those with matched siblings actually received an allogeneic transplant.  While one can 
reasonably expect that figure to increase with increasing acceptance of transplantation for high risk 
disease, it remains a question whether alternative donors can be found rapidly enough to treat those 
without matched family members.  Thus, the initial hypothesis to be tested in this trial is that with an 
organized effort, at least 60% of adults age < 61 with high risk AML in first CR can be treated with an 
allogeneic transplant, using matched related, matched unrelated or cord blood as the donor source. 
All of the studies suggesting roughly equivalent outcomes following matched related, matched 
unrelated and cord blood transplants were retrospective analyses. These studies were therefore 
subject to patient selection and other biases, which could dramatically affect outcomes.  There are no 
published prospective studies of the outcome of alternative donor transplants for a large cohort of 
adult patients with high risk AML identified at diagnosis which would allow for an estimation of the 
impact of HCT on eventual survival.  Thus, a second hypothesis is that by transplanting 60% of adults 
with high risk AML in first remission, and achieving a 44% DFS at 2 years (as achieved in references 
10 and 11), the overall disease-free survival at 2 years of all high risk patients can be improved from 
the historic level of 22% to at least 35%. 
 
Rationale for Translational Medicine: Prognostic Significance and Predictive Markers 
 
The following integrated studies are planned in order to distinguish genetic and biological 
subgroups associated with response, and to define mechanisms of actions of these agents.  
 
Mutational analyses of NPM1, IDH110, IDH210, TET211, DNMT3A12: Mutations in these genes 
have been demonstrated in approximately 10-40% of the AML population targeted in his 
proposal,  and have been associated with outcome. It is unknown if the addition of vorinostat will 
overcome the negative prognostic impact of these mutations. Furthermore mutations in these 
genes have been proposed to have a significant impact on epigenetic alterations in leukemia and 
potentially prognosis and response to therapy. (10-12) PCR and sequencing of these genes will 
be performed on pre-treatment specimens obtained from all patients. 
 


 
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The genetics of treatment response: Global gene and miRNA expression have been shown to be 
associated with survival outcome in AML. (13) The S1203 trial is the perfect complement to the 
Intergroup AML non-responder project, sponsored by the NCI and approved by CTEP. The non-
responder project is using multiple genetic platforms (miRNA, RNA, SNP, methylation) to identify 
the genetic elements that differentiate primary treatment failure and long-term remission in AML.  
It is unique in the question asked, the multiple genetic assays used on all samples, and the 
amount of Intergroup cooperation in performing the assays and analysis. The end product will be 
a set of bioassays associated with early response, and pathways that may be targetable to 
convert non-responders into responders. The non-responder protocol will have all assays 
completed by the end of 2012, and the bioinformatics analysis (the plan devised by Dr. Michael 
LeBlanc of SWOG, Dr. Lisa McShane of NCI, and Dr. Erich Huang of Sage Bionetworks) will be 
done by early spring.  
 
The AML non-responder project was promoted with the expectation that validation would take 
place in the next sets of Intergroup trials. S1203 is the logical starting place, and we will develop 
a multi-analyte assay (presumably a combination of mutations, mRNA, miRNA, methylation sites, 
etc.) to use on the pre-treatment samples from S1203 as a validation study of predicting initial 
treatment response. Once the biomarkers are chosen, the statistical plan for this validation will be 
performed by the above group (currently difficult to do since it is not known what 
genes/miRNAs/etc will be used, nor is the strength of the association known, which will largely 
drive the study design). 
 
Measuring HDAC exposure.  The induction of histone H3 acetylation is a biomarker of exposure 
to the HDAC inhibitor. (1)  This study hypothesizes that the level of H3 acetylation will be 
associated with treatment response in the vorinostat arm. The assay will be performed by ELISA 
or Western blot on peripheral blood specimens obtained at baseline and on Day 3. 
 
Measuring DNA damage and ROS pathway. GammaH2AX clusters to genomic areas of DNA 
damage, and thus the levels of gammaH2AX correlates with the amount of DNA damage induced 
by vorinostat and idarubicin. (2) This study hypothesizes that gammaH2AX levels will correlate 
with disease response, and indeed will be higher in the vorinostat arm.  GammaH2AX will be 
directly measured by immunocytochemistry and ELISA (Figure 1) on peripheral blood specimens 
obtained at baseline and by Day 3. In addition, Phase II studies from the MDACC suggest that 
increased levels of Nrf2 and CYYB mRNA are associated with a longer survival (Figure 2). These 
assays will be measured on peripheral blood specimens obtained at baseline and on Day 3.  
  


 
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Figure 1. Induction of gammaH2AX by vorinostat. Induction of H2AX was measured by 
immunohistochemistry in cell pellets recovered after treatment with vorinostat and/or idarubicin as 
indicated.
 
Figure 2. Survival effect of Nrf2 activation in patients with AML 
treated with vorinostat IA. mRNA levels of Nrf2 were sequentially 
measured in peripheral blood samples obtained sequentially during 
induction phase. 


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Inclusion of Women and Minorities 
 
This study was designed to include women and minorities, but was not designed to measure 
differences of intervention effects.  SWOG is unaware of any literature supporting an interactive 
treatment effect by sex or race; therefore, there is no current plan to alter the accrual for separate 
gender or racial subsets. The Group is committed to the continued accrual of non-white patients 
to all of its trials at current levels or better, and will explore the effect of treatment by race and sex 
in these trials. Anticipated accrual to this study by race and ethnicity, based on previous Group 
trials in this disease type, follows: 
 
Ethnic Category 
Females 
Males 
Total 
Hispanic or Latino 
13 
28 
41 
Not Hispanic or Latino 
355 
388 
743 
Total Ethnic 
368 
416 
784 
Racial Category 
American Indian or Alaskan Native 
0 
5 
5 
Asian 
10 
11 
21 
Black or African American 
41 
41 
82 
Native Hawaiian or other Pacific Islander 
3 
3 
6 
White 
314 
356 
670 
Racial Category: Total of all Subjects 
368 
416 
784 
 
 
3.0 
DRUG INFORMATION 
 
Investigator’s Brochures 
 
For information regarding Investigator’s Brochures, please refer to SWOG Policy 15. 
 
For this study, AraC, daunorubicin and idarubicin are commercially available; therefore, 
Investigator Brochures are not applicable to these drugs.  Information about commercial drugs is 
publicly available in the prescribing information and other resources. 
 
For this study, vorinostat is investigational and is being provided under an IND held by the 
National Cancer Institute.  The Investigator Brochures may be obtained by contacting the NCI’s 
Pharmaceutical Management Branch (PMB) at 240/276-6575. 
 
3.1 
Cytosine Arabinoside (AraC, Cytarabine) (NSC-63878) 
 
a. 
DESCRIPTION 
 
AraC is chemically 4-amino-1-S-D-arabino-furanosyl-2(1H)-primidinone.  AraC is 
metabolized to its active form, AraCTP.  The AraCTP functions as an inhibitor of 
DNA polymerase.  AraC exhibits cell phase specificity, killing cells undergoing 
DNA synthesis (S phase) and may also block cells from progressing to S phase 
from G1.  Extensive chromosomal damage, including chromatid breaks, occurs.  
AraC appears to be most effective in tumors with high growth fraction. 
 
AraC can cause fetal harm when administered to pregnant women, however, 
there are no adequate and well controlled studies in pregnant women. 


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b. 
TOXICOLOGY 
 
Human Toxicology:  Side effects of AraC include myelosuppression, nausea, 
vomiting, diarrhea, anorexia, anal ulceration, stomatitis, rash, headache, fever, 
myalgia, malaise, bone pain, chest pain, hepatic and renal dysfunction, and 
alopecia.  Central nervous system toxicity, i.e., significant cerebral and 
cerebellar, dysfunction, progression to coma, has been seen with high doses.  
Severe cardiomyopathy has been reported with high dose AraC in combination 
with cyclophosphamide.  Progressive ascending paralysis has occurred in two 
patients receiving IV and intrathecal AraC.  Marked keratoconjunctivitis has also 
occurred with high doses. 
 
AraC can cause fetal harm when administered to a pregnant woman, however, 
there are no adequate and well controlled studies in pregnant women. 
 
c. 
PHARMACOLOGY 
 
Kinetics:  AraC is metabolized by deoxycytidine kinase and related kinases to 
nucleotide triphosphate, which is an active inhibitor of DNA polymerase.  
Deoxycytidine prevents or delays cytotoxic activity.  The active form is converted 
to nontoxic uracil derivatives by pyrimidine nucleoside deaminases.  The balance 
of kinase and deaminase levels appears to be an important factor in 
sensitivity/resistance of the cell to AraC.  After IV injection, plasma 
disappearance of AraC is biphasic.  Initial half-life is 10 minutes, delayed half-life 
is 1 - 3 hours.  After 24 hours, 80% is excreted in the urine as its inactive 
metabolite, AraI.  After a single IV administration of AraC, levels in CSF are low.  
There is little conversion to AraU because of low CSF levels of diaminase.  Drug 
interaction of AraC has been reported with digoxin, gentamycin and 
fluorocytocine. 
 
Formulation:  AraC is supplied as a sterile powder in 100 mg and 500 mg vials 
for injection.  AraC is also available in 1 and 2 gram vials.  The drug should be 
reconstituted with sterile water for injection. 
 
Storage and Stability:  The sterile powder should be stored at room temperature 
15° - 30°C (59° - 86°).  The resulting solution has a stability of 48 hours if stored 
at ROOM TEMPERATURE.  Do not use if even a slight haze develops.  The 
reconstituted solution may be further diluted in 5% dextrose or sodium chloride 
injection. 
 
Administration:  AraC is usually administered by continuous IV infusion, but IV 
bolus and subcutaneous use have their place in treating certain leukemic 
responses (i.e., maintenance or remission). 
 
Supplier:  AraC is commercially available and therefore should be purchased by 
a third party.  This drug will NOT be supplied by the NCI. 
 
Please refer to the package insert for complete information. 


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3.2 
Daunorubicin Hydrochloride (Cerubidine) (NSC-82151) 
 
a. 
DESCRIPTION 
 
Daunorubicin (Cerubidine) is the hydrochloride salt of an anthracycline antibiotic 
produced by a strain of Streptomyces oeruleorubidus.  It inhibits synthesis of 
nucleic acids, exhibiting antimitotic and cytotoxic activity. 
 
b. 
TOXICOLOGY 
 
Human 
Toxicity: 
Dose-limiting 
toxicity 
includes 
myelosuppression 
and 
cardiotoxicity.  Cumulative dose beyond 550 mg/M2 results in increased risk for 
CHF.  Radiation therapy involving the heart and previous adriamycin 
administration increases the risk for cardiomyopathy.  Hepatic and renal 
dysfunction may occur.  Other reactions include reversible alopecia, nausea and 
vomiting, anorexia, diarrhea and mucositis.  If extravasation occurs during 
administration, tissue necrosis can result.  Rarely, chills, fever, skin rash and 
anaphylactoid reactions can occur.  Because of its teratogenic properties, women 
of childbearing potential should be advised to avoid pregnancy.  The occurrence 
of acute leukemia has been reported rarely in patients treated with 
anthracycline/alkylator combination chemotherapy. 
 
c. 
PHARMACOLOGY 
 
Kinetics:  Following IV injection, plasma levels rapidly decline.  Subsequently, 
levels decline slowly with half-life of 18.5 hours.  There is no evidence of the drug 
crossing the blood-brain barrier.  Active metabolites are present in the plasma 
one hour after injection.  Twenty-five percent of administered dose is excreted by 
the kidney and 40% by biliary excretion. 
 
Formulation: The drug is supplied in vials containing 20 mg of daunorubicin as a 
reddish lyophilized powder.  The daunorubicin should be reconstituted with 4 mL 
of Sterile Water for Injection, USP, or PF 0.9% Sodium Chloride for Injection, 
USP, to give a final concentration of 5 mg/ml. 
 
Storage and Stability:  The drug is stored at room temperature (15°-25°C).  The 
reconstituted solution is stable for 24 hours at room temperature and 48 hours 
under refrigeration.  Protect from sunlight. 
 
Administration:  When reconstituted with 4 ml of sterile water for injection, USP, 
each ml contains 5 mg of daunorubicin activity for intravenous administration 
only. 
 
Supplier:  This drug is commercially available for purchase by a third party.  This 
drug will not be supplied by the NCI. 
 
Please refer to the package insert for complete information. 
 


 
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3.3 
Idarubicin HCL (Idamycin®) (NSC-256439) 
 
a. 
DESCRIPTION 
 
A sterile, synthetic antineoplastic anthracycline for intravenous use.  Idarubicin is 
a DNA-intercalating analog of daunorubicin which has an inhibitory effect on 
nucleic acid synthesis and interacts with the enzyme topoisomerase II. 
 
b. 
TOXICOLOGY 
 
Idarubicin is a potent bone marrow suppressant.  Idarubicin should not be given 
to patients with pre-existing bone marrow suppression induced by previous drug 
therapy.  Deaths due to infection and/or bleeding have been reported during the 
period of severe myelosuppression.  Other warnings include pre-existing heart 
disease, previous therapy with anthracyclines, previous radiation to the 
mediastinal-pericardial area, myocardial toxicity typically presenting as CHF, 
arrhythmias or other cardiomyopathies, in patients with anemia, bone marrow 
depression, infections, leukemic pericarditis and/or myocarditis, and renal or 
hepatic impairment. The most common side effects (90% to 100%): infection. 
Other common side effects include (20% to 90%): nausea, vomiting, hair loss, 
abdominal cramps, diarrhea, hemorrhage, mucositis, dermatologic, mental 
status, pulmonary-clinical, fever, headache.  Other less common side effects 
include (10% to 20%): cardiac-clinical.  Infrequent side effects include (1% to 
10%): Neurologic-peripheral nerves, pulmonary allergy, seizure, cerebellar.  Rare 
side effects include (less than 1%): None reported in this range. 
 
c. 
PREGNANCY AND LACTATION 
 
Pregnancy Category D- Idarubicin was embryotoxic and teratogenic in the rat.  
Idarubicin was embryotoxic but not teratogenic in the rabbit.  There is no 
conclusive information about idarubicin adversely affecting human fertility or 
causing teratogenesis.  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 idarubicin mothers 
should discontinue nursing prior to taking this drug.  There has been one case 
reported of fetal fatality after maternal exposure to idarubicin during the 2nd 
trimester.  
 
d. 
PHARMACOLOGY 
 
Kinetics:  The plasma concentrations follow a 2 or 3 compartment mode.  
Idarubicin has a rapid distribution phase with a high volume of distribution 
reflecting extensive tissue binding.  Idarubicin undergoes extensive extrahepatic 
metabolism and a rapid distribution phase.  Idarubicin has a very high volume of 
distribution. Elimination occurs predominantly by biliary and to a lesser extent by 
renal excretion.  The mean terminal half-life 22 hours when used as a single 
agent and 20 hours when used in combination.  Elimination exceeds 45 hours. 
 
Formulation:  Idarubicin is a sterile, red-orange, isotonic parenteral preservative-
free solution. It is available in 5mg/5ml, 10mg/10ml and 20mg/20ml single use 
only vials. 
 


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Storage and Stability:  Idarubicin should be stored under refrigeration 2o - 8oC 
(36o  to 46oF), and protected from light. The vials are preservative-free and are for 
single use only. 
 
Administration:  Idarubicin should be administered over 10 - 15 minutes into a 
freely flowing line of NS or D5W. Unless there is specific data do not mix 
idarubicin with other drugs.  Prolonged contact in an alkaline pH will degrade 
Idarubicin.  Precipitation occurs with heparin.  Extravasation can cause severe 
local tissue necrosis.  Extravsation may occur with or without an accompanying 
burning sensation and even if blood returns well on aspiration of the infusion 
needle. If extravasation occurs terminate infusion immediately and restart in 
another vein.  Treat extravasation with intermittent ice packs (Place ice pack on 
area of extravasation for 1/2 hour immediately, then for 1/2 hour four times a day 
for 3 days) and elevate the affected extremity.  For more information see 
package insert and seek further medical treatment as deemed necessary. 
 
Supplier:  This drug is commercially available for purchase by a third party.  This 
drug will not be supplied by the NCI. 
 
Please refer to the package insert for complete information. 
 
3.4 
Vorinostat (Zolinza®, Suberoylanilide hydroxamic acid; SAHA)(NSC-701852)(IND-
117406) 
 
a. 
DESCRIPTION 
 
1. 
Vorinostat is a synthetic antineoplastic agent in the histone 
deacetylase (HDAC) inhibitor class. 
 
2. 
Molecular Formula: C14H20N203 
 
3. 
Molecular Weight:  
264.32 g/mol 
 
b. 
PHARMACOLOGY 
 
Mechanism of Action: Vorinostat inhibits the enzymatic activity of both class I and 
class II histone deacetylases. These enzymes are responsible for the removal of 
acetyl groups from lysine residues of proteins and transcription factors. Inhibition 
of HDAC activity interferes with the stabilization of chromatin structure through 
the accumulation of acetylated histones. The accumulation results in cell cycle 
arrest and/or apoptosis of transformed cells.  
 
c. 
PHARMACOKINETICS 
 
1. 
Absorption: High-fat meals increase the absorption of vorinostat 33%. 
Normal Cmax is achieved in 1.5 hours however high fat meals delay 
peak absorption by approximately 2.5 hours. 
 
2. 
Distribution: Vorinostat is approximately 71% bound to human plasma 
protein. 
 
3. 
Metabolism: Vorinostat is metabolized via glucuronidation and hydrolysis 
followed by beta-oxidation into 2 inactive metabolites - O-glucuronide 
and 4-anilino-4-oxobutanoic acid. Biotransformation of CYP P450 is 
negligible from in vitro studies. 


 
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4. 
Elimination: Renal excretion accounts for approximately 50% of 
Vorinostat elimination. Less than 1% of the dose is recovered as 
unchanged drug in the urine.  
 
d. 
TOXICOLOGY 
 
Human Toxicity: The most common dose limiting toxicities (DLTs) include 
anorexia, dehydration, diarrhea, nausea, vomiting, taste alteration (dysgeusia), 
fatigue, increased blood creatinine levels, hyperglycemia, hypocalcemia, 
hypokalemia, and anemia.  The majority of these DLTs occurred within the first 
month on oral vorinostat.  At continuous daily dosing of 600 mg every day, 300 mg 
twice daily, and 400 mg twice daily that exceeded the MTD, the pattern and severity 
of DLTs were similar.  The DLTs were manageable because these toxicities 
resolved quickly after drug administration was interrupted.   
 
Patient Care Implications:  Because vorinostat's dose limiting toxicities are 
anorexia, dehydration, diarrhea, and fatigue, patients should maintain adequate fluid 
and food intake.  Encourage patients to seek a nutritional consult. 
 
Treat diarrhea promptly with appropriate supportive care, including loperamide. 
Instruct patients to begin taking loperamide at the first signs of: 1) poorly formed 
or loose stool, 2) occurrence of more bowel movements than usual in one day, or 
3) unusually high volume of stool. Loperamide should be taken in the following 
manner: 4 mg at first onset of diarrhea, then 2 mg after each unformed stool. 
Daily dose should not exceed 16 mg/day. Loperamide should not be taken 
prophylactically. Advise patients to drink plenty of clear fluids to help prevent 
dehydration caused by diarrhea.  Avoid loperamide if there is the presence of 
blood or mucus in the stool or if diarrhea is accompanied by fever.  If Grade 3 or 
4 diarrhea develops, discontinue further treatment with vorinostat. 
 
Patients should not have taken valproic acid, another histone deacetylase inhibitor, 
for at least 2 weeks prior to study enrollment. Other toxicities by system are as 
follows: 
• 
CNS: dizziness, headache, shivering, fatigue, fever 
• 
Gastrointestinal: nausea, diarrhea, altered taste sensation, anorexia, 
constipation and xerostomia 
• 
Cardiovascular: peripheral edema, DVT, PE and QT prolongation 
• 
Renal: increased serum creatinine 
• 
Respiratory: cough, upper respiratory tract infection 
• 
Hematologic: anemia, thrombocytopenia 
• 
Dermatologic: pruritus, alopecia  
• 
Endocrine/Metabolic: hyperglycemia, weight decreased 
• 
Musculoskeletal effects: spasm 
 
Pregnancy and Lactation: Vorinostat is classified as FDA pregnancy category D 
in all trimesters. Based on animal study results, vorinostat can cause fetal harm 
when administered to a pregnant woman. If vorinostat is used during pregnancy 
or if the patient becomes pregnant while on vorinostat, the patient should be 
informed about the potential hazard to the fetus. It is unknown whether vorinostat 
is excreted in breast milk and therefore patients should be instructed to avoid 
breast feeding during treatment. 
 
 


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Comprehensive Adverse Events and Potential Risks list (CAEPR) for 
Vorinostat (SAHA, NSC 701852) 
 
The Comprehensive Adverse Event and Potential Risks list (CAEPR) provides a 
single list of reported and/or potential adverse events (AE) associated with an 
agent using a uniform presentation of events by body system. In addition to the 
comprehensive list, a subset, the Specific Protocol Exceptions to Expedited 
Reporting (SPEER), appears in a separate column and is identified with bold and 
italicized text. This subset of AEs (SPEER) is a list of events that are protocol 
specific exceptions to expedited reporting to NCI via CTEP-AERS (except as 
noted below).  Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting 
Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguide
lines.pdf for further clarification. Frequency is provided based on 702 patients. 
Below is the CAEPR for vorinostat (SAHA). 
 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in 
parentheses next to the AE in the SPEER.  If this CAEPR is part of a 
combination protocol using multiple investigational agents and has an AE listed 
on different SPEERs, use the lower of the grades to determine if expedited 
reporting is required. 
 
 
Version 2.8, December 18, 20131 
 
 
 Adverse Events with Possible  
 Relationship to Vorinostat (SAHA, Zolinza) 
 (CTCAE 4.0 Term) 
[n= 1076] 
 
 
 
Specific Protocol 
Exceptions to 
Expedited Reporting 
(SPEER)  
Likely (>20%) 
Less Likely 
(<=20%) 
Rare but 
Serious 
(<3%) 
 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
Anemia 
 
 
 Anemia (Gr 3) 
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
  
 
Constipation 
 
 Constipation (Gr 2) 
Diarrhea 
 
 
 Diarrhea (Gr 2) 
 
Dry mouth 
 
 Dry mouth (Gr 2) 
 
Dyspepsia 
 
 Dyspepsia (Gr 2) 
Nausea 
 
 
 Nausea (Gr 2) 
Vomiting 
 
 
 Vomiting (Gr 2) 
GENERAL DISORDERS AND ADMINISTRATION SITE 
CONDITIONS 
  
Fatigue 
 
 
 Fatigue (Gr 2) 
 
Fever 
 
  
INFECTIONS AND INFESTATIONS 
  
 
Infection2 
 
  
INVESTIGATIONS 
  
 
Alanine 
aminotransferase 
increased 
 
 Alanine 
aminotransferase 
increased  
(Gr 2) 


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INVESTIGATIONS 
  
 
Aspartate 
aminotransferase 
increased 
 
 Aspartate 
aminotransferase 
increased (Gr 2) 
 
Blood bilirubin 
increased 
 
  
 
Creatinine 
increased 
 
 Creatinine increased 
(Gr 2) 
 
Lymphocyte count 
decreased 
 
 Lymphocyte count 
decreased (Gr 4) 
 
Neutrophil count 
decreased 
 
 Neutrophil count 
decreased (Gr 4) 
Platelet count decreased  
 
 Platelet count 
decreased (Gr 3) 
 
Weight loss 
 
 Weight loss (Gr 2) 
 
White blood cell 
decreased 
 
 White blood cell 
decreased (Gr 4) 
METABOLISM AND NUTRITION DISORDERS 
  
Anorexia 
 
 
 Anorexia (Gr 2) 
 
Dehydration 
 
 Dehydration (Gr 2) 
 
Hyperglycemia 
 
 Hyperglycemia (Gr 2) 
 
Hypocalcemia 
 
  
 
Hypokalemia 
 
  
 
Hypophosphatemia  
 Hypophosphatemia 
(Gr 3) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE 
DISORDERS 
  
 
Muscle weakness3  
 Muscle weakness3 (Gr 
2) 
NERVOUS SYSTEM DISORDERS 
  
 
Dizziness 
 
 Dizziness (Gr 2) 
 
Dysgeusia 
 
 Dysgeusia (Gr 2) 
RESPIRATORY, THORACIC AND MEDIASTINAL 
DISORDERS 
  
 
Cough 
 
 Cough (Gr 2) 
 
Dyspnea 
 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Alopecia 
 
  
 
 
Skin and 
subcutane
ous tissue 
disorders - 
Other (skin 
necrosis) 
  
1 
This table will be updated as the toxicity profile of the agent is revised.  
Updates will be distributed to all Principal Investigators at the time of revision.  
The 
current 
version 
can 
be 
obtained 
by 
contacting 
PIO@CTEP.NCI.NIH.GOV. Your name, the name of the investigator, the 
protocol and the agent should be included in the e-mail.  
2 
Infection includes all 75 sites of infection under the INFECTIONS AND 
INFESTATIONS SOC. 
3 
Muscle weakness includes Generalized muscle weakness, Muscle weakness 
left-sided, Muscle weakness lower limb, Muscle weakness right-sided, 
Muscle weakness trunk, and Muscle weakness upper limb under the  


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MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS SOC. 
4 
Prolongation of prothrombin time and International Normalized Ratio have 
been observed in patients using vorinostat concomitantly with coumarin-
derivative anticoagulants.  
 
Also reported on vorinostat (SAHA, Zolinza) trials but with the relationship 
to vorinostat (SAHA, Zolinza) still undetermined: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Febrile neutropenia 
CARDIAC DISORDERS - Atrial fibrillation; Atrial flutter; Cardiac disorders - Other 
(supraventricular arrhythmia); Chest pain - cardiac; Left ventricular systolic 
dysfunction; Myocardial infarction; Palpitations; Pericardial effusion; Sinus 
bradycardia; Sinus tachycardia; Ventricular fibrillation 
EAR AND LABYRINTH DISORDERS - Tinnitus; Vertigo 
EYE DISORDERS - Blurred vision; Eye disorders - Other (retinal tear) 
GASTROINTESTINAL DISORDERS - Abdominal distension; Anal hemorrhage; 
Bloating; Cheilitis; Colitis; Dysphagia; Esophageal hemorrhage; Esophagitis; 
Flatulence; Gastric hemorrhage; Gastritis; Gastroesophageal reflux disease; 
Gastrointestinal 
disorders 
- 
Other 
(duodenitis); 
Lower 
gastrointestinal 
hemorrhage; Mucositis oral; Oral hemorrhage; Oral pain; Small intestinal 
obstruction; Stomach pain; Upper gastrointestinal hemorrhage 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; 
Edema limbs; Gait disturbance; General disorders and administration site 
conditions - Other (failure to thrive); Malaise; Multi-organ failure; Non-cardiac 
chest pain; Pain 
HEPATOBILIARY DISORDERS - Hepatic failure 
IMMUNE SYSTEM DISORDERS - Immune system disorders - Other 
(angioedema) 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Bruising; 
Vascular access complication; Wound dehiscence 
INVESTIGATIONS - Activated partial thromboplastin time prolonged4; Alkaline 
phosphatase increased; Cardiac troponin I increased; Electrocardiogram QT 
corrected interval prolonged; GGT increased; INR increased4; Investigations - 
Other (increased lactate dehydrogenase); Lipase increased 
METABOLISM AND NUTRITION DISORDERS - Acidosis; Hypercalcemia; 
Hyperkalemia; 
Hypermagnesemia; 
Hyperuricemia; 
Hypoalbuminemia; 
Hyponatremia; Metabolism and nutrition disorders - Other (decreased total 
protein); Tumor lysis syndrome 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Back pain; 
Chest wall pain; Musculoskeletal and connective tissue disorder - Other (muscle 
spasms); Musculoskeletal and connective tissue disorder - Other (myositis); 
Myalgia; Neck pain; Pain in extremity 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND 
POLYPS) - Neoplasms benign, malignant and unspecified (incl cysts and polyps) 
- Other (tumor hemorrhage); Tumor pain 
NERVOUS SYSTEM DISORDERS - Abducens nerve disorder; Ataxia; Cognitive 
disturbance; Depressed level of consciousness; Dysphasia; Encephalopathy; 
Facial muscle weakness; Facial nerve disorder; Headache; Intracranial 
hemorrhage; Ischemia cerebrovascular; Lethargy; Memory impairment; Nervous  
system disorders - Other (Guillain-Barre syndrome); Nervous system disorders - 
Other (head injury); Nervous system disorders - Other (polyneuropathy); 
Paresthesia; Peripheral motor neuropathy; Peripheral sensory neuropathy; 
Seizure; Somnolence; Stroke; Syncope; Tremor 
PSYCHIATRIC DISORDERS - Agitation; Anxiety; Confusion; Depression; 
Euphoria; Personality change; Psychosis 


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RENAL AND URINARY DISORDERS - Acute kidney injury; Hematuria; 
Proteinuria; Urinary frequency; Urinary incontinence; Urinary retention; Urinary 
tract pain 
REPRODUCTIVE 
SYSTEM 
AND 
BREAST 
DISORDERS 
- 
Irregular 
menstruation; Pelvic pain; Uterine hemorrhage; Vaginal hemorrhage 
RESPIRATORY, 
THORACIC 
AND 
MEDIASTINAL 
DISORDERS 
- 
Bronchopulmonary hemorrhage; Epistaxis; Hypoxia; Pharyngeal mucositis; 
Pleural effusion; Pleuritic pain; Pneumonitis 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Dry skin; Hyperhidrosis; 
Nail loss; Palmar-plantar erythrodysesthesia syndrome; Purpura; Rash maculo-
papular; Skin and subcutaneous tissue disorders - Other (brittle nails) 
VASCULAR DISORDERS - Flushing; Hematoma; Hot flashes; Hypertension; 
Hypotension; Thromboembolic event; Visceral arterial ischemia 
 
Note: Vorinostat (SAHA, Zolinza) in combination with other agents could cause 
an exacerbation of any adverse event currently known to be caused by the other 
agent, or the combination may result in events never previously associated with 
either agent. 
 
Drug interactions: 
 
Drug Class 
Examples 
Outcome 
Blood thinning 
agents 
NSAIDs, platelet 
inhibitors, high dose 
salicylates, 
anticoagulants 
Increased risk of bleeding 
Vaccines 
Any live vaccine ie. 
rotavirus 
Potential for infection with live 
virus 
Atypical 
antipsychotic 
Clozapine 
Increase possibility of 
developing myelosuppression 
HDAC inhibitor 
Valproic Acid 
Severe thrombocytopenia and 
GI bleeding 


 
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Drug Class 
Examples 
Outcome 
Anthracyclines 
Daunorubicin, 
doxorubicin 
Potential risk for anthracycline 
cardiac toxicity 
Any agent that can 
cause QT 
prolongation (list is 
not inclusive – 
please check 
appropriate 
reference)  
Disopyramide, 
amiodarone, 
ciprofloxacin, 
cyclobenzaprine, 
risperidone, saquinavir, 
ondansetron, 
paliperidone, 
telithromycin, tacrolimus, 
sunitinib and etc. 
Increase risk of QT 
prolongation 
Diuretics, antiviral, 
antifungal, platinum 
compound 
Acetazolamide, 
amphotericin B, 
cisplatin, conivaptan, 
foscarnet, loop diuretics, 
methazolamide, thiazide 
diuretics 
Electrolyte abnormalities – 
hypokalemia and 
hypomagnesemia 
 
e. 
DOSING & ADMINISTRATION 
 
1. 
See treatment plan 
  
2. 
Vorinostat capsules must be administered whole.  Administer doses of 
vorinostat with food, if possible. Vorinostat should not be given with other 
HDAC inhibitors. 
 
f. 
STORAGE AND STABILITY 
 
1. 
Compatibility information: NA 
2. 
Vorinostat is a cytotoxic drug and appropriate procedures for handling, 
administering, and destroying the drug should be followed. 
3. 
Store at 20-25C (68-77F), excursions permitted between 15-30C 
(59-86F). 
 
g. 
HOW SUPPLIED 
 
1. 
Vorinostat is supplied as a white, opaque gelatin, size 3 capsule, 
containing 100 mg of vorinostat.  The inactive ingredients contained in 
each capsule are microcrystalline cellulose, sodium croscarmellose, and 
magnesium stearate.  Vorinostat 100 mg capsules are supplied in bottles 
containing 120 capsules. 
 
2. 
Vorinostat is investigational and will be supplied by the NCI  
 
Drug ordering: NCI-supplied agents may be requested by the Principal 
Investigator (or their authorized designee) at each participating 
institution.  Pharmaceutical Management Branch (PMB) policy requires 
that drug be shipped directly to the institution where the patient is to be 
treated. PMB does not permit the transfer of agents between institutions 
(unless prior approval from PMB is obtained).  The CTEP assigned 
 


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Version Date 6/2/15 
 
 
 
protocol number (S1203) must be used for ordering all CTEP supplied 
investigational agents.  The responsible investigator at each participating 
institution must be registered with CTEP, DCTD through an annual 
submission of FDA Form 1572 and a CV.  If there are several 
participating 
investigators 
at 
one 
institution, 
CTEP-supplied 
investigational agents for the study should be ordered under the name of 
one lead investigator at that institution. Active CTEP-registered 
investigators and investigator-designated shipping designees and 
ordering designees can submit agent requests through the PMB Online 
Agent 
Order 
Processing 
(OAOP) 
application 
< 
https://eapps-
ctep.nci.nih.gov/OAOP/pages/login.jspx >.  Access to OAOP requires the 
establishment of a CTEP Identity and Access Management (IAM) 
account < https://eapps-ctep.nci.nih.gov/iam/ > and the maintenance of 
an “active” account status and a “current” password.   For questions 
about drug orders, transfers, returns, or accountability, call 240/276-6575 
Monday through Friday between 8:30 am and 4:30 pm (ET) or email 
PMBAfterHours@mail.nih.gov anytime. 
 
Note:  Initial drug orders must be placed at the time the first patient is 
being screened for registration.  Do not wait until the patient has been 
registered to order initial supply as it will not arrive in time to treat the 
patient. 
 
3. 
Drug Handling and Accountability 
 
Electronic Logs are allowed as long as a print version of the log process 
is the exact same appearance as the current NCI Oral DARF. 
 
4. 
Drug Return and/or Disposition Instructions 
 
a. 
Drug Returns: All unused drug supplies should be returned to the 
PMB. When it is necessary to return study drug (e.g., sealed 
vials remaining when expired vials are recalled by the PMB), 
investigators should return the study drug to the PMB using the 
NCI Return Agent Form available on the NCI home page 
(http://ctep.cancer.gov). 
 
Drug Accountability: The investigator, or a responsible party 
designated by the investigator, must maintain a careful record of 
the receipt, disposition, and return of all drugs received from the 
PMB using the NCI Oral Drug Accountability Record Form (NCI 
Oral DARF) available at http://ctep.cancer.gov. 
 
Questions about drug orders, transfers, returns or accountability 
should be addressed to the PMB by calling 240/276-6575 
Monday through Friday between 8:30 am and 4:30 pm Eastern 
Time. 
 
b. 
Drug expiration: If packaging has expiration date, indicate drug 
expiration date on the NCI Oral DARF under manufacturer and 
lot # and use the drug lots with shorter expiration dates first. 


 
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4.0 
STAGING CRITERIA 
 
4.1  
Diagnostic Criteria   
 
Acute Myeloid Leukemia (AML) is defined by ≥ 20% myeloblasts in the blood or marrow, 
with exceptions as in the World Health Organization (WHO) 2009 criteria. (19) 
 
NOTE:  Acute erythroleukemia (erythroid/myeloid subtype) is defined by the presence in 
the bone marrow of ≥ 50% erythroid precursors in the entire nucleated cell population 
and ≥ 20% myeloblasts in the non-erythroid population.  Pure erythroid leukemia is 
defined as a neoplastic proliferation of immature cells committed exclusively to the 
erythroid lineage (> 80% of the marrow nucleated cells) with no evidence of a significant 
myeloblastic component. 
 
4.2  
Staging Criteria 
 
Staging criteria are not applicable to this protocol. 


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5.0 
ELIGIBILITY CRITERIA 
 
Each of the criteria in the following section must be met in order for a patient to be considered eligible for 
registration.  Use the spaces provided to confirm a patient's eligibility.  For each criterion requiring test 
results and dates, please record this information on the Onstudy Form and submit via Medidata Rave® 
(see Section 14.0).  Any potential eligibility issues should be addressed to the Data Operations Center in 
Seattle at 206/652-2267 prior to registration. 
  
In calculating days of tests and measurements, the day a test or measurement is done is considered Day 
0.  Therefore, if a test is done on a Monday, the Monday 4 weeks later would be considered Day 28.  This 
allows for efficient patient scheduling without exceeding the guidelines.  If Day 28 or 42 falls on a 
weekend or holiday, the limit may be extended to the next working day. 
 
SWOG Patient No.   
 
 
Patient's Initials (L, F, M)   
 
 
All patients who are determined to be high-risk based on cytogenetics or FISH should be considered and 
referred for potential allogeneic stem cell transplant. High-risk patients may receive transplant at any point 
after achieving remission (CR or CRi).  In order to organize a donor, sites must follow instructions in 
Section 7.3 at the time of initial registration. 
 
5.1 
Registration Step 1 – Induction/Re-Induction  
 
a. 
Patients must have morphologically confirmed newly diagnosed acute 
myelogenous leukemia (AML) with blood or bone marrow disease. Patients with 
only extramedullary disease in the absence of bone marrow or blood involvement 
are not eligible. Note:  This protocol uses WHO diagnostic criteria for AML.  
Patients with acute promyelocytic leukemia (APL, FAB, M3) or blastic 
transformation of chronic myelogenous leukemia (CML) are not eligible.  Patients 
with known CBF or FLT3 related leukemias are eligible for this study, but should 
preferentially be placed on NCI-sponsored protocols specific for these subtypes, 
if available. 
 
b. 
Patients must have diagnostic/pre-treatment specimens obtained within 28 days 
prior to registration submitted as outlined in Section 15.2 for cytogenetic (and 
FISH if possible) analysis to determine risk status.  High risk classification will be 
defined as del(5q)/-5, del(7q)/-7, abn3q26 [inv(3)/t(3;3)], 11q23 rearrangement 
[except t(9;11)], 17p-, t(6;9), t(9;22), complex (at least 3 unrelated abn), and 
monosomal karyotype (either loss of two different chromosomes or loss of one 
chromosome along with a structural chromosome abnormality other than add, 
ring and mar). Karyograms and cytogenetics/FISH analysis reports must be 
submitted for discipline review as outlined in Section 12.0.  
 
c. 
Patients must be chemo-naïve, i.e., not have received any prior Induction 
chemotherapy for AML or MDS. Temporary prior measures such as apheresis or 
hydroxyurea are allowed.  Prior anthracycline therapy is allowed, but must not 
exceed a dose of 200 mg/m2 daunorubicin or equivalent. Prior ATRA for 
suspected APL is allowed.  Prior methotrexate for CNS involvement is allowed. 
Patients with prior history of MDS must not have received azacitidine, decitabine, 
lenalidomide or vorinostat.  


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SWOG Patient No.   
 
 
Patient's Initials (L, F, M)   
 
 
5.1 
Registration Step 1 – Induction/Re-Induction (cont.) 
 
d. 
Patients must have peripheral blood and bone marrow aspirate specimens 
obtained within 28 days prior to registration submitted for translational medicine 
as outlined in Section 15.1.  With patient consent, residuals will be banked for 
future research. 
 
e. 
Patients must be ≥ 18 and ≤ 60 years of age.   
 
f. 
Patients must have Zubrod Performance Status ≤ 3 (see Section 10.7). 
 
g. 
Patients must have either ECHO or MUGA with ejection fraction ≥ 45% within 28 
days prior to registration.   
 
h. 
Patients must not have prolonged QTc interval (> 500 msec) determined by EKG 
within 28 days prior to registration. 
 
i. 
Patients must not have cardiac disease defined as: New York Heart Association 
(NYHA) > Class II (see Appendix 18.2).  Patients must not have unstable angina 
(angina symptoms at rest) or new onset angina (began within the last 3 months) or 
myocardial infarction within the past 6 months. 
 
j. 
Patients must not have any coexisting medical condition that is likely to interfere with 
study procedures or results, and must be reasonable candidates for intensive 
chemotherapy, in the opinion of their treating physicians. 
 
k. 
Patients who are known to be HIV+ are eligible providing they meet all of the 
following additional criteria within 28 days prior to registration: 
 
• 
CD4 cells ≥ 500/mm3 
• 
Viral load of < 50 copies HIV mRNA/mm3 if on cART or < 25,000 copies HIV 
mRNA if not on cART 
• 
No zidovudine or stavudine as part of cART  
 
Patients who are HIV+ and do not meet all of these criteria are not eligible for this 
study. 
 
l. 
Patients with known Hepatitis B or Hepatitis C infection may be eligible providing they 
have viral load < 800,000 IU/mL within 28 days prior to registration. 
 
m. 
Patients must be able to take oral medications. 
 
n. 
Patients must have a history and physical examination obtained within 28 days prior 
to registration. 
 
 


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SWOG Patient No.   
 
 
Patient's Initials (L, F, M)   
 
 
5.1 
Registration Step 1 – Induction/Re-Induction (cont.) 
 
o. 
Patients must not be pregnant or nursing due to the teratogenic potential of the drugs 
used in this study.  Women/men of reproductive potential must have agreed to use 
an effective contraceptive method.  A woman is considered to be of "reproductive 
potential" if she has had menses at any time in the preceding 12 consecutive 
months.  In addition to routine contraceptive methods, "effective contraception" also 
includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a 
side-effect of pregnancy prevention) defined as a hysterectomy, bilateral 
oophorectomy or bilateral tubal ligation.  However, if at any point a previously celibate 
patient chooses to become heterosexually active during the time period for use of 
contraceptive measures outlined in the protocol, he/she is responsible for beginning 
contraceptive measures. 
 
p. 
Prior malignancy is allowed providing it does not require concurrent therapy.  
Exception:  Active hormonal therapy is allowed. 
 
q. 
Patients must not be receiving valproic acid. 
 
r. 
All patients must be informed of the investigational nature of this study.  Patients or a 
legally authorized representative must sign and give written informed consent in 
accordance with institutional and federal guidelines 
 
s. 
As part of the OPEN registration process (see Section 13.4 for OPEN access 
instructions) the treating institution's identity is provided in order to ensure that the 
current (within 365 days) date of institutional review board approval for this study has 
been entered in the system. 
 
5.2 
Registration Step 2 – Consolidation 
 
Patients may be registered for Consolidation provided that they were eligible for the initial 
Induction/Re-Induction registration and satisfy the following additional criteria.   
 
a. 
Patients must have achieved morphologic remission (complete remission [CR] or 
complete remission with incomplete blood count recovery [CRi]) after completion of 
Induction or Re-Induction therapy (see Section 10.1 for definitions of CR and CRi).  
Patient must remain in remission until beginning Consolidation and this must be 
documented by bone marrow and peripheral blood examination within 28 days prior 
to registration to Step 2. 
 
b. 
All non-hematologic treatment related toxicities that are deemed clinically significant 
by the treating physician must have resolved to ≤ Grade 2.   
 
c. 
Patients must not have received allogeneic stem cell transplant. 
 
 


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6.0 
STRATIFICATION FACTORS 
 
A dynamic allocation scheme will be used to balance the randomization on the following two 
stratification factors (20): 
 
1.   
Age at registration:  < 40 years vs. ≥ 40 years 
 
2.   
Onset of leukemia:  de novo vs. treatment related and/or AML arising from antecedent 
hematologic disease 
 
 
7.0 
TREATMENT PLAN   
 
For treatment or dose modification questions, please contact Dr. Guillermo Garcia-Manero at 
281/380-7813 or Dr. John Pagel at 206/667-1868.  For dosing principles or questions, please 
consult the SWOG Policy #38 "Dosing Principles for Patients on Clinical Trials" at http://swog.org 
(then click on "Policies and Manuals" under the "Visitors" menu and choose Policy 38). 
 
7.1 
General Considerations 
 
a. 
Patients must have the following tests within 28 days prior to treatment to obtain 
baseline measurements: 
• 
CBC, Differential, Platelets 
• 
Creatinine 
• 
Total bilirubin 
• 
SGPT/SGOT 
• 
If there is a clinical suspicion of CNS involvement, further evaluation with 
imaging or lumbar puncture 
 
b. 
Supportive Care  
 
Supportive care for prevention of tumor lysis syndrome (hydration, monitoring, 
etc.) must be performed per local institutional guidelines.  Additional supportive 
care (e.g. transfusions, prophylactic antibiotics, antifungals and/or antivirals, 
growth factor support) is also allowed per institutional guidelines.  All supportive 
care must be documented on the Treatment Form. 
 
Co-administration of corticosteroids and corticosteroid-containing eye drops (or 
equivalent) is recommended for patients receiving high-dose AraC containing 
regimens.  Eye drops should continue for at least 2 days following the last dose 
of AraC.  Methylprednisolone 40-50 mg or dexamethasone 10 mg IV daily may 
be given with high-dose AraC. 
 
Patients randomized to vorinostat should be counseled about the possibility of 
diarrhea and should have an anti-diarrheal (e.g., loperamide) readily available 
(see Section 3.4d). 
 
Antiemetic prophylaxis given per institutional guidelines is recommended for 
every cycle. 
 
Hospitalization for supportive care during Induction/Consolidation is not required, 
but is allowed per local institutional guidelines. 
 


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7.2 
Induction/Re-Induction   
 
a. 
Arm 1 – 7+3 
 
Induction 
 
Agent 
Dose 
Route 
Day 
 
 
AraC 
100 mg/m2/day  
Continuous IV 
1-7 
 
total dose = 700 mg/m2 
 
Daunorubicin1 
90 mg/m2/day 
IV Push2 
1-3 
 
 
total dose = 270 mg/m2 
 
1 BSA cap 2.5.  If daunorubicin is not available because of manufacturing issues, 
idarubicin at 12 mg/m2 daily x 3 on Days 1 to 3 can be substituted.  This must 
be noted on the Treatment Summary Form. 
2 Alternatively, daunorubicin may be administered via IV infusion over < 60 
minutes. 
 
Patients will have a bone marrow examination approximately 14 days (± 3 days) 
after the start of Induction chemotherapy.  If residual blasts are seen, patients 
may proceed to Re-Induction as outlined below starting on Day 15 (± 3 days).  
Patients with clearance of blasts should have a repeat bone marrow examination 
approximately 28 days (± 3 days) after the start of Induction chemotherapy to 
confirm CR/CRi.  Patients achieving CR or CRi may proceed to allogeneic stem 
cell transplant or to Consolidation, providing they meet the additional criteria 
outlined in Section 5.2.  If peripheral counts have not recovered to ANC > 
1,000/mm3 or PLT > 100,000/m3, the Day 28 bone marrow exam may be delayed 
for up to 14 days to allow for recovery. 
  
Re-Induction 
 
Agent 
Dose 
Route 
Day3 
 
 
AraC 
100 mg/m2/day  
Continuous IV 
1-7 
 
total dose = 700 mg/m2 
 
Daunorubicin1 
45 mg/m2 /day 
IV Push2 
1-3 
 
 
total dose = 135 mg/m2 
 
1 BSA cap 2.5.  If daunorubicin is not available because of manufacturing issues, 
idarubicin at 12 mg/m2 daily x 3 on days 1 to 3 can be substituted.  This must 
be noted on the Treatment Summary Form. 
2 Alternatively, daunorubicin may be administered via IV infusion over < 60 
minutes. 
3 Days are calculated from the start of Re-Induction therapy. 
 
Patients will have a follow-up bone marrow examination approximately 14 days 
after the start of Re-Induction chemotherapy.  Patients achieving CR or CRi may 
proceed to allogeneic stem cell transplant or to Consolidation, providing they 
meet the additional criteria outlined in Section 5.2.  If peripheral counts have not 
recovered to ANC > 1,000/mm3 or PLT > 100,000/m3, the Day 14 bone marrow 
exam may be delayed for up to 14 days to allow for recovery. 
 


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b. 
Arm 2 – IA 
 
Induction 
 
Agent 
Dose 
Route 
Day 
 
 
AraC  
1,500 mg/m2/day 
Continuous IV 
1-4 
 
total dose = 6,000 mg/m2 
 
Idarubicin 1 
12 mg/m2/day 
IV over 15 mins 
1-3 
 
 
total dose = 36 mg/m2 
 
 
 
 
 
  
 
1 BSA cap 2.5 
 
Patients will have a bone marrow examination approximately 28 days (± 3 days) 
after the start of Induction chemotherapy.  If residual blasts remain, patients may 
proceed to Re-Induction as outlined below at that point. Note:  patients on this 
Arm may not proceed to Re-Induction until Day 28, not Day 15 as in Arm 1.  
Patients achieving CR or CRi may proceed to allogeneic stem cell transplant or 
to Consolidation, providing they meet the additional criteria outlined in Section 
5.2.  If peripheral counts have not recovered to ANC > 1,000/mm3 or PLT > 
100,000/m3, the Day 28 bone marrow exam may be delayed for up to 14 days to 
allow for recovery.  
 
Re-Induction 
 
Agent 
Dose 
Route 
Day 2 
 
 
AraC  
1,500 mg/m2/day 
Continuous IV 
1-4 
 
total dose = 6,000 mg/m2 
 
Idarubicin 1 
12 mg/m2/day 
IV over 15 mins 
1-3 
 
 
total dose = 36 mg/m2 
 
 
 
 
 
  
 
1 BSA cap 2.5 
2 Days are calculated from the start of Re-Induction therapy. 
 
Patients will have a follow-up bone marrow examination 28 days (± 3 days) after 
the start of Re-Induction chemotherapy.  Patients achieving CR or CRi may 
proceed to allogeneic stem cell transplant or to Consolidation, providing they 
meet the additional criteria outlined in Section 5.2. 
 


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c. 
Arm 3 – IA + Vorinostat 3 
 
Arm 3 was permanently closed to accrual effective TBD. Effective TBD, 
patients previously randomized to Arm 3 have the option to remain on Arm 3 as a 
medical intervention and must follow the applicable treatment schedule below. 
 
Induction 
 
Agent 
Dose 
Route 
Day 
 
Vorinostat 2 
500 mg 3x/day 
PO 
1-3 
 
daily dose = 1,500 mg/day 
 
total dose = 4,500 mg/cycle 
 
AraC  
1,500 mg/m2/day 
Continuous IV 
4-7 
 
total dose = 6,000 mg/m2 
 
 
Idarubicin 1 
12 mg/m2/day 
IV over 15 mins 
4-6 
 
total dose = 36 mg/m2 
1 BSA cap 2.5 
2 Vorinostat is given in divided doses 3 times daily.  Missed doses of vorinostat should be 
skipped.  Drug compliance will be recorded by patients in the Intake Calendar (see 
Appendix 18.3).  Institutional CRAs will review and ascertain patient adherence with 
protocol therapy at the end of treatment for each cycle.  Calendar should be kept in the 
patient’s clinic chart.  Note that the Intake Calendar is provided only as a tool for 
tracking compliance.  Sites may utilize institutional pill diaries or other source 
documentation in place of the Intake Calendar at the discretion of the treating physician. 
3 Patients previously randomized to Arm 3 that opt to continue medical treatment with IA 
+ Vorinostat must follow protocol and protocol data submission requirements. 
 
Patients will have a bone marrow examination approximately 28 days (± 3 days) 
after the start of Induction chemotherapy.  If residual blasts remain, patients may 
proceed to Re-Induction as outlined below at that point. Note:  patients on this 
Arm may not proceed to Re-Induction until Day 28, not Day 15 as in Arm 1.  
Patients achieving CR or CRi may proceed to allogeneic stem cell transplant or 
to Consolidation, providing they meet the additional criteria outlined in Section 
5.2. If peripheral counts have not recovered to ANC > 1,000/mm3 or PLT > 
100,000/m3, the Day 28 bone marrow exam may be delayed for up to 14 days to 
allow for recovery. 
 
Re-Induction 
 
Agent 
Dose 
Route 
Day3 
 
Vorinostat 2 
500 mg 3x/day 
PO 
1-3 
 
daily dose = 1,500 mg/day 
 
total dose = 4,500 mg/cycle 
 
AraC  
1,500 mg/m2/day 
Continuous IV 
4-7 
 
total dose = 6,000 mg/m2 
 
Idarubicin 1 
12 mg/m2/day 
IV over 15 mins 
4-6 
 
total dose = 36 mg/m2 
1 BSA cap 2.5 
2 Vorinostat is given in divided doses 3 times daily.  Missed doses of vorinostat should be 
skipped.  Drug compliance will be recorded by patients in the Intake Calendar (see 
Appendix 18.3).  Institutional CRAs will review and ascertain patient adherence with 
protocol therapy at the end of treatment for each cycle.  Calendar should be kept in the 
patient’s clinic chart.  Note that the Intake Calendar is provided only as a tool for 
tracking compliance.  Sites may utilize institutional pill diaries or other source 
documentation in place of the Intake Calendar at the discretion of the treating physician. 
3 Days are calculated from the start of Re-Induction therapy. 


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Patients will have a follow-up bone marrow examination approximately 28 days 
(± 3 days) after the start of Re-Induction chemotherapy.  Patients achieving CR 
or CRi may proceed to allogeneic stem cell transplant or to Consolidation, 
providing they meet the additional criteria outlined in Section 5.2. 
 
Arm 3 – IA * 
 
Induction 
 
Agent 
Dose 
Route 
Day 
 
 
AraC  
1,500 mg/m2/day 
Continuous IV 
1-4 
 
total dose = 6,000 mg/m2 
 
Idarubicin 1 
12 mg/m2/day 
IV over 15 mins 
1-3 
 
 
total dose = 36 mg/m2 
 
 
 
 
 
  
 
1 BSA cap 2.5 
* Arm 3 was permanently closed to accrual effective TBD.  Patients previously 
randomized to Arm 3 that opt to continue medical treatment with IA must follow 
protocol and protocol data submission requirements.  
 
Patients will have a bone marrow examination approximately 28 days (± 3 days) 
after the start of Induction chemotherapy.  If residual blasts remain, patients may 
proceed to Re-Induction as outlined below at that point. Note:  patients on this 
Arm may not proceed to Re-Induction until Day 28, not Day 15 as in Arm 1.  
Patients achieving CR or CRi may proceed to allogeneic stem cell transplant or 
to Consolidation, providing they meet the additional criteria outlined in Section 
5.2.  If peripheral counts have not recovered to ANC > 1,000/mm3 or PLT > 
100,000/m3, the Day 28 bone marrow exam may be delayed for up to 14 days to 
allow for recovery.  
 
Re-Induction 
 
Agent 
Dose 
Route 
Day 2 
 
 
AraC  
1,500 mg/m2/day 
Continuous IV 
1-4 
 
total dose = 6,000 mg/m2 
 
Idarubicin 1 
12 mg/m2/day 
IV over 15 mins 
1-3 
 
 
total dose = 36 mg/m2 
 
 
 
 
 
  
 
1 BSA cap 2.5 
2 Days are calculated from the start of Re-Induction therapy. 
* Arm 3 was permanently closed to accrual effective TBD.  Patients previously 
randomized to Arm 3 that opt to continue medical treatment with IA must follow 
protocol and protocol data submission requirements.  
 
Patients will have a follow-up bone marrow examination 28 days (± 3 days) after 
the start of Re-Induction chemotherapy.  Patients achieving CR or CRi may 
proceed to allogeneic stem cell transplant or to Consolidation, providing they 
meet the additional criteria outlined in Section 5.2. 
 


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7.3 
Allogeneic Stem Cell Transplant 
 
Patients will undergo HLA-typing at the time of study entry.  Those with high-risk disease 
by cytogenetics should be referred for consultation with a transplant team with the goal of 
conducting an allogeneic transplant while in first remission.  The transplantation, 
including donor selection, will not be guided by this protocol but will be at the discretion of 
the specific transplant center.  However, referral to BMTCTN trial CTN0903 (for HIV 
infected patients) or BMTCTN trial CTN0901 is strongly encouraged.  The process for 
donor identification is outlined in the AML transplant study flow-chart (see Appendix 18.5) 
and Transplant Donor Search Process (see Appendix 18.6). 
 
Patients will have a buccal swab specimen collected at the time of enrollment to facilitate 
HLA typing and a preliminary unrelated donor search following a cytogenetic diagnosis of 
high risk disease.   
 
7.4 
Consolidation 
 
For patients receiving Consolidation, therapy should be started as soon as possible (and 
within 14 days) after recovery from Induction/Re-Induction therapy.  Patients must be 
registered to Step 2 before beginning Consolidation therapy (within 14 days after 
recovery from Induction/Re-Induction). 
 
Subsequent to Consolidation Cycle 1, cycles will be given at 28 day intervals provided 
both the ANC has recovered to > 1,000/mm3 and the platelet count to > 50,000/mm3.  If 
these levels are not met, at physicians discretion, cycles may be continued at 28 day 
intervals, provided that the ANC has recovered to > 1,000/mm3 and the platelet count to 
> 30,000/mm3, where determined that continued protocol therapy is in the best interest of 
the patient. 
 
Patients may receive up to 4 cycles of Consolidation therapy, depending on transplant 
availability.  Patients who are not classified as high risk will be removed from protocol 
treatment after completion of Consolidation.  Patients who are classified as high risk will 
remain on protocol treatment for up to one year after documentation of CR or CRi, or until 
they receive transplant, whichever comes first. 
 
a. 
Arm 1 – 7+3  
 
Agent 
Dose 
Route 
Day 
Schedule*  
 
AraC 
3,000 mg/m2/dose 
IV over 3 hrs 
1, 3, 5 
every 12 hours on  
 
daily dose = 6,000 mg/m2 
 
each day it’s given 
 
total dose = 18,000 mg/m2 
* Note:  One cycle = 28 days 
 
b. 
Arm 2 – IA  
 
Agent 
Dose 
Route 
Day  
 
AraC  
750 mg/m2/day 
Continuous IV 
1-3 
 
total dose = 2,250 mg/m2 
 
Idarubicin 1 
8 mg/m2/day 
IV over 15 mins 
1-2 
 
total dose = 16 mg/m2 
 
* Note:  One cycle = 28 days 
1 BSA cap 2.5 
 


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c. 
Arm 3 – IA + Vorinostat  
 
Effective TBD, patients have the option to remain on Arm 3 as a medical 
intervention with or without vorinostat and must follow the applicable 
treatment schedule below. 
 
Agent 
Dose 
Route 
Day  
 
 
Vorinostat 2  500 mg 3x/day 
PO 
1-3 
 
 
 
daily dose = 1,500 mg/day 
 
total dose = 4,500 mg/cycle 
 
AraC  
750 mg/m2/day 
Continuous IV 
4-6 
 
total dose = 2,250 mg/m2 
 
Idarubicin 1 
8 mg/m2/day 
IV over 15 mins 
4-5 
 
total dose = 16 mg/m2 
 
*  Note:  One cycle = 28 days 
1 BSA cap 2.5 
2 Drug compliance will be recorded by patients in the Intake Calendar (see 
Appendix 18.3). Institutional CRAs will review and ascertain patient adherence 
with protocol therapy at the end of treatment for each cycle.  Calendar should be 
kept in the patient's clinic chart.  Note that the Intake Calendar is provided only as 
a tool for tracking patient compliance.  Sites may utilize institutional pill diaries or 
other source documentation in place of the Intake Calendar at the discretion of 
the treating physician. 
 
Arm 3 – IA 2 
 
Agent 
Dose 
Route 
Day  
 
AraC  
750 mg/m2/day 
Continuous IV 
1-3 
 
total dose = 2,250 mg/m2 
 
Idarubicin 1 
8 mg/m2/day 
IV over 15 mins 
1-2 
 
total dose = 16 mg/m2 
 
* Note:  One cycle = 28 days 
1 BSA cap 2.5 
2 Arm 3 was permanently closed to accrual effective TBD.  Patients previously 
randomized to Arm 3 that opt to continue medical treatment with IA must follow 
protocol and protocol data submission requirements. 
 
7.5 
Criteria for Removal from Protocol Treatment 
 
a. 
Relapse from remission (CR or CRi) (as defined in Section 10.3). 
 
b. 
Unacceptable toxicity. 
 
c. 
Patient does not achieve remission (CR or CRi) after Induction or Re-Induction. 
 
d. 
Patient is not high-risk and completes 4 cycles of Consolidation. 
 
e. 
Patient receives transplant. 


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f. 
Patient is high-risk and does not receive transplant within 1 year of 
documentation of remission (CR or CRi). 
 
g. 
The patient may withdraw from the study at any time for any reason. 
 
7.6 
Discontinuation of Treatment 
 
All reasons for discontinuation of treatment must be documented in the Off Treatment 
Notice. 
 
7.7 
Follow-Up Period 
 
All patients will be followed until death or 5 years after initial registration, whichever 
occurs first. 
 
 


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8.0 
TOXICITIES TO BE MONITORED AND DOSAGE MODIFICATIONS 
 
8.1 
NCI Common Terminology Criteria for Adverse Events 
 
This study will utilize the CTCAE (NCI Common Terminology Criteria for Adverse Events) 
Version 4.0 for toxicity and Serious Adverse Event reporting.  A copy of the CTCAE 
Version 4.0 can be downloaded from the CTEP home page (http://ctep.cancer.gov).  All 
appropriate treatment areas should have access to a copy of the CTCAE Version 4.0. 
 
8.2 
Dose Modifications   
 
a. 
General considerations 
 
1. 
Dose modifications will be based on the toxicity requiring the largest 
dose reduction. 
 
2. 
Dose modifications may be made for individual drugs if in the judgment 
of the treating physician, the toxicity is attributable to one drug. 
 
3. 
All dose reductions must be outlined on the Treatment Form. 
 
4. 
Concomitant administration of any other therapy for treatment of AML, 
including systemic retinoids, is prohibited. 
 
5. 
If any individual drug is permanently discontinued due to toxicity, the 
patient may remain on protocol treatment with the remaining drugs. 
 
6. 
Dose modification of AraC or Idarubicin in the setting of renal or hepatic 
dysfunction will be left to the discretion of the treating physician, but the 
Study Chair should be notified of any modifications.  Any modification 
should be based on labs obtained the day of drug administration and 
should follow guidelines below.  If dose modifications are required and 
toxicities subsequently resolve, AraC or Idarubicin may be re-introduced 
in full dose for the next cycle. 
 
7. 
Other dose modifications may be acceptable after discussion with the 
Study Chair.  No dose reductions will be made for myelosuppression 
during Induction 
 
b. 
Arm 1 – 7+3 
 
1. 
Induction/Re-Induction 
 
AraC:  No dose reductions allowed. 
 
Daunorubicin:  No dose reduction allowed during Induction.  For Re-
Induction, dose reductions may be made in the setting of hepatotoxicity 
as follows:   
 
For SGPT/SGOT 150-300 U/L OR bilirubin 1.5-3.0 mg/dL, reduce to 
Dose Level -1.  For SGPT/SGOT > 300 U/L OR bilirubin > 3.0-5.0 mg/dL, 
reduce to Dose Level -2. For bilirubin > 5.0 mg/dL, omit daunorubicin. 
 
Drug 
Dose Level 0 
Dose Level -1 
Dose Level -2 
Daunorubicin 
45 mg/m2/day 
22.5 mg/m2/day 
11.25 
mg/m2/day 
 


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2. 
Consolidation 
 
No dose reductions allowed for Cycle 1 except in the instance of renal 
dysfunction.  For subsequent cycles, doses of AraC may be reduced to 
Level -1 for the following reasons: 
• 
Grade 3-4 non-hematologic toxicity 
• 
Severe life-threatening infection 
 
If toxicity persists, AraC dose may be further reduced to Level -2. 
 
Drug 
Dose Level 0 
Dose Level -1 
Dose Level -2 
AraC 
3,000 mg/m2/ 
dose 
2,250 mg/m2/ 
dose 
1,125 mg/m2/ 
dose 
 
AraC Dose Modifications for Renal Dysfunction: 
• 
For creatinine greater than 2 mg/dL or calculated creatinine 
clearance of < 50 mL/min, decrease AraC to 1,000 mg/m2/dose. 
• 
For creatinine, greater than 3 mg/dL or calculated creatinine 
clearance of < 30 mL/min, change AraC to 100 mg/m2/day IV 
infusion over 24 hours daily for 5 days. 
 
c. 
Arm 2 - IA 
 
1. 
Induction/Re-Induction   
 
AraC:  No dose reductions allowed for Induction.  For Re-Induction, 
doses of AraC may be reduced to Level -1 for the following reasons: 
• 
Grade 3-4 non-hematologic toxicity 
• 
Severe life-threatening infection 
 
AraC Dose Modifications for Renal Dysfunction: 
• 
For creatinine greater than 2 mg/dL or calculated creatinine 
clearance of < 50 mL/min, decrease AraC to Level -2. 
• 
For creatinine, greater than 3 mg/dL or calculated creatinine 
clearance of < 30 mL/min, change AraC to 100 mg/m2/day IV 
infusion over 24 hours daily for 7 days. 
 
Idarubicin: No dose reduction allowed during Induction.  For Re-
Induction, doses of idarubicin may be reduced to Level -1 for the 
following reasons: 
• 
Grade 3-4 non-hematologic toxicity 
• 
Severe life-threatening infection 
 
For Re-Induction, doses of idarubicin may be reduced to Level -2 in the 
setting of hepatotoxicity: bilirubin 2.6 – 5 mg/dL. For bilirubin > 5.0 mg/dL 
during treatment, omit idarubicin. 
 
Drug 
Dose Level 0 
Dose Level -1 
Dose Level -2 
AraC  
1,500 
mg/m2/day 
1,125 mg/m2/day 
850 mg/m2/day 
Idarubicin  
12 mg/m2/day 
9 mg/m2/day 
6 mg/m2/day 
 


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2. 
Consolidation 
 
Doses of AraC and/or idarubicin may be reduced to Level -1 for the 
following reasons: 
• 
Grade 3-4 non-hematologic toxicity 
• 
Severe life-threatening infection 
• 
Bilirubin 2.6 – 5 mg/dL (Idarubicin) 
 
For bilirubin > 5.0 mg/dL during treatment, omit idarubicin. 
 
AraC Dose Modifications for Renal Dysfunction: 
• 
For creatinine greater than 2 mg/dL or calculated creatinine 
clearance of < 50 mL/min, decrease AraC to Level -2. 
• 
For creatinine, greater than 3 mg/dL or calculated creatinine 
clearance of < 30 mL/min, change AraC to 100 mg/m2/day IV 
infusion over 24 hours daily for 5 days. 
 
Drug 
Dose Level  0 
Dose Level -1 
Dose Level -2 
AraC 
750 mg/m2/day 
560 mg/m2/day 
375 mg/m2/day 
Idarubicin 
8 mg/m2/day 
6 mg/m2/day 
Discontinue 
 
d. 
Arm 3 – IA + Vorinostat 
 
1. 
Induction/Re-Induction 
 
AraC:  No dose reductions allowed for Induction.  For Re-Induction, 
doses of AraC may be reduced to Level -1 for the following reasons: 
• 
Grade 3-4 non-hematologic toxicity 
• 
Severe life-threatening infection 
 
AraC Dose Modifications for Renal Dysfunction: 
• 
For creatinine greater than 2 mg/dL or calculated creatinine 
clearance of < 50 mL/min, decrease AraC to Level -2. 
• 
For creatinine, greater than 3 g/dL or calculated creatinine 
clearance of < 30 mL/min, change AraC to 100 mg/m2/day IV 
infusion over 24 hours daily for 7 days. 
 
Idarubicin: No dose reduction allowed during Induction.  For Re-
Induction, doses of idarubicin may be reduced to Level -1 for the 
following reasons: 
• 
Grade 3-4 non-hematologic toxicity 
• 
Severe life-threatening infection 
 
For Re-Induction, doses of idarubicin may be reduced to Level -2 in the 
setting of hepatotoxicity: bilirubin 2.6 – 5 mg/dL. 
 
For bilirubin > 5.0 mg/dL during treatment,  omit idarubicin. 
 
Vorinostat:  No dose reductions allowed for Induction.  For Re-Induction, 
patients may receive vorinostat at Dose Level -1 if they experienced any 
of the following during Induction: 
• 
Nausea 
• 
Vomiting 
• 
Fatigue 
• 
Grade 3-4 extramedullary toxicity 
 


Revised 3/22/13 
Revised 6/2/15 
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Revised 6/28/13 
Page 41 
 
Version Date 6/2/15 
 
 
 
For bilirubin > 3.0 mg/dL during treatment, discontinue vorinostat. 
 
Drug 
Dose Level 0 
Dose Level -1 
Dose Level -2 
AraC  
1,500 mg/m2/day 
1,125 mg/m2/day 
850 mg/m2/day 
Idarubicin  
12 mg/m2/day 
9 mg/m2/day 
6 mg/m2/day 
Vorinostat 
1,500 mg/day 
1,200 mg/day 
Discontinue 
 
2. 
Consolidation 
 
AraC/Idarubicin:  Doses may be reduced to Level -1 for the following 
reasons: 
• 
Grade 3-4 non-hematologic toxicity 
• 
Severe life-threatening infection 
• 
Bilirubin 2.6 – 5 mg/dL (idarubicin) 
 
For bilirubin > 5.0 mg/dL during treatment, omit idarubicin. 
 
AraC Dose Modifications for Renal Dysfunction: 
• 
For creatinine greater than 2 mg/dL or calculated creatinine 
clearance of < 50 mL/min, decrease AraC to Level -2. 
• 
For creatinine, greater than 3 mg/dL or calculated creatinine 
clearance of < 30 mL/min, change AraC to 100 mg/m2/day IV 
infusion over 24 hours daily for 5 days. 
 
Vorinostat:  For patients who did not have dose reduced for Re-
Induction, no dose reductions are allowed for the first cycle of 
Consolidation.  For subsequent cycles, or for patients who had dose 
reduction during Re-Induction, patients may receive vorinostat at Dose 
Level -1 if they experienced any of the following: 
• 
Nausea 
• 
Vomiting 
• 
Fatigue 
• 
Grade 3-4 extramedullary toxicity 
 
For bilirubin > 3.0 mg/dL during treatment, discontinue vorinostat. 
 
Dose modification of AraC in the setting of renal or hepatic dysfunction 
will be left to the discretion of the treating physician, but the Study Chair 
should be notified of any modifications.  Any modification should be 
based on labs obtained the day of drug administration.  If dose 
modifications are required and toxicities subsequently resolve, AraC may 
be re-introduced in full dose for the next cycle. 
 
Drug 
Dose Level 0 
Dose Level -1 
Dose Level -2 
AraC 
750 mg/m2/day 
560 mg/m2/day 
400 mg/m2/day 
Idarubicin 
8 mg/m2/day 
6 mg/m2/day 
Discontinue 
Vorinostat 
1,500 mg/day 
1,200 mg/day 
Discontinue 
 
8.3 
Dose Modification Contacts 
 
For treatment or dose modification questions, please contact Dr. Guillermo Garcia-
Manero at 281/380-7813 or Dr. John Pagel at 206/667-1868.   
 


 
S1203 
 
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Version Date 6/2/15 
 
Revised 6/28/13 
 
 
 
8.4 
Adverse Event Reporting 
 
Unexpected or fatal toxicities (including suspected reactions) must be reported to the 
Operations Office, to the Study Chair, to the IRB and the NCI.  The procedure for 
reporting adverse reactions is outlined in Section 16.0. 
 
9.0 
STUDY CALENDARS 
 
 


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Revised 6/2/15 
Page 43 
Revised 4/17/14 
Version Date 6/2/15 
 
 
9.1 
Arm 1 (7+3) – Induction 
 
Pre 
Induction 
Re-Induction # 
 
£ 
  
Tx 
D1 
D2 
D3 
D4 
D5 
D6 
D7 
Wks 
2-4 
D1 
D2 
D3 
D4 
D5 
D6 
D7 
Wks 
2-4  
Prog 
FU 
REQUIRED STUDIES 
  
  
  
  
  
  
  
  
  
  
  
  
  
` 
  
  
  
  
  
History & Physical Exam & 
X 
X 
X 
X 
X 
X 
X 
Weight & Performance Status 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Toxicity Notation 
  
  
  
  
  
  
  
  
  
XΔ 
  
  
  
  
  
  
  
X 
  
LABORATORY STUDIES 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
CBC, Diff, Platelets & 
X 
X 
X 
X 
X 
X 
X 
Serum Creatinine % & 
X 
X 
X 
X 
X 
  
X 
Bilirubin % & 
X 
X 
X 
X 
X 
  
X 
SGOT/SGPT % & 
X 
X 
X 
X 
X 
  
X 
CNS Assessment % 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Disease Assessment/BM Asp/Bx # 
X 
  
  
  
  
  
  
  
X 
  
  
  
  
  
  
  
X 
X 
X 
Cytogenetics/FISH  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
  
SPECIMEN SUBMISSIONS 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Buccal Swabs/Donor Search ƒ 
 
X 
  
  
  
  
  
  
  
  
  
  
Peripheral Blood   
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bone Marrow Aspirate  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X-RAYS/SCANS 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
EKG  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
ECHO or MUGA  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 
TREATMENT 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
AraC 
  
X 
X 
X 
X  
X  
 X 
X  
  
X 
X 
X 
X 
X 
X 
X 
  
  
  
Daunorubicin   
  
X 
X 
X 
 
 
 
 
  
X 
X 
X 
 
 
 
 
  
  
  
# If Day 14 (± 3 days) marrow exam shows residual blasts, Re-Induction should be considered starting on Day 15 (± 3 days). If blasts are cleared, marrow 
 
should be repeated on Day 28 (± 3 days) to confirm CR or CRi. After CR, marrows will be obtained at the discretion of the treating physician for disease 
assessment. 
% Prior to starting treatment; baseline measurements do not affect eligibility (see Section 7.1). 
& Weekly, or more often if clinically indicated.  
ƒ Upon receipt of swab kit; see Sections 15.3 and 18.6. 
Δ Prior to beginning Re-Induction therapy. 
 See Section 15.2. 
 Alliance sites only, see Section 15.2b. 
£ After off protocol treatment or transplant all indicated assessments will be performed every 3 months for the first year, then every  
 
6 months for the second and third year, then annually until  5 years from initial registration.  Additional tests may be performed at the  
 
discretion of the treating physician. 


Revised 3/22/13 
Revised 11/19/13 
Revised 7/28/14 
S1203 
Revised 6/28/13 
Revised 4/17/14 
Revised 6/2/15 
Page 44 
 
Version Date 6/2/15 
 
 
9.2 
Arm 1 (7+3) – Consolidation 
 
  
Pre 
Consolidation (1 Cycle) ¶ 
  
£ 
 
  
Tx 
D1 
D2 
D3 
D4 
D5 
D6 
D7 
Wk2 
Wk3 
Wk4 
Prog 
FU 
REQUIRED STUDIES 
  
  
  
  
  
  
  
  
  
  
  
  
  
History & Physical Exam % & 
X 
  
  
  
  
  
  
  
 X 
 X 
 X 
X 
X 
Weight & Performance Status  
  
  
  
  
  
  
  
  
  
  
  
  
  
Toxicity Notation 
X 
  
  
  
  
  
  
  
  
  
  
X 
  
LABORATORY STUDIES 
  
  
  
  
  
  
  
  
  
  
  
  
  
CBC, Diff, Platelets & 
  
X 
X 
X 
X 
X 
Serum Creatinine & 
  
X 
X 
X 
  
X 
Bilirubin & 
  
X 
X 
X 
  
X 
SGOT/SGPT & 
  
X 
X 
X 
  
X 
Disease Assessment/                  
BM Asp/Bx #  
  
  
  
  
  
  
  
  
  
  
  
X 
X 
Cytogenics/FISH 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X-RAYS/SCANS 
  
  
  
  
  
  
  
  
  
  
  
  
  
EKG µ 
X 
  
  
  
  
  
  
  
  
  
  
  
  
ECHO or MUGA µ 
X 
  
  
  
  
  
  
  
  
  
  
 
 
TREATMENT 
  
  
  
  
  
  
  
  
  
  
  
  
  
AraC 
  
X 
  
X 
  
X 
  
  
  
  
  
  
  
 
#   After CR or CRi, marrows will be obtained at the discretion of the treating physician for disease assessment. 
%  Pre-study results do not determine eligibility.  
&   Weekly, or more often if clinically indicated. 
£   After off protocol treatment or transplant all indicated assessments will be performed every 3 months for the first year, then every  
 
6 months for the second and third year, then annually until  5 years from initial registration.  Additional tests may be performed at the  
 
discretion of the treating physician. 
µ  
Prior to Consolidation treatment, then as  indicated. 
¶  
Up to 4 cycles, or until transplant. 
 
Alliance sites only, see Section 15.2b. 


Revised 3/22/13 
Revised 11/19/13 
Revised 7/28/14 
S1203 
Revised 6/28/13 
Revised 4/17/14 
 
Page 45 
 
Version Date 6/2/15 
 
 
9.3 
Arm 2 (IA) – Induction 
 
Pre 
Induction 
Re-Induction # 
 
£ 
  
Tx 
D1 
D2 
D3 
D4 
D5 
D6 
D7 
Wks 
2-4 
D1 
D2 
D3 
D4 
D5 
D6 
D7 
Wks 
2-4 
Prog 
FU 
REQUIRED STUDIES 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
History & Physical Exam & 
X 
X 
X 
X 
X 
X 
X 
Weight & Performance Status 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Toxicity Notation 
  
  
  
  
  
  
  
  
  
XΔ 
  
  
  
  
  
  
  
X 
  
LABORATORY STUDIES 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
CBC, Diff, Platelets & 
X 
X 
X 
X 
X 
X 
X 
Serum Creatinine % & 
X 
X 
X 
X 
X 
  
X 
Bilirubin % & 
X 
X 
X 
X 
X 
  
X 
SGOT/SGPT % & 
X 
X 
X 
X 
X 
  
X 
CNS Assessment % 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Disease Assessment/ 
BM Asp/Bx # 
X 
  
  
  
  
  
  
  
X 
  
  
  
  
  
  
  
X 
X 
X 
Cytogenetics/FISH  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
SPECIMEN SUBMISSION 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Buccal Swabs/Donor Search ƒ 
 
X 
  
  
  
  
  
  
  
  
  
  
Bone Marrow Aspirate  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Peripheral Blood  
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X-RAYS/SCANS 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
EKG  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
ECHO or MUGA 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 
TREATMENT 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
AraC 
  
X 
X 
X 
X  
  
  
  
  
X 
X 
X 
X  
  
  
  
  
  
  
Idarubicin   
  
X 
X 
X 
 
  
  
  
  
X 
X 
X 
 
  
  
  
  
  
  
# If Day 28 (± 3 days) marrow exam shows residual blasts, Re-Induction should be considered starting on Day 29. After CR or CRi, marrows will  
  
be obtained at the discretion of the treating physician for disease assessment. 
% Prior to starting treatment; baseline measurements do not affect eligibility (see Section 7.1).  
& Weekly, or more often if clinically indicated.  
ƒ Upon receipt of swab kit; see Sections 15.3 and 18.6. 
Δ Prior to beginning Re-Induction therapy. 
 See Section 15.2. 
 Alliance sites only, see Section 15.2b. 
£   After off protocol treatment or transplant all indicated assessments will be performed every 3 months for the first year, then every  
 6 months for the second and third year, then annually until  5 years from initial registration.  Additional tests may be performed at the  
 
discretion of the treating physician. 


Revised 3/22/13 
Revised 11/19/13 
Revised 7/28/14 
S1203 
Revised 6/28/13 
Revised 4/17/14 
 
Page 46 
 
Version Date 6/2/15 
 
 
9.4 
Arm 2 (IA) – Consolidation 
 
  
Pre 
Consolidation (1 Cycle)  ¶ 
  
£ 
 
 
  
Tx 
D1 
D2 
D3 
D4 
D5 
D6 
D7 
Wk2 
Wk3 
Wk4 
Prog 
FU 
 
 
REQUIRED STUDIES 
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 
History & Physical Exam & % 
X 
  
  
  
  
  
  
  
 X 
X 
 X 
X 
X 
 
 
Weight & Performance Status 
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 
Toxicity Notation 
X 
  
  
  
  
  
  
  
  
  
  
X 
  
 
 
LABORATORY STUDIES 
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 
CBC, Diff, Platelets & 
  
X 
X 
X 
 
 
Serum Creatinine & 
  
X 
  
X 
 
 
Bilirubin & 
  
X 
  
X 
 
 
SGOT/SGPT & 
  
X 
  
X 
 
 
Disease Assessment/                  
BM Asp/Bx #  
  
  
  
  
  
  
  
  
  
  
  
X 
X 
 
 
Cytogenetics/FISH 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X-RAYS/SCANS 
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 
EKG µ 
X 
  
  
  
  
  
  
  
  
  
  
  
  
 
 
ECHO or MUGA µ 
X 
  
  
  
  
  
  
  
  
  
  
 
 
 
 
TREATMENT 
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 
AraC   
  
X 
X 
X  
  
  
  
  
  
  
  
  
  
 
 
Idarubicin 
  
X 
X 
 
  
  
  
  
  
  
  
  
  
 
 
#  After CR or CRi, marrows will be obtained at the discretion of the treating physician for disease assessment. 
% Pre-study results do not determine eligibility.  
&  Weekly, or more often if clinically indicated. 
£  After off protocol treatment or transplant all indicated assessments will be performed every 3 months for the first year, then every 
 
 6 months for the second and third year, then annually until  5 years from initial registration.  Additional tests may be performed at the  
 
discretion of the treating physician.  
µ  Prior to Consolidation treatment, then as indicated. 
¶  Up to 4 cycles, or until transplant. 
 
Alliance sites only, see Section 15.2b. 


Revised 3/22/13 
Revised 11/19/13 
Revised 7/28/14 
S1203 
Revised 6/28/13 
Revised 4/17/14 
Revised 6/2/15 
Page 47 
 
Version Date 6/2/15 
 
 
9.5 
Arm 3 (IA+V or IA) – Induction 
 
Pre 
Induction 
Re-Induction # 
 
£ 
 
Tx 
D1 
D2 
D3 
D4 
D5 
D6 
D7 
Wks 2-4 
D1 
D2 
D3 
D4 
D5 
D6 
D7 
Wks 2-4 
Prog 
FU 
REQUIRED STUDIES 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
History & Physical Exam & 
X 
X 
X 
X 
X 
X 
X 
Weight & Performance Status 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Toxicity Notation 
  
  
  
  
  
  
  
  
  
XΔ 
  
  
  
  
  
  
  
X 
  
LABORATORY STUDIES 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
CBC, Diff, Platelets & 
X 
X 
X 
X 
X 
X 
X 
Serum Creatinine % & 
X 
X 
X 
X 
X 
  
X 
Bilirubin % & 
X 
X 
X 
X 
X 
  
X 
SGOT/SGPT % & 
X 
X 
X 
X 
X 
  
X 
CNS Assessment % 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Disease Assessment/                   
BM Asp/Bx # 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
X 
Cytogenetics/FISH  
X 
 
 
 
 
 
 
 
 
  
  
  
  
  
  
  
  
X 
  
SPECIMEN SUBMISSION 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Buccal Swabs/Donor Search ƒ 
 
X 
  
  
  
  
  
  
  
  
  
  
Bone Marrow Aspirate  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Peripheral Blood Submission  
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X-RAYS/SCANS 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
EKG  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
ECHO or MUGA 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 
IA + V TREATMENT √ 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Vorinostat 
  
X 
X 
X 
  
  
  
  
  
X 
X 
X 
  
  
  
  
  
  
  
AraC 
  
  
  
  
X 
X 
X 
X  
  
  
  
  
X 
X 
X 
X  
  
  
  
Idarubicin   
  
  
  
  
X 
X 
X 
 
  
  
  
  
X 
X 
X 
 
  
  
  
IA TREATMENT √ 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
AraC 
  
X 
X 
X 
X  
  
  
  
  
X 
X 
X 
X  
  
  
  
  
  
  
Idarubicin   
  
X 
X 
X 
 
  
  
  
  
X 
X 
X 
 
  
  
  
  
  
  
# If Day 28 (± 3 days) marrow exam shows residual blasts, Re-Induction should be considered starting on Day 29. After CR or CRi, marrows will be obtained at 
the discretion of the treating physician for disease assessment. 
% Prior to starting treatment; baseline measurements do not affect eligibility (see Section 7.1).  
& Weekly, or more often if clinically indicated. 
£ After off protocol treatment or transplant all indicated assessments will be performed every 3 months for the first year, then every 6 months for the second and 
third year, then annually until 5 years from initial registration.  Additional tests may be performed at the discretion of the treating physician. 
ƒ Upon receipt of swab kit; see Sections 15.3 and 18.6. 
Δ Prior to beginning Re-Induction therapy. 
 See Section 15.2. 
 Alliance sites only, see Section 15.2b. 
√ Arm 3 was permanently closed to accrual, effective TBD. Patients previously randomized to Arm 3 may opt to continue medical treatment with IA or IA + V, 
and if so, must follow protocol and protocol data submission requirements. 


Revised 3/22/13 
Revised 11/19/13 
Revised 7/28/14 
S1203 
Revised 6/28/13 
Revised 4/17/14 
Revised 6/2/15 
Page 48 
 
Version Date 6/2/15 
 
 
9.6 
Arm 3 (IA+V or IA) - Consolidation 
 
  
Pre 
Consolidation (1 Cycle) ¶ 
  
£ 
 
 
  
Tx 
D1 
D2 
D3 
D4 
D5 
D6 
D7 
Wk2 
Wk3 
Wk4 
Prog 
FU 
 
 
REQUIRED STUDIES 
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 
History & Physical Exam & % 
X 
  
  
  
  
  
  
  
 X 
 X 
 X 
X 
X 
 
 
Weight & Performance Status 
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 
Toxicity Notation 
X 
  
  
  
  
  
  
  
  
  
  
X 
  
 
 
LABORATORY STUDIES 
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 
CBC, Diff, Platelets & 
  
X 
X 
X 
 
 
Serum Creatinine & 
  
X 
  
X 
 
 
Bilirubin & 
  
X 
  
X 
 
 
SGOT/SGPT & 
  
X 
  
X 
 
 
Disease Assessment/                  
BM Asp/Bx #  
  
  
  
  
  
  
  
  
  
  
  
X 
X 
 
 
Cytogenetics/FISH 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X-RAYS/SCANS 
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 
EKG µ 
X 
  
  
  
  
  
  
  
  
  
  
  
  
 
 
ECHO or MUGA µ 
X 
  
  
  
  
  
  
  
  
  
  
 
 
 
 
IA + V TREATMENT √ 
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 
Idarubicin 
  
  
  
  
X 
X 
  
  
  
  
  
  
  
 
 
AraC 
  
  
  
  
X 
X 
X 
  
  
  
  
  
  
 
 
Vorinostat 
  
X 
X 
X 
  
  
  
  
  
  
  
  
  
 
 
IA TREATMENT √ 
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 
AraC   
  
X 
X 
X  
  
  
  
  
  
  
  
  
  
 
 
Idarubicin 
  
X 
X 
 
  
  
  
  
  
  
  
  
  
 
 
 
#  After CR or CRi, marrows will be obtained at the discretion of the treating physician for disease assessment. 
%  Pre-study results do not determine eligibility.  
&  Weekly during Induction and Consolidation, or more often if clinically indicated. 
£ After off protocol treatment or transplant all indicated assessments will be performed every 3 months for the first year, then every 6 months for the second 
and third year, then annually until  5 years from initial registration.  Additional tests may be performed at the discretion of the treating physician. 
µ  Prior to Consolidation treatment, then as indicated. 
¶  Up to 4 cycles, or until transplant. 
 
Alliance sites only, see Section 15.2b. 
√ 
Arm 3 was permanently closed to accrual, effective TBD. Patients previously randomized to Arm 3 may opt to continue medical 
treatment with IA or IA + V, and if so, must follow protocol and protocol data submission requirements. 


Revised 3/22/13 
S1203 
 
Page 49 
 
Version Date 6/2/15 
 
 
 
10.0 
CRITERIA FOR EVALUATION AND ENDPOINT DEFINITIONS 
 
10.1  
Remission Definitions 
 
a.  
Morphologic complete remission (CR): ANC ≥ 1,000/mcl, platelet count ≥ 
100,000/mcl, < 5% bone marrow blasts, no Auer rods, no evidence of 
extramedullary disease. (No requirements for marrow cellularity, hemoglobin 
concentration). 
 
b.  
Morphologic complete remission with incomplete blood count recovery (CRi): 
Same as CR but ANC may be < 1,000/mcl or platelet count < 100,000/mcl. 
 
c.  
Partial remission (PR): ANC ≥ 1,000/mcl, platelet count > 100,000/mcl, and at 
least a 50% decrease in the percentage of marrow aspirate blasts to 5-25%, or 
marrow blasts < 5% with persistent Auer rods. 
 
10.2  
Treatment Failures 
 
Patients who fail to achieve CR, CRi or PR following Induction will be classified according 
to the type of failure: 
 
a.  
Resistant Disease: Patient survives ≥ 7 days following completion of initial 
treatment course and has persistent leukemia in the peripheral blood smear or 
bone marrow after completion of therapy. 
 
b.  
Aplasia: Patient survives ≥ 7 days following completion of initial treatment course 
then dies while cytopenic, with the last post-induction bone marrow aplastic to 
hypoplastic (i.e. < 20% cellularity) and without leukemic blasts. 
 
c.  
Indeterminate: 
 
1.  
Patient survives < 7 days after completion of initial treatment course. 
 
2.  
Patient survives ≥ 7 days following completion of initial treatment course 
then dies with no persistent leukemia in the peripheral smear but no 
post-induction bone marrow examination. 
 
10.3  
Relapse from CR or CRi 
 
Reappearance of leukemic blasts in the peripheral blood; or > 5% blasts in the bone 
marrow not attributable to another cause (e.g., recovery of normal cells following 
chemotherapy-induced aplasia); or appearance or reappearance of extramedullary 
disease. If there are no circulating blasts and no extramedullary disease and the bone 
marrow blast percentage is > 5% but ≤ 20%, then a repeat bone marrow performed at 
least 7 days after the first marrow examination and documenting bone marrow blast 
percentage is > 5% is necessary to establish relapse. 
 
10.4  
Event Free Survival (EFS) 
 
EFS is calculated for all patients from the date of initial registration on study until the first 
of the following events:  death from any cause, relapse from remission (CR or CRi) or 
completion of protocol Induction/Re-Induction therapy without documentation of CR or 
CRi.  Patients last known to be alive and in CR or CRi are censored at the date of last 
contact. 
 


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10.5 
Disease Free Survival (DFS) 
 
DFS is calculated for patients who have achieved a CR or CRi. DFS will be measured 
from the date of CR or CRi until relapse from CR or CRi for death from any cause. 
Observation is censored at the date of last follow-up for patients last known to be alive 
without report of relapse. 
 
10.6  
Time to Death 
 
Time to death calculated for all patients from date of registration to date of death due to 
any cause.  Patients last known to be alive are censored at date of last contact. 
 
10.7  
Performance Status 
 
Patients will be graded according to the Zubrod performance status scale. 
 
POINT  
DESCRIPTION 
 
0  
Fully active, able to carry on all pre-disease performance without restriction. 
 
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. 
 
2  
Ambulatory and capable of self-care but unable to carry out any work 
activities; up and about more than 50% of waking hours. 
 
3  
Capable of limited self-care, confined to bed or chair more than 50% of 
waking hours. 
 
4  
Completely disabled; cannot carry on any self-care; totally confined to bed or 
chair. 
 
11.0 
STATISTICAL CONSIDERATIONS 
 
11.1 
Accrual Goals  
 
Assuming 10% of registered patients will be ineligible, 784 registered patients will be 
needed to accrue 705 eligible patients (235 eligible patients per arm). 
 
Based on data from S0106 (SWOG’s most recent trial in this population), it is estimated 
that 418 patients will need to be registered in order to have 53 patients available for the 
transplant objective (assuming 10% of registered patients will be ineligible, 27% of 
eligible patients with be high-risk, and 54% of eligible high-risk patients will achieve CR).  
Given the estimated accrual rate, it is expected that it will take less than 2.5 years to 
accrue 418 patients. In contrast to S0106, S1203 allows patients with complete remission 
with incomplete blood count recovery (CRi) to register to consolidation (S0106 required 
patients to be in complete remission [CR] to register for consolidation).  Due to this 
difference, the accrual rate of high-risk patients in CR has been slower than expected 
based on S0106 data.  Rather than 13% of patients being eligible for the transplant 
objective (53/418), the observed rate has been approximately 9%.  Given the slower than 
expected accrual to this objective and the desire to have more precise estimates of 
outcomes after transplant, accrual to this objective will be open for all patients registered 
to the trial. 
 
If accrual to the randomization associated with the chemotherapy objective (primary 
objective) is stopped early due to efficacy or futility before 53 eligible patients are 
registered for the transplant objective (secondary objective), the trial will temporarily 
suspend accrual while a decision is made by the Study Chairs, the study statistician, 
CTEP, and the DSMC whether to close the trial or to amend the trial to omit 
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objective.  The decision will take into account the number of patients still needed to reach 
53 eligible patients registered for the transplant objective. 
 
11.2 
Primary Chemotherapy Objective 
 
The primary goal of this study is to determine whether EFS is improved with IA + 
vorinostat (IA+V) compared to IA or 7+3 for patients with AML.  
 
EFS estimates from the 7+3 arm of S0106 (SWOG’s most recent trial in this population) 
indicate that a proportion of patients may be long-term survivors of their disease, in the 
sense that they will not be observed to fail during the study follow-up.  A cure exponential 
mixture model fit to the 7+3 arm of S0106 estimated that 35% of patients were long-term 
survivors and that median EFS for patients who were not long-term survivors was 4.7 
months (null). (19) This survival model can be written S(t) = 0.35+0.65*exp(-λt), where 
S(t) denotes survival at time t and λ is the exponential hazard parameter that 
corresponds to a median of 4.7 months.  
 
Power and sample size were determined via simulation (5,000 replications) generating 
survival data from cure exponential mixture models.   
 
IA+V will be considered superior to IA or to 7+3 if EFS is improved with a hazard ratio 
(HR) of 1.46 from a proportional hazards model (alternative).  With a cure exponential 
model, an HR of 1.46 corresponds to increasing the proportion of long-term survivors 
from 35% to 45%, and increasing median EFS among patients who are not long-term 
survivors from 4.7 months to 7.1 months.  A 1:1:1 randomization is assumed with 4.5 
years of uniform accrual, and an additional year of follow-up after accrual is complete, 
with administrative censoring at that time. All analyses will be intent-to-treat among 
eligible patients. 
 
In addition to routine monitoring, five formal interim analyses will be performed.  The first 
two interim analyses will be based on the CR rates. The first analysis will check for harm 
and the second analysis will test for futility. It is assumed that the null CR rate is 68% 
(based on 7+3 arm of S0106) and the alternative CR rate is 78%. The third, fourth, and 
fifth interim analyses will be based the HRs comparing 7+3: IA+V and IA: IA+V from a 
proportional hazards model including covariates for the stratification factors. Interim 
analyses 3-5 will include both futility and efficacy analyses.  The final analysis will also be 
based on the HRs comparing 7:3 versus IA+V and IA versus IA+V from proportional 
hazards models including covariates for the stratification factors.  For interim and final 
analyses, two separate regression models will be fit to compare 1) 7:3 versus IA+V and 
2) IA versus IA+V. 
 
Up to five interim analyses will be completed. Each interim analysis will test both IA+V 
versus IA and IA+V versus 7+3. Early termination of an arm or the study will be 
considered if: 
 
1.  
Based on the first 60 patients on each arm (about 1 year after trial opens). 
 
a. 
If the proportion of CRs with IA+V is observed to be more than 8% less 
than the proportion of CRs on IA, early termination of the study will be 
considered. 
 
b. 
If the proportion of CRs with 1A+V is observed to be more than 8% less 
than the proportion of CRs in 7+3, early termination of the study will be 
considered. 
 


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2. 
Based on the first 100 patients on each arm (about 2 years after trial opens): 
 
a. 
if the proportion of CRs with IA+V is observed to be less than the 
proportion of CRs on IA, early termination of the study will be considered. 
 
b. 
if the proportion of CRs with IA+V is observed to be less than the 
proportion of CRs on 7+3, early termination of the study will be 
considered. 
 
3.   
At approximately 40% information (at 61 events on the IA arm, about 2.5 years 
after trial opens): 
 
a. 
if a two-sided test of the alternative hypothesis (HR=1.46) for IA: IA+V is 
rejected at the 0.05 level (futility test), early termination of the study will 
be considered. 
 
b. 
if a two-sided test of the alternative hypothesis (HR=1.46) for 7+3: IA+V 
is rejected at the 0.05 level (futility test), early termination of the study will 
be considered. 
 
c. 
if a two-sided test of the null hypothesis (HR=1) for IA: IA+V is rejected at 
the 0.001 level (efficacy test), early termination of the IA arm will be 
considered. 
 
d. 
if a two-sided test of the null hypothesis (HR=1) for 7+3: IA+V is rejected 
at the 0.001 level (efficacy test), early termination of the 7+3 arm will be 
considered. 
 
4.   
At approximately 60% information (at 91 events on the IA arm, about 3.5 years 
after the first patient is registered): 
 
a. 
if a two-sided test of the alternative hypothesis (HR=1.46) for IA: IA+V is 
rejected at the 0.02 level (futility test), early termination of the study will 
be considered. 
 
b. 
if a two-sided test of the alternative hypothesis (HR=1.46) for 7+3: IA+V 
is rejected at the 0.02 level (futility test), early termination of the study will 
be considered. 
 
c. 
if a two-sided test of the null hypothesis (HR=1) for IA: IA+V is rejected at 
the 0.001 level (efficacy test), early termination of the IA arm will be 
considered. 
 
d. 
if a two-sided test of the null hypothesis (HR=1) for 7+3: IA+V is rejected 
at the 0.001 level (efficacy test), early termination of the 7+3 arm will be 
considered. 
 
5. 
At approximately 80% information (at 121 events on the IA arm, about 4.5 years 
after the first patient is registered): 
 
a. 
if a two-sided test of the alternative hypothesis (HR=1.46) for IA: IA+V is 
rejected at the 0.02 level (futility test), early termination of the study will 
be considered. 
 
b. 
if a two-sided test of the alternative hypothesis (HR=1.46) for 7+3: IA+V 
is rejected at the 0.02 level (futility test), early termination of the study will 
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c. 
if a two-sided test of the null hypothesis (HR=1) for IA: IA+V is rejected at 
the 0.001 level (efficacy test), early termination of the IA arm will be 
considered. 
 
d. 
if a two-sided test of the null hypothesis (HR=1) for 7+3: IA+V is rejected 
at the 0.001 level (efficacy test), early termination of the 7+3 arm will be 
considered. 
 
The final analysis (at 100% information, 152 events on IA arm, or one year after the last 
patient is registered) will consist of two two-sided tests of the null hypothesis (HR=1) at 
the 0.045 level (7+3: IA+V and IA: IA+V). 
 
For the secondary objective of comparing the EFS of 7+3 versus IA, at the time of the 
final analysis (at 100% information, 152 events on the IA arm, or one year after the last 
patient is registered), a two-sided test of the hazard ratio of 7:3: IA (versus the null 
hypothesis of HR =1) will be done using a proportional hazards regression model with the 
stratification factors included as covariates. 
 
With 235 eligible patients per arm, if IA+V is efficacious (alternative), the probability the 
trial concludes IA+V is superior to IA is 80%, the probability the trial concludes IA+V is 
superior to 7+3 is 80%, and the probability the trial concludes IA+V is superior to at least 
one of IA and 7+3 is 87%.   
 
If IA+V has a CR rate of 78% and IA and 7+3 have CR rates of 68%, but EFS is the same 
and follows the null in all three arms, the probability the trial will incorrectly conclude that 
IA+V EFS is superior to IA or to 7+3 is less than 5% (type-1 error) or incorrectly conclude 
that IA+V EFS is superior to 7+3 is less than 5% (type-1 error). 
 
If IA+V, IA, and 7+3 all follow the null assumptions, the probability the trial will stop early 
for futility is 97% and the probability the trial will stop for futility within the first two years is 
74%. 
 
If there is an interim analysis with at least one significant harm or futility result, the trial 
will temporarily suspend accrual while a decision is made by the Study Chairs, the study 
statistician, and the DSMC whether to close the trial or to continue the trial with two arms, 
IA and 7+3.   
 
If the trial continues with the two arms IA and 7+3, interim monitoring will continue with 
the following schedule: 
 
1. 
Based on the first 100 patients on each arm, termination of the study will be 
considered: 
 
a. 
if the proportion of CRs with IA is observed to be less than the proportion 
of CRs on 7+3. 
 
2. 
At approximately 40% information (at 61 events on the 7+3 arm), termination of 
the study will be considered: 
 
a. 
if a two-sided test of the alternative hypothesis (HR=1.46) for 7+3: IA is 
rejected at the 0.05 level (futility test). 
 
b. 
if a two-sided test of the null hypothesis (HR=1) for 7+3: IA is rejected at 
the 0.01 level (efficacy test). 


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3. 
At approximately 60% information (at 91 events on the 7+3 arm), termination of 
the study will be considered: 
 
a. 
if a two-sided test of the alternative hypothesis (HR=1.46) for 7+3: IA is 
rejected at the 0.02 level (futility test). 
 
b. 
if a two-sided test of the null hypothesis (HR=1) for 7+3: IA is rejected at 
the 0.001 level (efficacy test). 
 
 
4. 
At approximately 80% information (at 121 events on the 7+3 arm), termination of 
the study will be considered: 
 
a. 
if a two-sided test of the alternative hypothesis (HR=1.46) for 7+3: IA is 
rejected at the 0.02 level (futility test). 
 
b. 
If a two-sided test of the null hypothesis (HR=1) for 7+3: IA is rejected at 
the 0.01 level (efficacy test) 
 
Additionally, the following will be performed: compare the 1-year, 2-year and 3-year EFS 
and OS rates between patients who receive standard 7+3 or IA to patients who receive 
IA + V; compare the complete response rate, DFS, and OS between patients who receive 
standard 7+3 therapy versus IA; and compare the 1-year, 2-year and 3-year EFS and OS 
rates between patients who receive standard 7+3 versus IA.  
 
11.3 
Transplant Objective 
 
The goal of the transplant objective is to determine whether it is possible to conduct 
allogeneic HCT on 60% or more of adults with high-risk AML in first complete remission 
(alternative).  If 40% or fewer of high-risk patients in CR can be transplanted, the 
proposed transplant support system will not be considered feasible (null).  A one-sided 
binomial test compared to the null transplant rate will be conducted. 
 
Fifty-three eligible high-risk patients in CR will provide 89% power for this test with a 
critical level of 4%  
 
11.4 
Translational Medicine Objective 
 
Objectives: 
 
1. 
To define the prevalence and prognostic implication of known AML-associated 
mutations. 
 
2. 
To evaluate the prognostic significance of histone H3 acetylation (measured pre-
treatment and at Day 3) among patients treated with vorinostat.  
 
3. 
To evaluate the prognostic significance of gammaH2Ax (measured pre-treatment 
and at Day 3). 
 
4. 
To evaluate the prognostic significance Nrf2 and CYYB mRNA levels (measured 
pre-treatment and at Day 3). 
 
5. 
To investigate potential predictive markers based on mRNA and miRNA 
expression. 
 
6. 
To investigate potential predictive markers based on DNA methylation. 


 
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The total sample size for S1203 is planned to be 705 eligible patients (235 eligible 
patients per arm).  Given historical specimen submission, it is expected that 90% of 
eligible patients will provide pre-treatment peripheral blood specimens (n=633 total, 
211/arm).  Historically SWOG has not requested Day 3 specimens, so all calculations will 
be conservatively done assuming that specimens will be received from 50% of patients 
(n=351 total, 117/arm).  If more patients have Day 3 specimens available, power for 
associated analyses will be higher. 
 
Objectives 1-4: Each biomarker will be binary. Overall survival (OS, primary endpoint), 
event-free survival (EFS), and relapse-free survival (RFS) will be estimated using the 
Kaplan-Meier method.  Univariate associations will be assessed with the log-rank test.  
Regression modeling will use the Cox model.  Associations with complete remission (CR) 
will be assessed using Fisher’s exact test and regression models will use logistic 
regression. Regression modeling will control for the known pre-treatment prognostic 
variables including age, performance status, white blood cell count, marrow blasts, 
cytogenetic risk, and FLT3-ITD and will stratify for treatment arm. 
 
Power calculations are provided for the overall survival endpoint.  In the following 
calculations, it is assumed (based on the most recent SWOG study in this population, 
S0106) that median OS for all patients is 3.4 years.  Following the design assumptions of 
S1203, it is assumed that patients will be accrued over a period of 4.5 years and that 
there will be at least one year of follow-up on all patients.  Calculations are done 
assuming a one-sided test with a significance level of 0.05.  Calculations for each 
objective are outlined below. 
 
Objective 1:  Calculations done for each gene.  For each gene patients will be classified 
as mutant (mut) or wild-type (WT). All genes will be tested in all patients with samples.  
Prevalence for each gene can be estimated within +/- 4%.  Historical prevalences are 
assumed for power calculations.  It is assumed that 633 patients will have pretreatment 
samples available and provide power for one-sided tests. 
 
• 
NPM1: Calculations assume 25% prevalence. If median OS is 3.1 years in the 
NPM1-WT cohort, this project will have 90% power to detect an improvement in OS 
to 4.7 years in the NPM-mut cohort (corresponds to a hazard ratio [mut/WT] of 1.52). 
 
• 
IDH1/2: Calculations assume 10% prevalence. If median OS is 2.1 years in the 
IDH1/2-mut cohort, this project will have 91% power to detect an improvement in OS 
to 3.6 years in the IDH1-WT cohort (corresponds to a hazard ratio [WT/mut] of 1.71) 
• 
TET2: Calculations assume 8% prevalence. If median OS is 2.1 years in the TET2-
mut cohort, this project will have 91% power to detect an improvement in OS to 3.58 
years in the TET2-WT cohort (corresponds to a hazard ratio [WT/mut] of 1.7). 
 
• 
DNMT3A: Calculations assume 20% prevalence. If median OS is 2.5 years in the 
TET2-mut cohort, this project will have 90% power to detect an improvement in OS to 
3.7 years in the TET2-WT cohort (corresponds to a hazard ratio [WT/mut] of 1.48). 
 
Objective 2:  Tests of histone H3 acetylation will only be done on patients on the 
vorinostat arm.  The biomarker will be binary (yes/no).  To be conservative, the study 
assumes that 211 patients will have pre-treatment samples and 117 patients will have 
Day 3 samples.  If more patients have Day 3 samples available, power for associated 
analyses will be higher. 
 


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At pre-treatment, if 25% of patients have histone H3 acetylation, and median OS is 2.95 
years among patients without histone H3 acetylation, this project will have 80% power to 
detect an improvement in OS to 5.6 years in the cohort with histone H3 acetylation 
(corresponds to a hazard ratio [yes/no] of 1.9). 
 
At Day 3, if 50% of patients have histone H3 acetylation, and median OS is 2.3 years 
among patients without histone H3 acetylation, this project will have 91% power to detect 
an improvement in OS to 5.25 years in the cohort with histone H3 acetylation 
(corresponds to a hazard ratio [yes/no] of 2.28). 
 
An exploratory analysis will be done on patients with both pretreatment and Day 3 
samples (assume 117 patients will have both).  OS will be estimated among the possible 
four groups of patients based on combinations of histone H3 acetylation at each time 
point (yes/yes, no/no, yes/no, no/yes). 
 
Objectives 3 and 4:  Tests of gammaH2Ax, Nrf2, and CYYB will be done all patients.  The 
biomarkers will be categorized into high versus low based on the observed median value 
of the data set.  The study assumes that 633 patients will have pre-treatment samples 
and 351 patients will have Day 3 samples.  One set power calculations is done assuming 
the same characteristics for each biomarker. 
 
At pre-treatment, if 25% of patients have low levels of the biomarker, and median OS is 
3.15 years among patients with low biomarker levels, this project will have 81% power to 
detect an improvement in OS to 4.5 years in the cohort with high biomarker levels 
(corresponds to a hazard ratio [high/low] of 1.42). 
 
At Day 3, if 50% of patients have low levels of the biomarker, and median OS is 2.75 
years among patients with low biomarker levels, this project will have 90% power to 
detect an improvement in OS to 4.3 years in the cohort with high biomarker levels 
(corresponds to a hazard ratio [high/low] of 1.56). 
 
An exploratory analysis will be done on patients with both pretreatment and Day 3 
samples (assume 351 patients will have both).  OS will be estimated among the possible 
four groups of patients based on combinations of each biomarker at each time point 
(high/high, low/low, high/low, low/high). 
 
Objectives 5 and 6:  Will use bioinformatics personnel and algorithms from the SAGE 
group based at FHCRC to build prediction models.  The models will be provided to a 
SWOG Leukemia Committee statistician to apply to validation data. 
 
11.5 
Data and Safety Monitoring Committee 
 
A Data and Safety Monitoring Committee will oversee the conduct of the study.  The 
Committee consists of four members from outside of the SWOG, 3 SWOG members, 3 
non-voting representatives from the National Cancer Institute (NCI), and the Group 
Statistician (non-voting).  The members of this Committee will receive confidential reports 
every 6 months from the SWOG Statistical Center, and will meet at the Group's bi-annual 
meetings as necessary.  The Committee will be responsible for decisions regarding 
possible termination and/or early reporting of the study. 
 
In addition to the above DSMC review, toxicity and accrual monitoring are done routinely 
by the Study Chair, study Statistician, and the Disease Committee Chair.  Endpoint 
monitoring is done by the study Statistician and Study Chair. Accrual reports are 
generated weekly, and formal toxicity reports are generated every 6 months.  In addition, 
the Statistical Center, Adverse Event Coordinator at the Operations Office, SAE 
Physician Reviewer, and Study Chair monitor toxicities on an ongoing basis. 


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12.0 
DISCIPLINE REVIEW 
 
Cytogenetics/FISH Review 
 
All patients registered to this study will undergo central cytogenetics/FISH review by the SWOG 
Leukemia Cytogenetics Committee.  The purpose of this review is to verify the cytogenetic 
diagnosis of acute myeloid leukemia and determination of risk status.  Diagnostic karyograms, 
FISH images and local cytogenetics and FISH reports and the S1203 Mutational Analysis and 
Cytogenetics Report Form (see Section 15.2) must be submitted within 28 days after registration 
via MediData Rave® (see Section 14.3).  Failure to submit these items will make the patient 
ineligible. 
 
Karyogram/FISH images (.ppt/.pptx, gif or .jpeg files) will be submitted as follows: 
 
• 
if only normal cells are present: submit two karyograms of the normal 
• 
if an abnormal clone is present: submit two karyograms of each abnormal clone 
• 
if a mixture of normal and abnormal clonal cells is present: only two karyograms representing 
each abnormal clone need to be submitted 
• 
If any non-clonal abnormalities (except random loss) are present: submit one karyogram of 
each non-clonal cell 
 
Institutional cytogenetics and FISH reports must be of diagnostic/pre-treatment bone marrow.  
Cytogenetics/FISH studies from peripheral blood will be accepted ONLY if marrow aspirations 
were dry tap. 
 
 
13.0 
REGISTRATION GUIDELINES 
 
13.1 
Registration Timing 
 
Patients must be registered prior to initiation of treatment (no more than one working day 
prior to planned start of treatment).  
 
NOTE:  If a patient was assigned a SWOG patient ID prior to registration, that patient ID 
must be used at the time of study registration.  For questions about entering a previously 
assigned patient ID please contact the SWOG Data Operations Center at 206/652-2267. 
 
13.2 
Investigator/Site Registration 
 
Prior to the recruitment of a patient for this study, investigators must be registered 
members of a Cooperative Group.  Each investigator must have an NCI investigator 
number and must maintain an “active” investigator registration status through the annual 
submission of a complete investigator registration packet to CTEP. 
 
a. 
CTEP Investigator Registration Procedures 
 
Food and Drug Administration (FDA) regulations and National Cancer Institute 
(NCI) policy require all investigators participating in any NCI-sponsored clinical 
trial to register and to renew their registration annually. 
 
Registration requires the submission of: 
 
• 
a completed Statement of Investigator Form (FDA Form 1572) with an 
original signature 
• 
a current Curriculum Vitae (CV) 
• 
a completed and signed Supplemental Investigator Data Form (IDF) 
• 
a completed Financial Disclosure Form (FDF) with an original 
signature 


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Fillable PDF forms and additional information can be found on the CTEP website 
at <http://ctep.cancer.gov/investigatorResources/investigator_registration.htm>.   
 
For questions, please contact the CTEP Investigator Registration Help Desk 
by email at <pmbregpend@ctep.nci.nih.gov>. 
 
b. 
CTEP Associate Registration Procedures 
 
The Cancer Therapy Evaluation Program (CTEP) Identity and Access 
Management (IAM) application is a web-based application intended for use by 
both Investigators (i.e., all physicians involved in the conduct of NCI-sponsored 
clinical trials) and Associates (i.e., all staff involved in the conduct of NCI-
sponsored clinical trials). 
 
Associates will use the CTEP-IAM application to register (both initial registration 
and annual re-registration) with CTEP and to obtain a user account. 
 
Investigators will use the CTEP-IAM application to obtain a user account only. 
(See CTEP Investigator Registration Procedures above for information on 
registering with CTEP as an Investigator, which must be completed before a 
CTEP-IAM account can be requested.) 
 
An active CTEP-IAM user account will be needed to access all CTEP and CTSU 
(Cancer Trials Support Unit) websites and applications, including the CTSU 
members’ website. 
 
Additional information can be found on the CTEP website at  
<http://ctep.cancer.gov/branches/pmb/associate_registration.htm>.  
For 
questions, please contact the CTEP Associate Registration Help Desk by 
email at <ctepreghelp@ctep.nci.nih.gov>. 
 
c. 
CTSU Registration Procedures 
 
Each investigator or group of investigators at a clinical site must obtain IRB 
approval for this protocol and submit IRB approval and supporting documentation 
to the CTSU Regulatory Office before they can be approved to enroll patients.  
Study centers can check the status of their registration packets by querying the 
Regulatory Support System (RSS) site registration status page of the CTSU 
members’ website by entering credentials at https://www.ctsu.org. For sites 
under the CIRB initiative, IRB data will automatically load to RSS. 
 
Note:  Sites participating on the NCI CIRB initiative and accepting CIRB approval 
for the study are not required to submit separate IRB approval documentation to 
the CTSU Regulatory Office for initial, continuing or amendment review.  This 
information will be provided to the CTSU Regulatory Office from the CIRB at the 
time the site’s Signatory Institution accepts the CIRB approval.  The Signatory 
site may be contacted by the CTSU Regulatory Office or asked to complete 
information verifying the participating institutions on the study.  Other site 
registration requirements (i.e., laboratory certifications, protocol-specific training 
certifications, or modality credentialing) must be submitted to the CTSU 
Regulatory Office or compliance communicated per protocol instructions. 
 
1. 
Downloading Site Registration Documents: 
 
 
Site registration forms may be downloaded from the S1203 protocol 
page located on the CTSU members’ website.  
▪ 
Go to https://www.ctsu.org and log in to the members’ area using 
your CTEP-IAM username and password 


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▪ 
Click on the Protocols tab in the upper left of your screen 
▪ 
Click on the SWOG link to expand, then select S1203. Click on 
the Site Registration Documents link. 
 
2. 
Requirements for S1203 Site Registration: 
 
▪ 
CTSU IRB Certification (for sites not participating via the NCI 
CIRB) 
▪ 
CTSU IRB/Regulatory Approval Transmittal Sheet (for sites not 
participating via the NCI CIRB) 
 
3. 
Submitting Regulatory Documents: 
 
Submit completed forms along with a copy of your IRB Approval and 
Model Informed Consent to the CTSU Regulatory Office, where they will 
be entered and tracked in the CTSU RSS.  
 
CTSU Regulatory Office 
1818 Market Street, Suite 1100 
Philadelphia, PA 19103 
Phone: 1-866-651-2878 
Fax: 215-569-0206 
E-mail: 
CTSURegulatory@ctsu.coccg.org 
(for 
regulatory 
document submission only) 
 
4. 
Checking Your Site’s Registration Status: 
 
Check the status of your site’s registration packets by querying the RSS 
site registration status page of the members’ section of the CTSU 
website.  (Note: Sites will not receive formal notification of regulatory 
approval from the CTSU Regulatory Office.) 
▪ 
Go to https://www.ctsu.org and log in to the members’ area using 
your CTEP-IAM username and password 
▪ 
Click on the Regulatory tab at the top of your screen 
▪ 
Click on the Site Registration tab 
▪ 
Enter your 5-character CTEP Institution Code and click on Go 
 
13.3 
OPEN Registration Requirements 
 
The individual registering the patient must have completed the appropriate SWOG 
Registration Worksheet.  The completed form must be referred to during the registration 
but should not be submitted as part of the patient data. 
 
Patient enrollment will be facilitated using the Oncology Patient Enrollment Network 
(OPEN).  OPEN is a web-based registration system available on a 24/7 basis.  To access 
OPEN, the site user must have an active CTEP-IAM account (check at < https://eapps-
ctep.nci.nih.gov/iam/index.jsp >) and a 'Registrar' role on either the LPO or participating 
organization roster. 
 
OPEN will also ask additional questions that are not present on the SWOG Registration 
Worksheet.  The individual registering the patient must be prepared to provide answers to 
the following questions: 
 
a. 
Institution CTEP ID 
 
b. 
Protocol Number 


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c. 
Registration Step 
 
d. 
Treating Investigator 
 
e. 
Credit Investigator 
 
f. 
Patient Initials 
 
g. 
Patient’s Date of Birth 
 
h. 
Patient SSN (SSN is desired, but optional.  Do not enter invalid numbers.) 
 
i. 
Country of Residence 
 
j. 
ZIP Code 
 
k. 
Gender (select one): 
• 
Female Gender 
• 
Male Gender 
 
l. 
Ethnicity (select one): 
• 
Hispanic or Latino 
• 
Not Hispanic or Latino 
• 
Unknown 
 
m. 
Method of Payment (select one): 
• 
Private Insurance 
• 
Medicare 
• 
Medicare and Private Insurance 
• 
Medicaid 
• 
Medicaid and Medicare 
• 
Military or Veterans Sponsored NOS 
• 
Military Sponsored (Including Champus & Tricare) 
• 
Veterans Sponsored 
• 
Self Pay (No Insurance) 
• 
No Means of Payment (No Insurance) 
• 
Other 
• 
Unknown 
 
n. 
Race (select all that apply): 
• 
American Indian or Alaska Native 
• 
Asian 
• 
Black or African American 
• 
Native Hawaiian or other Pacific Islander 
• 
White 
• 
Unknown 
 
13.4 
Registration Procedures 
 
a. 
All site staff will use OPEN to enroll patients to this study.  OPEN is integrated 
with the CTSU Enterprise System for regulatory and roster data and, upon 
enrollment, initializes the patient in the Rave database.  OPEN can be accessed 
at https://open.ctsu.org, from the OPEN tab on the CTSU members’ side of the 
website at https://www.ctsu.org, or from the OPEN Patient Registration link on 
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b. 
Prior to accessing OPEN site staff should verify the following: 
 
• 
All eligibility criteria have been met within the protocol stated timeframes 
and the affirmation of eligibility on the Registration Worksheet has been 
signed 
by 
the 
registering 
investigator 
or 
another 
investigator 
designate. Site staff should refer to Section 5.0 to verify eligibility. 
 
• 
All patients have signed an appropriate consent form and HIPAA 
authorization form (if applicable).  
 
  
c. 
Access requirements for OPEN: 
  
• 
Site staff will need to be registered with CTEP and have a valid and 
active CTEP-IAM account. This is the same account (user ID and 
password) used for the CTSU members' web site.  
 
• 
To perform registrations, the site user must have been assigned the 
'Registrar' role on the SWOG or CTSU roster:  
 
1. If you are a SWOG member, to perform registrations on SWOG 
protocols you must have an equivalent 'Registrar' role on the SWOG 
roster.  Role assignments are handled through SWOG.  
 
2. If you are not a SWOG member, to perform registrations on SWOG 
protocols you must have the role of Registrar on the CTSU roster. 
Site and/or Data Administrators can manage CTSU roster roles via 
the new Site Roles maintenance feature under RSS on the CTSU 
members' web site. This will allow them to assign staff the 
"Registrar" role.  
 
Note:  The OPEN system will provide the site with a printable confirmation of 
registration and treatment information.   Please print this confirmation for your 
records.   
 
d. 
Further instructional information is provided on the OPEN tab of the CTSU 
members’ side of the CTSU website at https://www.ctsu.org or at 
https://open.ctsu.org.  For any additional questions contact the CTSU Help Desk 
at 1-888-823-5923 or ctsucontact@westat.com. 
 
13.5 
Exceptions to SWOG Registration Policies will Not be Permitted 
 
a. 
Patients must meet all eligibility requirements. 
 
b. 
Institutions must be identified as approved for registration. 
 
c. 
Registrations may not be cancelled. 
 
d. 
Late registrations (after initiation of treatment) will not be accepted. 
 
14.0 
DATA SUBMISSION SCHEDULE 
 
14.1 
Data Submission Requirement 
 
Data must be submitted according to the protocol requirements for ALL patients 
registered, regardless of Group affiliation, whether or not assigned treatment is 
administered, including patients deemed to be ineligible.  Patients for whom 
documentation is inadequate to determine eligibility will generally be deemed ineligible. 


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14.2 
Master Forms 
 
Master forms can be found on the protocol abstract page on the SWOG website 
(www.swog.org) and (with the exception of the sample consent form and the Registration 
Worksheet) must be submitted on-line via the Web; see Section 14.3a for details.   
 
14.3 
Data Submission Procedures 
 
a. 
Data collection for this study will be done exclusively through the Medidata 
Rave® clinical data management system. Access to the trial in Rave is granted 
through the iMedidata application to all persons with the appropriate roles 
assigned in Regulatory Support System (RSS). To access Rave via iMedidata, 
you must have an active CTEP-IAM account (check at https://eapps-
ctep.nci.nih.gov/iam/index.jsp) and the appropriate Rave role (Rave CRA, Read-
Only, Site Investigator) on either the LPO or participating organization roster at 
the enrolling site. 
 
Upon initial site registration approval for the study in RSS, all persons with Rave 
roles assigned on the appropriate roster will be sent a study invitation e-mail from 
iMedidata. To accept the invitation, site users must log into the Select Login 
(https://login.imedidata.com/selectlogin) using their CTEP-IAM user name and 
password, and click on the “accept” link in the upper right-corner of the iMedidata 
page. Please note, site users will not be able to access the study in Rave until all 
required Medidata and study specific trainings are completed. Trainings will be in 
the form of electronic learnings (eLearnings), and can be accessed by clicking on 
the link in the upper right pane of the iMedidata screen. 
 
Users that have not previously activated their iMedidata/Rave account at the time 
of initial registration approval for the study in RSS will also receive a separate 
invitation from iMedidata to activate their account. Account activation instructions 
are located on the CTSU website, Rave tab under the Rave resource materials 
(Medidata Account Activation and Study Invitation Acceptance). Additional 
information on iMedidata/Rave is available on the CTSU members’ website 
under the Rave tab at www.ctsu.org/RAVE/ or by contacting the CTSU help Desk 
at 1-888-823-5923 or by e-mail at ctsucontact@westat.com 
 
b. 
You may also access Rave® via the SWOG CRA Workbench.  Go to the SWOG 
web site (http://swog.org) and logon to the Members Area using your SWOG 
Roster ID Number and password. After you have logged on, click on 
Workbenches, then CRA Workbench to access the home page for the CRA 
Workbench and follow the link to Rave® provided in the left-hand navigation 
panel. 
 
To access the CRA Workbench the following must be done (in order): 
 
1. 
You are entered into the SWOG Roster and issued a SWOG Roster ID 
Number, 
2. 
You are associated as an investigator or CRA/RN at the institution where 
the patient is being treated or followed,  
3. 
Your Web User Administrator has added you as a web user and has 
given you the appropriate system permissions to view data for that 
institution. 
 
For assistance with points 1 and 2 call the Operations Office at 210/614-8808.  
For point 3, contact your local Web User Administrator (refer to the "Who is my 
Web User Administrator?" function on the swog.org Members logon page).  


 
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For difficulties with the CRA Workbench, please email 
technicalquestion@crab.org. 
 
c. 
Institutions participating through the Cancer Trials Support Unit (CTSU) please 
refer to the CTSU Participation Table on Page 3. 
 
14.4 
Data Submission Overview and Timepoints 
 
a. 
WITHIN 7 DAYS AFTER INITIAL REGISTRATION (STEP 1) 
 
Submit the following: 
 
Onstudy Form 
 
Pathology Report 
 
Radiology reports from all scans performed to assess disease at baseline 
 
See Section 15.0 for specimen submission requirements. 
 
b. 
WITHIN 28 DAYS AFTER INITIAL REGISTRATION (STEP 1) 
 
Submit the following: 
 
Institutional Cytogenetics and FISH Reports from lab 
 
Karyogram Images 
 
Mutational Analysis and Cytogenetic Report Form 
 
c. 
WITHIN 14 DAYS AFTER COMPLETION OF INDUCTION, RE-INDUCTION 
AND EACH CYCLE OF CONSOLIDATION TREATMENT 
 
Submit the following: 
 
S1203 Treatment Form 
 
S1203 Adverse Event Summary Form 
 
d. 
WITHIN 14 DAYS AFTER EACH RESPONSE ASSESSMENT 
 
Submit the following: 
 
AML Disease Assessment Form documenting results from the assessment 
 
Pathology Report 
 
If bone marrow is performed; bone marrow report, flow cytometric report and 
cytogenetic report, as applicable. 
 
e. 
WITHIN 
14 
DAYS 
AFTER 
GOING 
OFF 
INDUCTION/RE-INDUCTION 
TREATMENT 
 
Submit the Off Treatment Notice indicating off treatment for Step 1 
 
 


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f. 
(HIGH RISK PATIENTS) EVERY 3 MONTHS FOR THE FIRST YEAR OR UNTIL 
TRANSPLANT 
 
1. 
Submit the S1203 High Risk Transplant Form if HTC performed and not 
previously reported. 
 
OR 
 
2. 
Submit the S1203 High Risk Follow-Up Form if HTC not performed but 
may be done in the future. 
 
g. 
WITHIN 14 DAYS AFTER REGISTRATION FOR CONSOLIDATION (STEP 2) 
 
Submit the S1203 Consolidation Eligibility Form 
 
h. 
WITHIN 14 DAYS AFTER GOING OFF CONSOLIDATION TREATMENT 
 
Submit the Off Treatment Notice indicating off treatment for Step 2 
 
i. 
WITHIN 14 DAYS AFTER PROGRESSION/RELAPSE 
 
Submit the AML Disease Assessment Form (if the patient was still on protocol 
treatment) or Leukemia Follow-Up Form (if the patient was off protocol treatment) 
documenting date, site and method for determining progression/relapse. 
 
j. 
EVERY 3 MONTHS FOR THE FIRST YEAR, EVERY 6 MONTHS FOR THE 
SECOND AND THIRD YEARS, THEN ANNUALLY UNTIL FIVE YEARS FROM 
THE INITIAL REGISTRATION 
 
Submit the following: 
 
Follow-Up Form 
 
Leukemia Late Effects Form (if prior to treatment for progression or relapse or a 
second primary and prior to non-protocol treatment, the patient experiences any 
severe [≥ Grade 3] long-term toxicity that has not previously been reported) 
 
k. 
WITHIN 4 WEEKS AFTER KNOWLEDGE OF DEATH 
 
Submit the Notice of Death and a final S1203 Treatment Form and S1203 
Adverse Event Summary Form (if the patient was still on protocol treatment) or 
Leukemia Follow-Up Form (if the patient was off protocol treatment) documenting 
death information. 
 


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15.0 
SPECIAL INSTRUCTIONS 
 
Specimen Submission Overview 
 
 
SWOG (and other 
Groups not affiliated 
with ECOG-ACRIN or 
Alliance) 
ECOG-ACRIN 
Alliance 
Translational 
Medicine  
via SWOG to Lab 
#200 (Section 15.1) 
via SWOG to Lab 
#200 (Section 15.1) 
via SWOG to Lab 
#200 (Section 15.1) 
 
AND 
 
Prior to 1/15/14:  
CALGB 20202 
(Section 15.5b) 
As of 3/1/14:  
Temporarily Closed 
Cytogenetic    
Local CLIA-approved 
laboratory (Section 
15.2) 
 
Local CLIA-approved 
laboratory (Section 
15.2) 
Prior to 7/1/14 
CALGB-8461 (Section 
15.2b) 
As of 7/1/14  
Local CLIA-approved 
laboratory (Section 
15.2) 
HLA Typing 
CIBMTR (Section 
15.3) 
CIBMTR (Section 
15.3) 
CIBMTR (Section 
15.3) 
Banking 
via SWOG to Lab 
#200 (Section 15.2) 
Prior to 1/15/14:  
E3903 (Section 15.4) 
As of 1/15/14: via 
SWOG to Lab #200 
(Section 15.2) 
Prior to 3/1/14:  
CALGB 9665 (Section 
15.5c) 
As of 3/1/14:  CALGB 
9665 Temporarily 
Closed; submit via 
SWOG to Lab #200 
(Section 15.2) 
 
All sites, regardless of Group affiliation, must submit specimens for protocol-specific translational 
medicine as outlined in Section 15.1 and for cytogenetic risk analysis as outlined in Section 15.2. 
Because these specimens are being used to meet protocol objectives (See Sections 1.1b, 1.2f 
and 1.3h), these submissions are to be prioritized over Group-specific additional 
correlative specimen submissions outlined in Sections 15.4 and 15.5. 
 
15.1 
Correlative Studies and Banking (REQUIRED FOR ALL GROUPS) 
 
Specimens for correlative studies must be submitted to the SWOG Specimen Repository 
– Leukemia Division, Lab #200. (Required) Indicated correlative studies to be performed 
when funding is finalized. 
 
a.  
Specimens (peripheral blood and bone marrow aspirate) must be submitted at 
the following times (see Section 9.0): 
 
1. 
Peripheral blood 
 
a. 
Pretreatment (within 28 days prior to registration) 
 


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b. 
After treatment on Day 3* 
 
* If day 3 peripheral blood draw falls on a weekend or holiday making 
overnight shipment impossible, blood should be held in a refrigerator 
(4°C) until specimen can be shipped.  Blood should be stored in 
purple top EDTA tubes or in the institution’s prepared shipping media 
tubes.  Proper storage conditions ensure specimen viability when 
shipment will be delayed.  Reminder:  Specimens can be received by 
the repository on Saturdays. 
 
2. 
Bone marrow aspirate 
 
a. 
Pretreatment (within 28 days prior to registration)* 
 
* If the pre-treatment/diagnostic bone marrow aspiration is a dry tap, 
then an additional 25 ml of blood can be submitted in place of bone 
marrow aspirate.  If there is not enough bone marrow remaining after 
diagnostic testing to submit marrow, or the pre-treatment/diagnostic 
bone marrow is not available for submission for any other reason, and 
if the peripheral blood absolute blast count is ≥ 1,000 blasts per 
microliter, then an additional 25 ml of peripheral blood can be 
submitted in place of a repeat bone marrow aspirate. 
 
b. 
Specimen collection and submission instructions can be accessed on the SWOG 
Specimen Submission webpage 
(https://swog.org/members/clinicaltrials/specimens/LeuSpecimens.asp). 
 
c. 
Specimen collection kits are not being provided for this submission; sites will use 
institutional supplies. 
 
d. 
Residual specimens will be banked at the repository for future research only with 
patient consent. 
 
NOTE:  In instances when a pre-treatment specimen must be submitted before the 
patient is consented to S1203, sites may consent patients to specimen submission only 
using local IRB approved specimen submission consent forms.  For sites that do not 
have local specimen submission consents, a template has been included in Appendix 
18.9.  Please note the requirement in the consent instructions for sites to obtain a SWOG 
patient ID from the Data Operations Center (206/652-2267) to be used on the specimen 
label. 
 
15.2  
Cytogenetics and FISH (REQUIRED FOR ALL PATIENTS) 
 
Specimens for cytogenetic (and FISH if possible) analysis must be submitted to the site’s 
preferred local CLIA-approved laboratory, regardless of Group affiliation.  (Required) 
 
a. 
Diagnostic/pre-treatment specimens (bone marrow aspirate, or peripheral blood if 
dry tap) obtained within 28 days prior to registration must be submitted for 
cytogenetic (and FISH if possible) analysis.  Use of SWOG approved laboratories 
is encouraged, but not mandatory. 
 
b. 
Specimen collection and submission instructions and a list of approved 
laboratories can be accessed on the SWOG Cytogenetics webpage 
(www.swog.org/Members/ClinicalTrials/Specimens/Cytogenetics.asp).  
 
 


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c. 
The S1203 Cytogenetics Lab Report Form must be submitted to the laboratory 
along with the specimen. The laboratory will then return the completed form with 
the results. The lab will also need to send .ppt/.pptx, .gif or .jpeg files of the 
karyograms for the institution. E-mail contact information for the Data Manager 
must be provided to the lab performing the cytogenetics studies. The Institution 
will complete the Mutational Analysis and Cytogenetics Report Form Medidata 
Rave® using the information and ppt/pptx/jpeg/gif files provided by the lab. 
 
NOTE:  Only abnormal FISH results should have images submitted; submission 
of normal FISH images is not necessary. 
 
 
 


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15.3 
Buccal Swab for Transplant Donor Identification (REQUIRED FOR ALL PATIENTS) 
 
Buccal swab specimens for use in HLA typing for donor identification must be submitted 
to the Center for International Blood and Marrow Transplant Research (CIBMTR).  
(Required) 
 
a.     
Specimens (buccal swabs) must be collected at the time of registration (as soon 
as specimen collection kit is received) for every patient enrolled and submitted 
per the instructions provided in the specimen collection kit within 14 days after 
kit receipt.  A shipping label will be provided as part of the kit. 
 
b. Specimens collection kits are provided for this submission.  The SWOG Transplant 
Investigator will be notified at the time of patient registration, and will prompt the CIBMTR 
to ship kits directly to the registering site.  Kits will consist of 4 cotton swabs, label set for 
the swabs, collection/submission instructions, unrelated donor search request form 
(capturing information required to optimize the search process including weight, sex, 
race/ethnicity and birth month/year) and a postage paid envelope to ship the specimens 
to CIBMTR.  Specimens should be submitted at the time of collection per the provided 
instructions.  For a detailed description of the transplant donor search process, see 
Appendix 18.6. 
 
c.  
Residual specimens and specimens from patients who are not determined to 
have high risk disease will be destroyed. 
 
NOTE:  This specimen submission will NOT utilize the SWOG Specimen Tracking 
System. 
 


 
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16.0 
ETHICAL AND REGULATORY CONSIDERATIONS 
 
The following must be observed to comply with Food and Drug Administration regulations for the 
conduct and monitoring of clinical investigations; they also represent sound research practice: 
 
Informed Consent 
 
The principles of informed consent are described by Federal Regulatory Guidelines (Federal 
Register Vol. 46, No. 17, January 27, 1981, part 50) and the Office for Protection from Research 
Risks Reports:  Protection of Human Subjects (Code of Federal Regulations 45 CFR 46).  They 
must be followed to comply with FDA regulations for the conduct and monitoring of clinical 
investigations. 
 
Institutional Review 
 
This study must be approved by an appropriate institutional review committee as defined by 
Federal Regulatory Guidelines (Ref. Federal Register Vol. 46, No. 17, January 27, 1981, part 56) 
and the Office for Protection from Research Risks Reports:  Protection of Human Subjects (Code 
of Federal Regulations 45 CFR 46). 
 
Drug Accountability   
 
An investigator is required to maintain adequate records of the disposition of investigational drugs 
according to procedures and requirements governing the use of investigational new drugs as 
described in the Code of Federal Regulations 21 CFR 312.  
 
Publication and Industry Contact 
 
The agent (hereinafter referred to as "Agent"), vorinostat, used in this protocol is provided to the 
NCI under a Clinical Trials Agreement (CTA) between Merck (hereinafter referred to as 
"Collaborator") and the NCI Division of Cancer Treatment and Diagnosis.  Therefore, the 
following obligations/guidelines in addition to the provisions in the "Intellectual Property Option to 
Collaborator" 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_proeprty) 
contained 
within the terms of award apply to the use of the Agent in this study: 
 
1. 
Agent may not be used outside the scope of this protocol, nor can Agent be transferred 
or licensed to any party not participating in the clinical study.  Collaborator data for Agent 
are confidential and proprietary to the Collaborator and should be maintained as such by 
the investigators.  The protocol documents for studies utilizing investigational Agents 
contain confidential information and should not be shared or distributed without the 
permission of the NCI.  If a copy of this protocol is requested by a patient or patient’s 
family member participating on the study, the individual should sign a confidentiality 
agreement. A suitable model agreement can be downloaded from: http://ctep.cancer.gov. 
 
2. 
For a clinical protocol where there is an investigational Agent used in combination with 
another investigational Agent, each the subject of different CTAs or CRADAs, the access 
to and use of data by each Collaborator shall be as follows (data pertaining to such 
combination use shall hereinafter be referred to as "Multi-Party Data"): 
 
a. 
NCI must provide all Collaborators with written notice regarding the existence 
and nature of any agreements governing their collaboration with NIH, the design 
of the proposed combination protocol, and the existence of any obligations which 
would tend to restrict NCI's participation in the proposed combination protocol. 
 
b. 
Each Collaborator shall agree to permit use of the Multi-Party Data from the 
clinical trial by any other Collaborator to the extent necessary to allow said other 
Collaborator to develop, obtain regulatory approval or commercialize its own 
investigational Agent. 
 
 


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c. 
Any Collaborator having the right to use the Multi-Party Data from these trials 
must agree in writing prior to the commencement of the trials that it will use the 
Multi-Party 
Data 
solely 
for 
development, 
regulatory 
approval, 
and 
commercialization of its own investigational Agent. 
 
3. 
Clinical Trial Data and Results and Raw Data developed under a Collaborative 
Agreement will be made available exclusively to Collaborator(s), the NCI, and the FDA, 
as appropriate and unless additional disclosure is required by law or court order as 
described in the IP option Collaborator  
 
 (http://ctep.cancer.gov/industryCollaborations2/intellectual_proeprty.htm).  
 
Additionally, all Clinical Data and Results and Raw Data will be collected, used and 
disclosed consistent with all applicable federal statutes and regulations for the protection 
of human subjects, including, if applicable, the Standards for Privacy of Individually 
Identifiable Health Information set forth in 45 C.F.R. Part 164. 
 
4. 
When a Collaborator wishes to initiate a data request, the request should first be sent to 
the NCI, who will then notify the appropriate investigators (Group Chair for cooperative 
group studies, or PI for other studies) of Collaborator's wish to contact them. 
 
5. 
Any data provided to the Collaborator for Phase III studies must be in accordance with 
the guidelines and policies of the responsible Data Monitoring Committee (DMC), if there 
is a DMC for this clinical trial. 
 
6. 
Any manuscripts reporting the results of this clinical trial must be provided to CTEP for 
immediate delivery to the Collaborator for advisory review and comment prior to 
submission for publication.  Collaborator will have 30 days from the date of receipt for 
review.  Collaborator shall have the right to request that publication be delayed for up to 
an additional 30 days in order to ensure that Collaborator's confidential and proprietary 
data, in addition to the Collaborator's intellectual property rights, are protected.  Copies of 
abstracts must be provided to CTEP for forwarding to the Collaborator for courtesy 
review as soon as possible and preferably at least three (3) days prior to submission, but 
in any case, prior to presentation at the meeting or publication in the proceedings.  Press 
releases and other media presentation must also be forwarded to CTEP prior to release.  
Copies of any manuscript, abstract and/or press release/media presentation should be 
sent to: 
 
E-mail:  ncicteppubs@mail.nih.gov  
 
The Regulatory Affairs Branch will then distribute them to the Collaborator.  No 
publication, manuscript or other form of public disclosure shall contain any of the 
Collaborator's confidential/proprietary information. 
 
Monitoring 
 
This study will be monitored by the Clinical Data Update System (CDUS) Version 3.0.  
Cumulative CDUS data will be submitted quarterly to CTEP by electronic means.  Reports are 
due January 31, April 30, July 31 and October 31. 
 
Confidentiality 
 
Please note that the information contained in this protocol is considered confidential and should 
not be used or shared beyond the purposes of completing protocol requirements until or unless 
additional permission is obtained. 
 
 
 


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16.1 
Adverse Event Reporting Requirements  
 
a. 
Purpose 
 
Adverse event data collection and reporting, which are required as part of 
every clinical trial, are done to ensure the safety of patients enrolled in the 
studies as well as those who will enroll in future studies using similar agents. 
Adverse events are reported in a routine manner at scheduled times during a 
trial. (Directions for routine reporting are provided in Section 14.0.) 
Additionally, certain adverse events must be reported in an expedited manner 
to allow for more timely monitoring of patient safety and care. The following 
guidelines describe expedited adverse event reporting for this protocol. See 
also Appendix 18.1 for general and background information about expedited 
reporting. 
 
b. 
Reporting method 
 
This study requires that expedited adverse event reporting use CTEP’s 
Adverse Event Reporting System (CTEP-AERS).  The NCI’s guidelines for 
CTEP-AERS can be found at 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_
events.htm.  
 
c. 
When to report an event in an expedited manner 
 
Some adverse events require 24-hour notification (refer to Table 16.1) via 
CTEP-AERS.    
When the adverse event requires expedited reporting, submit the report within 
the number of calendar days of learning of the event, as specified in Table 
16.1 or 16.2, as applicable.  
 
In the rare event when internet connectivity is disrupted a 24-hour notification 
is made to NCI by telephone at 301-897-7497.  An electronic report MUST be 
submitted immediately upon re-establishment of internet connection.  Please 
note that all paper CTEP-AERS forms have been removed from the CTEP 
website and will NO LONGER be accepted. 
 
Any supporting documentation requested by CTEP should be submitted in 
accordance with instructions provided by the CTEP-AERS system. 
 
d. 
Other recipients of adverse event reports 
 
The SWOG Operations Office will forward reports and documentation to the 
appropriate regulatory agencies and drug companies as required. 
 
Adverse events determined to be reportable to the Institutional Review Board 
responsible for oversight of the patient must be reported according to local 
policy and procedures. 


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e. 
Expedited reporting for investigational agents 
 
Expedited reporting is required if the patient has received at least one dose of 
the investigational agent(s) as part of the trial. Reporting requirements are 
provided in Table 16.1. The investigational agent used in Arm 3 of this study 
is vorinostat. If there is any question about the reportability of an adverse 
event or if on-line CTEP-AERS cannot be used, please telephone or email the 
SAE Specialist at the Operations Office, 210/614-8808 or adr@swog.org, 
before preparing the report. 


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Table 16.1: 
Late Phase 2 and Phase 3 Studies:  Expedited Reporting Requirements for Adverse Events 
that Occur on Studies under a CTEP IND within 30 Days of the Last Administration of the 
Investigational Agent/Intervention1 Vorinostat (Arm 3) 
 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or 
not they are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
 
 An adverse event is considered serious if it results in ANY of the following outcomes:   
1) 
Death 
2) 
A life-threatening adverse event  
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 
24 hours  
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions  
5) 
A congenital anomaly/birth defect.  
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon medical judgment, they may jeopardize 
the patient or subject and may require medical or surgical intervention to prevent one of the outcomes 
listed in this definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via 
CTEP-AERS within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 
Timeframes 
Grade 2 
Timeframes 
Grade 3 Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 
Calendar 
Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
10 Calendar Days 
NOTE:  Protocol specific exceptions to expedited reporting of serious adverse events are found in the 
Specific Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR or [Section 
16.1f.]  
Expedited AE reporting timelines are defined as: 
o 
“24-Hour; 5 Calendar Days” - The AE must initially be reported via CTEP-AERS within 24 hours of 
learning of the AE, followed by a complete expedited report within 5 calendar days of the initial 
24-hour report. 
 
o 
“10 Calendar Days” - A complete expedited report on the AE must be submitted within 10 
calendar days of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
 
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• All Grade 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
• Grade 3 adverse events 
 
May 5, 2011 
 


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f. 
Additional Instructions or Exceptions to CTEP-AERS Expedited 
Reporting Requirements for Late Phase 2 and Phase 3 Studies Utilizing 
an Agent under a CTEP-IND: 
 
1) 
Group-specific instructions. 
 
Submission of the on-line CTEP-AERS report plus any necessary 
amendments generally completes the reporting requirements In 
addition, you may be asked to submit supporting clinical data to 
the SWOG Operations Offices in order to complete the evaluation 
of the event.  If requested, the supporting data should be sent 
within 5 calendar days by fax to 210-614-0006.  Supporting 
clinical data submitted should include: 
• 
Printed copy of the first page of the CTEP-AERS Report. 
• 
Copies of clinical sourced documentation of the event. 
• 
If applicable, and they have not yet been submitted to the 
SWOG Data Operations Center copies of Off Treatment 
Notice and/or Notice of Death. 
 
2) 
For this study, the adverse events listed below do not require 
expedited reporting via CTEP-AERS: 
• 
≤ Grade 4 myelosuppression 
• 
≤ Grade 4 fatigue 
• 
≤ Grade 4 infection 
 
g. 
Expedited reporting for commercial agents 
 
Commercial reporting requirements are provided in Table 16.2. The 
commercial agent(s) used in this study are AraC, daunorubicin and idarubicin. 
If there is any question about the reportability of an adverse event, please 
telephone or email the SAE Program at the Operations Office, 210-614-8808 
or adr@swog.org, before preparing the report. 
 


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Table 16.2. Expedited reporting requirements for adverse events experienced by 
patients on this study who have received only the commercial drugs listed in 
16.1g above within 30 days of the last administration of the commercial 
agent(s). 
 
ATTRIBUTION 
 
Grade 4 
 
Grade 5a 
Unexpected 
Expected 
Unexpected 
Expected 
Unrelated or 
Unlikely 
 
 
CTEP-
AERS 
CTEP-
AERS 
Possible, 
Probable, 
Definite 
CTEP-AERS 
 
CTEP-
AERS 
CTEP-
AERS 
CTEP-AERS:  Indicates an expedited report is to be submitted via NCI CTEP-AERS within 
10 calendar days of learning of the eventb. 
a This includes all deaths within 30 days of the last dose of treatment with a commercial 
agent(s), regardless of attribution.  Any death that occurs more than 30 days after the last 
dose of treatment with a commercial agent(s) and is attributed (possibly, probably, or 
definitely) to the agent(s) and is not due to cancer recurrence must be reported according 
to the instructions above. 
 
b Submission of the on-line CTEP-AERS report plus any necessary amendments generally 
completes the reporting requirements. You may, however, be asked to submit supporting 
clinical data to the Operations Office in order to complete the evaluation of the event. If 
requested, the specified data should be sent within 5 calendar days by fax to 210-614-
0006.  
 
 
h. 
Reporting Secondary Malignancies, including AML/ALL/MDS 
 
1. 
A secondary malignancy is a cancer caused by treatment for a 
previous 
malignancy 
(e.g., 
treatment 
with 
investigational 
agent/intervention, radiation or chemotherapy).  A secondary 
malignancy is not considered a metastasis of the initial neoplasm. 
 
 
CTEP requires all secondary malignancies that occur following 
treatment with an agent under an NCI IND to be reported via CTEP-
AERS.  Three options are available to describe the event. 
 
• 
Leukemia secondary to oncology chemotherapy (e.g., 
Acute Myelocytic Leukemia [AML]) 
 
• 
Myelodysplastic syndrome (MDS) 
 
• 
Treatment-related secondary malignancy 
 
 
Any malignancy possibly related to cancer treatment (including 
AML/MDS) should also be reported via the routine reporting 
mechanisms outlined in each protocol. 
 
For more information see: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/d
osc/aeguidelines.pdf.  
 


 
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2. 
Supporting documentation should be submitted to CTEP in 
accordance with instructions provided by the CTEP-AERS system.  A 
copy of the report and the following supporting documentation must 
also be submitted to SWOG Operations Office within 30 days: 
 
• 
a copy of the pathology report confirming the AML/ALL 
/MDS diagnosis 
• 
(if available) a copy of the cytogenetics report   
 
SWOG 
ATTN: SAE Program 
4201 Medical Drive, Suite 250 
San Antonio, Texas 78229 
 
NOTE: If a patient has been enrolled in more than one NCI-
sponsored study, the report must be submitted for the most recent 
trial. 
  
 


 
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17.0 
BIBLIOGRAPHY 
 
1. 
Fernandez HF, Sun Z, Yao X, et al. Anthracycline dose intensification in acute myeloid leukemia. 
N Engl J Med 361:1249-1259, 2009. 
2. 
Löwenberg B, Pabst T, Vellenga E, et al. Cytarabine dose for acute myeloid leukemia. NEJM 
364: 1027-1036, 2011. 
3. 
Jabbour E, Kantarjian H, Ravandi F, et al. A phase 1-2 study of a farnesyltransferase inhibitor, 
tipifarnib, combined with idarubicin and cytarabine for patients with newly diagnosed acute 
myeloid leukemia and high-risk myelodysplastic syndrome. Cancer 117:1236-1244. 
4. 
Ravandi F, Cortes JE, Jones D, et al. Phase I/II study of combination therapy with sorafenib, 
idarubicin, and cytarabine in younger patients with acute myeloid leukemia. J Clin Oncol 28:1856-
1862. 
5. 
Garcia-Manero G, Yang H, Bueso-Ramos C, et al. Phase 1 study of the histone deacetylase 
inhibitor vorinostat (suberoylanilide hydroxamic acid [SAHA]) in patients with advanced leukemias 
and myelodysplastic syndromes. Blood 111:1060-1066, 2008. 
6. 
Sanchez-Gonzalez B, Yang H, Bueso-Ramos C, et al. Antileukemia activity of the combination of 
an anthracycline with a histone deacetylase inhibitor. Blood 108:1174-1182, 2006. 
7. 
Kadia TM, Yang H, Ferrajoli A, et al. A phase I study of vorinostat in combination with idarubicin 
in relapsed or refractory leukemia. Br J Haematol 150:72-82. 
8. 
Shiozawa K, Nakanishi T, Tan M, et al. Preclinical studies of vorinostat (suberoylanilide 
hydroxamic acid) combined with cytosine arabinoside and etoposide for treatment of acute 
leukemias. Clin Cancer Res 5:1698-1707, 2009. 
9. 
Garcia-Manero G, Tambaro FP, Bekele N, et al. Final report of a phase II trial of vorinostat, 
idarubicin and cytarabine in previously untreated acute myelogenous leukemia (AML) or high risk 
myelodysplastic syndrome (MDS). Blood 116: 903, #2189, 2010.   
10. 
Cassileth PA, Harrington DP, Appelbaum FR et al. Chemotherapy compared with autologous or 
allogeneic bone marrow transplantation in the management of acute myeloid leukemia in first 
remission. N Engl J Med 339: 1649-1656, 1998. 
11. 
Slovak ML, Kopecky KJ, Cassileth PA, et al. Karyotypic analysis predicts outcome of 
preremission and postremission therapy in adult acute myeloid leukemia: a Southwest Oncology 
Group/Eastern Cooperative Oncology Group study.  Blood 96: 4075-4083, 2000.  
12. 
Döhner H, Estey EH, Amadori S, et al. Diagnosis and management of acute myeloid leukemia in 
adults: recommendations from an international expert panel, on behalf of the European 
LeukemiaNet. Blood 115:453-74, 2010.  
13. 
Cornelissen,J.J., van Putten,W.L., Verdonck,L.F., et al. Results of a HOVON/SAKK donor versus 
no-donor analysis of myeloablative HLA-identical sibling stem cell transplantation in first 
remission acute myeloid leukemia in young and middle-aged adults: benefits for whom?  Blood 
109: 3658-3666, 2007. 
14. 
Yanada M, Matsuo K, Emi N, et al. Efficacy of allogeneic hematopoietic stem cell transplantation 
depends on cytogenetic risk for acute myeloid leukemia in first disease remission: a 
metaanalysis.  Cancer 103: 1652-1658, 2005.  
15. 
Koreth J, Schlenk R, Kopecky KJ, et al. Allogeneic stem cell transplantation for acute myeloid 
leukemia in first complete remission: a systematic review and meta-analysis of prospective 
clinical trials.  JAMA 301: 2349-2360, 2009.  
16. 
Walter RB, Pagel JM, Gooley TA, et al. Comparison of matched unrelated and matched related 
donor myeloablative hematopoietic cell transplantation for adults with acute myeloid leukemia in 
first remission.  Leukemia, in press.  


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Version Date 6/2/15 
 
 
 
17. 
Eapen M, Rocha V, Sanz G, et al. Effect of graft source on unrelated donor haemopoietic stem-
cell tranpslantation in adults with acute leukemia: a retrospective analysis.  Lancet Oncol 11: 653-
660, 2010. 
18. 
Brunstein CG, Gutman JA, Weisdorf DJ et al. Allogeneic hematopoietic cell transplantation for 
hematological malignancy: relative risks and benefits of double umbilical cord blood. Blood 
116:4693-4699, 2010. 
 
19. 
Swerdlow SH, Campo E, Harris NL, et al.  Editors. WHO Classification of Tomours of 
Haemotopoietic and Lymphoid Tissues. Lyon, France: lARC. Press, 2008. 
 
20. 
Pocock SJ, Simon R.  Sequential treatment assignment with balancing for prognostic factors in 
the controlled clinical trial.  Biometrics (1):103-15, 1975. 
 


 
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18.0 
APPENDIX 
 
18.1 
Determination of Expedited Adverse Event Reporting Requirements 
 
18.2 
New York Heart Association Classifications 
 
18.3 
Intake Calendar 
 
18.4 
Hematopoietic Cell Transplant-Comorbidity Index 
 
18.5 
AML Transplant Study Flowchart 
 
18.6 
Transplant Donor Search Process 
 
18.7 
ECOG-ACRIN Ancillary Study – NO SUBMISSIONS AFTER 1/29/14 
 
18.8 
Alliance Ancillary Studies – NO SUBMISSIONS AFTER 2/28/14 
 
18.9 
Specimen Submission Consent 
 


 
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18.1  
Determination of Expedited Adverse Event Reporting Requirements 
 
Adverse event data collection and reporting, which are required as part of every clinical trial, are 
done to ensure the safety of patients enrolled in the studies as well as those who will enroll in 
future studies using similar agents. Adverse events are reported in a routine manner at scheduled 
times during a trial. (Directions for routine reporting are provided in Section 14.0.) Additionally, 
certain adverse events must be reported in an expedited manner to allow for more timely 
monitoring of patient safety and care. Expedited adverse event reporting principles and general 
guidelines follow; specific guidelines for expedited adverse event reporting on this protocol are 
found in Section 16.1. 
 
All serious adverse events determined to be reportable to the Institutional Review Board 
responsible for the oversight of the patient must be reported according to local policy and 
procedures.  Documentation of this reporting should be maintained for possible inspection during 
quality assurance audits. 
 
Steps to determine if an adverse event is to be reported in an expedited manner (This 
includes all events that occur while on treatment or within 30 days of the last dose of protocol 
treatment.) 
 
Step 1: Determine whether the patient has received an investigational agent, commercial agent, 
or a combination of investigational and commercial agents. 
 
An investigational agent is a protocol drug administered under an Investigational New Drug 
Submission (IND). In some instances, the investigational agent may be available commercially, 
but is actually being tested for indications not included in the approved package label.  
 
Commercial agents are those agents not provided under an IND but obtained instead from a 
commercial source. The NCI, rather than a commercial distributor, may on some occasions 
distribute commercial agents for a trial. 
 
When a study includes both investigational and commercial agents, the following rules apply.   
• 
Concurrent administration: When an investigational agent(s) is used in combination 
with a commercial agent(s), the combination is considered to be investigational and 
expedited reporting of adverse events would follow the guidelines for investigational 
agents. 
• 
Sequential administration:   When a study includes an investigational agent(s) and a 
commercial agent(s) on the same study arm with sequential administration all expedited 
reporting of adverse events should follow the guidelines for the type of agent being given.  
For example, if the patient begins the study on the investigational agent(s), then all 
expedited reporting of adverse events should follow guidelines for the investigational 
agent(s).  Once the patient begins receiving the commercial agent(s) then all expedited 
reporting of adverse events should follow the guidelines for commercial agent(s).   
 
Step 2: Identify the type of event using the NCI Common Terminology Criteria for Adverse Events 
(CTCAE). The CTCAE provides descriptive terminology and a grading scale for each adverse 
event listed. A copy of the CTCAE can be downloaded from the CTEP home page 
(http://ctep.cancer.gov). Additionally, if assistance is needed, the NCI has an Index to the CTCAE 
that provides help for classifying and locating terms.  
 
Step 3:  Grade the event using the NCI CTCAE version specified in the protocol for reporting 
serious adverse events. 
 


 
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Step 4: Determine if the adverse event is Expected or an Exception to Expedited Reporting.  
Expected events are those that have been previously identified as resulting from administration 
of the agent and are listed in one of the following:   
 
• 
The current NCI SPEER (Specific Protocol Exceptions to Expedited Reporting) for 
treatments using agents provided under an NCI-held IND, or an equivalent listing for 
treatments using agents provided under a Non-CTEP-held IND; located in Section 3.0 of 
the protocol. 
• 
For treatments using commercial agents, the current CAEPR (Comprehensive Adverse 
Event and Potential Risks), ASAEL (Agent Specific Adverse Event List), or other list of 
expected toxicities located in Section 3.0 of the protocol, or the drug package insert.   
• 
Exception to Expedited reporting located in Section 16.1f of the protocol. 
 
An adverse event is considered unexpected, for expedited reporting purposes only, when either 
the type of event or the severity of the event is not listed in one of the areas outlined above. 
 
Step 5:  Determine whether the adverse event involved hospitalization or a prolongation of 
hospitalization (≥ 24 hours). 
 
Step 6:  Additionally, for commercial drugs, determine whether the adverse event is related to the 
protocol therapy. Attribution categories are as follows: Unrelated, Unlikely, Possible, Probable, 
and Definite.  Consult the appropriate table for expedited reporting criteria for commercial 
agent(s). 
 
NOTE:   Any event that occurs more than 30 days after the last dose of study agent and is 
attributed (possible, probable, or definite) to the study agent(s) must be reported according to the 
instructions above and as outlined in the appropriate table in Section 16.1. 
 
 
 


 
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18.2 
New York Heart Association Classifications 
 
 
 
 
 
Need for 
Physical Ability 
 
Class 
Cardiac Symptoms 
Limitations 
Additional Rest* 
To Work** 
 
 
I 
None 
None 
None 
Full Time 
 
II 
Only moderate 
Slight 
Usually only slight 
Usually full time 
 
 
 
or occasional 
 
III 
Defined, with less 
Marked 
Usually moderate 
Usually part time 
 
than ordinary 
 
activity 
 
IV 
May be present 
Extreme 
Marked 
Unable to work 
 
even at rest, & any 
 
activity increases 
 
discomfort 
 
 
 
 
 
* 
To control or relieve symptoms, as determined by the patient, rather than as advised by the 
physician. 
 
** 
At accustomed occupation or usual tasks. 
 


 
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18.3 
Intake Calendar 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sunday 
Monday 
Tuesday 
Wednesday 
Thursday 
Friday 
Saturday 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patient Signature: 
 
Instructions for the participant: 
 
This is a monthly calendar on which you are to record the number of tablets/pills/capsules you 
take each day.  Be sure you have enough calendars to last until your next appointment.  If you 
develop any side effects from the tablets/pills/capsules, mark this on the calendar on the day 
you note the effect.  Bring your calendars with you each time you have an appointment. 
 
If you have questions contact: ____________________ Telephone: _____________________ 
 
Your next appointment is: _______________________ 
Special instructions: 
 
Month: 
 
Year: 
 


 
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18.4 
Hematopoietic Cell Transplant-Comorbidity Index (HCT-CI) 
 
Comorbidity 
Definition/compartments 
Yes 
Score 
 
1.  Arrhythmia 
-Atrial fibrillation* 
  
 
 
 
-Atrial flutter* 
  
 
-Sick sinus syndrome* 
  
 
-Ventricular arrhythmia 
  
 
2.  Cardiovascular 
-Coronary artery disease* 
  
 
-Congestive heart failure* 
  
 
-Myocardial infarction* 
  
 
-Ejection fraction ≤ 50% £ 
  
 
3.  Inflammatory bowel disease 
-Crohn’s disease* 
  
 
-Ulcerative colitis 
  
 
4.  Diabetes 
-Treated with insulin or hypoglycemic drugs* 
 
5.  Cerebro-vascular 
-Transient ischemic attacks* 
  
 
-Cerebro-vascular ischemic or hemorrhagic stroke* 
  
 
6.  Depression/anxiety 
-Requiring psychological consult and/or specific treatment £ 
 
7.  Hepatic – mild 
-Chronic hepatitis £ 
  
 
-Bilirubin > ULN – 1.5 x ULN £ 
  
 
-AST/ALT > ULN – 2.5 x ULN £ 
  
 
8.  Obesity 
-Body mass index > 35 (adults) £ 
  
 
-Body mass index – for age ≥ 95% percentile (children) £ 
  
 
9.  Infection 
-Requiring anti-microbial treatment before, during  
 
  and after the start of conditioning regimen £ 
 
10.  Rheumatologic 
-Required treatment* 
 
11.  Peptic ulcer 
-Confirmed by endoscopy and required treatment* 
 
12.  Renal 
-Serum creatinine > 2 mg/dl (or > 177 mcmol/L) £ 
  
 
-On dialysis 
  
 
-Prior renal transplantation 
  
 
13.  Pulmonary – Moderate 
-DLco corrected for hemoglobin 66-80 % of predicted £ 
  
 
-FEV1 66-80% of predicted £ 
  
 
-Dyspnea on slight activity £ 
  
 
14.  Pulmonary – Severe 
-DLco corrected for hemoglobin ≤ 65% of predicted £ 
  
 
-FEV1 ≤ 65% of predicted £ 
  
 
-Dyspnea at rest or requiring oxygen therapy £ 
  
 
15.  Heart valve disease 
-Exept asymptomatic mitral valve prolapse £ 
 
16.  Prior solid malignancy 
-Treated with surgery, chemotherapy, and/or radiotherapy 
 
  excluding non-melanoma skin cancer* 
 
17.  Hepatic – moderate/severe 
-Liver cirrhosis £ 
  
 
-Bilirubin > 1.5 x ULN £ 
  
 
-AST/ALT > 2.5 x ULN £ 
  
 
 
 
Total score 
_______________________________________________________________________________________________ 
 
 
*Diagnosed at any time in the patient’s past history 
£Detected at the time of pre-transplant assessment 
ULN indicates upper limit of normal; DLco, diffusion capacity of carbon monoxide; FEV1, forced expiratory volume in one second; 
AST, Aspartate aminotransferase; and ALT, alanine aminotransferase 
1 
1 
1 
1 
1 
1 
1 
1 
1 
2 
2 
2 
2 
3 
3 
3 
3 


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18.5 
AML Transplant Study Flowchart 
                                                                                                                                                                           Receive sibling HLA typing from referring center? 
Intergroup AML Study – NMDP HLA Typing/Search Support for Allogeneic HCT 
Referring Physician 
                                                                       
                                                                                7-10 days                                                             Send detail to referring physician? 
John Pagel Team 
FHCRC 
 
NMDP 
 
Transplant Center 
 
Enroll newly 
diagnosed 
AML patient. 
Randomization 
and 
Induction/Re-
Induction
Collect 
patient 
buccal swab 
specimen 
Complete 
cytogenetic 
testing 
Consolidation 
HLA 
Results 
HLA type 
sibling? 
Receive AML 
patient 
enrollment 
Receive 
cytogenetic 
test results 
HIGH 
RISK? 
Receive HLA 
typing and 
preliminary 
search results 
Receive 
notification of 
enrollment with 
kit shipping 
details; send 
swab kit 
Receive 
buccal swab 
specimen 
for storage 
Complete HR typing 
and generate 
preliminary search 
strategy report – pre-
search contacts for 
best donors 
Receive referral 
for high risk 
patients for 
treatment arm 
and preliminary 
search 
details/reference 
HLA type 
siblings 
and 
activate 
formal 
search 
Matched 
sibling? 
URD/
DUCB
TX 
MSD 
TX 
No 
Yes 
Yes 
No 


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18.6 
Transplant Donor Search Process 
 
A primary objective of this protocol is to facilitate the matching of unrelated donors to 
high-risk patients (by cytogenetics) for transplant at first complete remission.  To achieve 
this, SWOG has teamed with the Center for Blood and Marrow Transplant and Research 
(CIBMTR), OneMatch stem cell and marrow network (OneMatch) and Héma-Québec and 
developed an unrelated donor search process that will be utilized for this study. 
 
a. 
The SWOG Data Operations Office will notify the SWOG Transplant Investigator, 
Study Chair and CIBMTR of new enrollments weekly.  The notification will 
include the physician name, e-mail address, telephone number (and alternate 
contact person with corresponding e-mail address if available), shipping address 
for the registering institution and the patient's SWOG ID.  The Transplant 
Investigator will follow up with CIBMTR to ensure the registration notification was 
received. 
 
b. 
Upon notification of enrollment, CIBMTR will send a buccal swab collection kit 
with specimen collection and shipping instructions to the contact person listed for 
the registering institution. 
 
c. 
The physician/CRA will collect the patient buccal swab specimen, complete the 
patient unrelated donor search request form (capturing information required to 
optimize the search process including weight, sex, race/ethnicity and birth 
month/year) and return it to CIBMTR using the pre-printed shipping label, per the 
provided instructions within 14 days after of kit receipt. 
 
d. 
Institutions are required to submit local cytogenetics and FISH reports and the 
S1203 Cytogenetics Report Form via MediDataRAVE® within 28 days after initial 
registration.  Upon receipt, the SWOG Data Operations Center will notify the 
SWOG Transplant Investigator of the patient’s risk status. 
 
e. 
Institutions are required to submit AML Disease Assessment Form documenting 
results from the each response assessment within 14 days of the assessment.  
Upon receipt of an assessment documenting complete response (CR), the 
SWOG Data Operations Center will notify the SWOG Transplant Investigator. 
 
f. 
Upon notification of a patient’s CR, the SWOG Transplant Investigator will 
compare to determine whether the patient was reported as high-risk.  If the 
patient’s risk status has not been reported, the Transplant Investigator will 
contact the site to request that the necessary documentation be submitted in an 
expeditious manner. 
 
g. 
The SWOG Transplant Investigator will notify CIBMTR when a patient is 
designated as high-risk and CIBMTR will initiate patient HLA typing.  Upon 
completion of HLA typing, CIBMTR will conduct an unrelated donor/cord blood 
search and produce a search strategy report. For Canadian sites participating via 
NCIC CTG, CIBMTR will forward the necessary search information to OneMatch 
(for non-Québec sites) or to Héma-Québec (for Québec sites) and 
OneMatch/Héma-Québec will perform the donor search and produce the search 
strategy report. The patient HLA typing and search strategy report will be 
submitted to the SWOG Transplant Investigator within two weeks of initiation of 
patient HLA typing.     


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h. 
When a patient that achieves CR is also high-risk, the Transplant Investigator will 
contact the site to determine if a sibling donor has already been identified and will 
provide a copy of the patient HLA typing and CIBMTR/OneMatch/Héma-Québec 
unrelated donor search strategy report.  The subsequent transplant plan will be 
at the discretion of the treating site. 
 
Note:  The Study Chair will act as primary backup to the Transplant Investigator upon 
request during the donor search process.   


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18.7 
ECOG-ACRIN Ancillary Study – NO SUBMISSIONS AFTER 1/29/14 
 
 
As of January 29, 2014 ECOG-ACRIN patients under consideration for 
S1203 are NOT to be registered to E3903 and no specimens are to be 
submitted to the ECOG Leukemia Translational Studies Laboratory (LTSL) 
from patients participating in S1203. Instructions below are retained for 
archival information only. 
 
The following instructions are specific to additional specimens submitted for 
ECOG-ACRIN patients.  
 
All ECOG-ACRIN patients must be registered to E3903, Ancillary Laboratory 
Protocol for the Collection of Diagnostic Material on Patients Considered for 
ECOG Treatment Trials for Leukemia or Related Hematologic Disorders.  
Pretreatment specimens must be collected and submitted to the ECOG-ACRIN 
Leukemia Translational Studies Laboratory (LTSL) within 28 days prior to 
registration to SWOG S1203. 
 
NOTE:  Copies of the patient’s signed E3903 consent, S1203 consent and 
signed authorization must be submitted to the Leukemia Translational Studies 
Laboratory (LTSL) prior to or with the pre-treatment sample submissions on the 
respective trial. 
 
a. 
Mandatory Specimens 
 
The following specimens must be submitted for all ECOG-ACRIN 
patients at pretreatment (within 28 days prior to registration): 
 
1. 
Peripheral Blood (Heparinized) 
 
2. 
Bone Marrow Aspirate (Heparinized and smear) 
 
b. 
Optional Specimens 
 
The following specimens must be submitted for patients answering YES 
to the question My specimens may be kept for use in research to learn 
about, prevent, treat or cure cancer. 
 
1. 
Buccal cells (mouthwash) at pretreatment (within 28 days prior to 
registration) via E3903 
 
2. 
Peripheral blood (in red top tubes) at pre-treatment (within 28 
days prior to registration) via E3903 
 
3. 
Peripheral Blood (Heparinized) at  
 
• 
Time of Outcome Following Induction (Prior to Consolidation) 
 
• 
End of Consolidation, if applicable 
• 
Relapse 
 


 
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4. 
Bone Marrow Aspirate (Heparinized and smear) at  
 
• 
Time of Outcome Following Induction (Prior to Consolidation) 
 
• 
End of Consolidation, if applicable 
• 
Relapse 
 
All specimens submitted to the ECOG LTSL must be logged into the 
ECOG Sample Tracking System (ECOG-STS) and a shipping manifest 
generated by this system is to accompany all submissions.  See 
Appendix 18.7 for additional specimen preparation and shipping and 
ECOG-STS instructions. 
 
c. 
Specimen Preparation 
 
1. 
Bone marrow aspirate: Heparinized (10 units heparin/ml), two (2) 
4-5mL tubes   
 
Note:   For patients with an inaspirable bone marrow (“dry 
tap”) call Dr. Paietta’s laboratory at (718) 920-9992 to discuss 
the case and the possibility for submitting peripheral blood only.  
Be prepared to report the WBC 
 
2. 
Peripheral blood: Heparinized (green top tubes) 30-40 cc 
 
3. 
One air dried bone marrow smear must be submitted 
 
NOTE:  Additionally, prior to treatment buccal cells (mouthwash) 
and peripheral blood collected in a red top tube are requested on 
E3903 from consenting patients.  Buccal cells submitted on 
E3903 will NOT be used for HLA typing and do not replace the 
submission requirements outlined in Section 15.3 
 
d. 
Shipping of specimens to LTSL 
 
The bone marrow and peripheral blood must be sent fresh (on the day of 
collection) on cool packs, packaging so that samples DO NOT FREEZE 
by wrapping them at least in bubble wrap. 24 hours prior to arrival of the 
samples at the LTSL, the following must be done: 
 
• 
If the ECOG – STS is unavailable, The Leukemia Translational 
Studies Laboratory must be notified by telephone.  Fax is not 
acceptable. 
 
Phone: (718) 920-9992     Beeper (off hours):  (917) 729-7231 
 
If you want to notify the laboratory of a sample submission during 
off hours, please leave a message on the laboratory’s answering 
machine (718-920-9992). Page Dr. Paietta at the beeper number 
above only if there are questions regarding the sample 
submission. 


 
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• 
Ship by overnight courier (preferably Federal Express) to arrive 
within 24 hours to: 
Elisabeth Paietta, Ph.D. 
Montefiore Medical Center - North Campus  
600 East 233rd Street 
6th Floor, Immunology Laboratory 
Bronx, NY 10466-2697 
Tel: (718) 920-9992 
 
The laboratory is open to receive shipments Monday through 
Saturday.  Shipments on Fridays for Saturday delivery must 
have “Saturday Delivery” marked on the overnight courier slip. 
 
If you have questions, contact the Leukemia Translational 
Studies Laboratory (718) 920-9992.    
 
The LSTL will forward specimens for the protocol-defined studies 
per protocol requirements. 
   
e. 
ECOG Sample Tracking System (ECOG-STS) 
 
It is required that all samples submitted on this trial be entered and 
tracked using the ECOG Sample Tracking System (ECOG-STS). The 
software will allow the use of either 1) an ECOG user-name and 
password previously assigned (for those already using ECOG-STS), or 
2) a CTSU username and password.   
 
When you are ready to log the collection and/or shipment of the samples 
required for this study, please access the Sample Tracking System 
software by clicking https://webapps.ecog.org/Tst. 
 
Important:  Any case reimbursements associated with specimen 
submissions will not be credited if specimens are not logged into ECOG-
STS. Additionally, please note that the ECOG-STS software creates pop-
up windows, so you will need to enable pop-ups within your web browser 
while using the software.  A user manual and interactive demo are 
available by clicking this link: 
http://www.ecog.org/general/stsinfo.html Please take a moment to 
familiarize yourself with the software prior to using the system. 
 
An ECOG-STS generated shipping manifest should be shipped with all 
specimen submissions. 
 
Please direct questions or comments pertaining to the ECOG-STS to 
ecog.tst@jimmy.harvard.edu 
 
ECOG Generic Specimen Submission Form (#2981v2) will be required 
only if STS is unavailable at time of sample submission. Notify the 
laboratory of the shipment as outlined above. Indicate the appropriate 
Lab ID# on the submission form: 
 
• 
0003 = Leukemia Translational Studies Laboratory (LTSL) 
 
Retroactively enter all specimen collection and shipping information 
when ECOG-STS is available. 


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18.8 
Alliance Ancillary Studies – NO SUBMISSIONS AFTER 2/28/14 
 
As of February 28, 2014, CALGB 20202 and CALGB 9665 have been 
Temporarily Closed.  Patients already enrolled on these studies should 
continue to submit specimens as outlined below. Instructions below are 
retained for archival information only. 
 
As of 7/1/14, CALGB 8461 will no longer accrue patients from S1203.  
Patients already enrolled in this study should continue to submit 
specimens as outlined in Section 18.8f. 
 
NOTE:  Patients already enrolled on these ancillaries should continue to 
submit specimens as outlined in each study. 
 
a. 
Registration to Ancillary Studies 
 
In addition to the CALGB 8461 cytogenetics correlative registration (see 
Section 15.2a), Alliance institutions participating in S1203 are required to 
register patients to CALGB 20202 (see Section 15.5b). All patients must 
also be offered participation in CALGB 9665, the Alliance specimen 
repository (see Section 15.5c); it is highly recommended that patients 
enroll on CALGB 9665. 
 
Patient registration to CALGB 9665 and CALGB 20202, should take 
place using OPEN, and will occur separately from registration to S1203.  
 
b. 
Specimens for the assessment of novel molecular markers in AML 
(CALGB 20202) (Temporarily Closed 2/28/14): 
 
As of February 28, 2014, CALGB 20202 has been Temporarily 
Closed, so Alliance patients under consideration for S1203 are NOT 
to be registered to CALGB 20202 and no specimens are to be 
submitted via this ancillary study.  Patients already enrolled on 
CALGB 20202 should continue to submit specimens as outlined 
below. 
 
Alliance institutions participating in S1203 are required to consent and 
enroll patients on CALGB 20202. A marrow aspirate, peripheral blood 
sample, buccal cell sample, and bone marrow biopsy slides are required 
at the following intervals: 
 
1. 
At diagnosis; 
 
2. 
At complete remission (bone marrow aspirate and blood sample 
only); 
 
3. 
At relapse (bone marrow aspirate and blood sample only). 
 
Follow specimen collection and submission instructions as outlined in 
CALGB 20202 and Appendix 18.8. 
 
 


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c. 
Specimens for banking (submitted to the Alliance Hematologic 
Malignancy Biorepository via CALGB 9665) (Temporarily Closed 
2/28/14): 
 
As of February 28, 2014, CALGB 9665 has been Temporarily Closed, 
so Alliance patients under consideration for S1203 are NOT to be 
registered to CALGB 9665 and no specimens are to be submitted 
via this ancillary study.  Patients already enrolled on CALGB 9665 
should continue to submit specimens as outlined below. 
 
Alliance institutions participating in S1203 must offer all patients the 
opportunity to take part in CALGB 9665; it is highly recommended that 
patients take part in CALGB 9665.  For consenting patients, a marrow 
aspirate, whole blood sample, and buccal cell sample must be submitted 
at the following intervals: 
 
1. 
At diagnosis; 
 
2. 
At complete remission (bone marrow aspirate and blood sample 
only); 
 
3. 
At relapse (bone marrow aspirate and blood sample only) 
 
Follow specimen collection and submission instructions as outlined in 
CALGB 9665 and Appendix 18.8. 
 
NOTE:  The buccal cell samples for Sections 15.5b and 15.5c should be 
obtained from each patient by rinsing with 10 mL of mouth wash for 30 to 
60 seconds, and then spitting the mouth wash back into a 50 mL sterile 
tube.  This buccal cell sample is in addition to the buccal swab that is 
 
d. 
CALGB 20202 
 
All specimens must be logged and shipped using the Biospecimen 
Management System (BioMS). All submitted specimens must be labeled 
with the protocol number (CALGB 20202), CALGB patient ID, patient’s 
initials, date and time of specimen collection and type of specimen 
collected (e.g., whole blood, bone marrow aspirate, etc.). 
 
All specimens must be shipped on the same day they are obtained. 
Please be sure to use a method of shipping that is secure and traceable. 
Shipment on Monday through Friday by overnight service to assure 
receipt is encouraged. If sampling on Friday, check Saturday delivery on 
the Federal Express invoice.  
 
Ship specimens along with the shipment manifest produced by BioMS to 
the following address: 
 
Michael Caligiuri, M.D. 
Attn.: CALGB 20202 Sample 
Alliance Hematologic Malignancy Biorepository 
The Arthur G. James Cancer Hospital and 
Richard J. Solove Research Institute 
300 W. 10th Avenue, Lobby 
Columbus, OH 43210 
Phone: 614/688-4754 
Fax: 614/688-4755 
 


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If holiday schedule prevents same day shipment, please contact the 
Alliance Hematologic Malignancy Biorepository for instructions at 
614/292-5888. 
 
e. 
CALGB 9665 (for consenting patients) 
 
All specimens must be logged and shipped using the Biospecimen 
Management System (BioMS). All submitted specimens must be labeled 
with the protocol number (CALGB 9665), CALGB patient ID, patient’s 
initials, date and time of specimen collection, and type of specimen 
collected (e.g., whole blood, bone marrow aspirate, etc.). 
 
Samples must be shipped on the same day they are obtained. If 
holiday schedules prevent same day shipment, please contact the 
Alliance Hematologic Malignancy Biorepository Lab Supervisor at 
614/292-5888 for sample shipment instructions. Send bone marrow, 
blood and buccal cell sample along with the shipment manifest produced 
by BioMS at ambient temperatures, any day of the week, via overnight 
carrier for next day (check AM) delivery to: 
 
Michael A. Caligiuri, M.D. 
Alliance Hematologic Malignancy Biorepository 
The Arthur G. James Cancer Hospital and Research Institute 
300 W. 10th Avenue, Lobby 
Columbus, OH 43210 
Phone: 614/688-4754 
Fax: 614/688-4755 
 
Note: If specimen is sent on Friday, CHECK SATURDAY DELIVERY 
on the FEDERAL EXPRESS INVOICE. 
 
f. 
CALGB 8461 (for patients enrolled prior to 7/1/14) 
 
Alliance institutions participating in S1203 are required to consent and 
enroll patients on CALGB 8461 using OPEN (Oncology Patient 
Enrollment Network) in order to enroll on S1203. Specimens must be 
submitted to an Alliance-approved institutional cytogeneticist.  Patient 
registration to CALGB 8461 occurs separately from registration to 
S1203.  
 
A bone marrow aspirate and/or peripheral blood sample are required at 
the following intervals: 
 
1. 
At diagnosis; 
 
2. 
At complete remission, if diagnostic specimen is abnormal (bone 
marrow aspirate sample only); 
 
3. 
At relapse. 
 
Follow specimen collection and submission instructions as outlined in 
CALGB 8461 and below.  Alliance institutions are required to submit 
both of the following forms along with the specimen to an Alliance-
approved cytogeneticist. 


 
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1. 
CALGB 8461 Form C-030 (see CALGB 8461 protocol 
document). 
 
2. 
S1203 Cytogenetics Lab Report Form (see Sections 12.0 and 
15.2.a). 
 
The cytogenetics laboratory will then return the completed S1203 
Cytogenetics Lab Report Form and images to the Data Manager at the 
institution. The institution will then complete and submit the S1203 
Mutational Analysis and Cytogenetics Report Form via Medidata RAVE 
using the information and pdf/jpeg/gif files provided by the lab (see 
Section 15.2.a). The Alliance Cytogenetic Office will not facilitate any 
data submission in Medidata RAVE for the SWOG Leukemia 
Cytogenetics Committee; please direct all inquiries to the SWOG 
Protocol Coordinator 
 
NOTE:  Institutions must have either an Alliance-approved cytogeneticist 
or an agreement from a Alliance-approved main member cytogenetics 
laboratory to enroll a patient on CALGB 8461.  See the list of Alliance-
approved institutional cytogeneticists under the “Studies” tab of the 
CALGB website.  Contact the Alliance Cytogenetic Office at 614/292-
2088 for questions regarding Alliance-approved cytogeneticists. 
 
Specimen Shipment  
 
Each sample should be submitted to the institution’s Alliance-approved 
Cytogeneticist with a completed CALGB Form C-030 (CALGB 
Cytogenetic Sample Referral Form). Submit a copy of the CALGB Form 
C-030 to the Alliance Statistical Center, Data Operations at Duke 
University along with copies of local cytogenetic reports. 
 
To obtain a copy of the CALGB Cytogenetic Sample Referral Form, (C-
030), contact the Administrative Secretary at the Alliance Statistical 
Center at 919/668-9350. You will need to provide the following 
information: 
 
• 
Your name 
• 
Your institution 
• 
Fax number 
• 
Number of forms needed 
 
 


 
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18.9 
Specimen Submission Consent 
 
* NOTES FOR LOCAL INVESTIGATORS:  
 
• 
This template specimen submission consent is provided as a tool to be 
used when specimens must be submitted prior to the patient being 
consented to the clinical trial if a local specimen submission consent is not 
available.  This consent is not mandatory.  Sites may use local specimen 
consent forms, modify specimen collection consents to include specimen 
submission information, or consent the patient to the clinical trial for the 
purpose of specimen submission, so long as specimen submission consent 
is obtained in some written and IRB approved form prior to specimen 
shipment.     
• 
This template has been reviewed by the DCTD/NCI. Local IRB changes to 
this document are allowed without prior approval from the SWOG 
Operations Office. It is suggested that sections of this document that are in 
bold type be used in their entirety.   
 
* These notes for investigators are instructional and should not be included in 
the informed consent form given to the prospective research participant.  
 
NOTE:  For patients submitting specimens prior to study registration, a SWOG 
patient ID must be obtained prior to submission.  This patient ID will be used to 
label the specimen and log it into SpecTrack, and will be entered into the 
registration system if/when the patient is registered to the study.  See Sections 
13.1 and 15.1 for additional information. 


 
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Specimen Submission Consent 
 
What is the purpose of this consent form? 
 
You are going to have a bone marrow exam and blood tests to see if you have cancer. 
Your doctor will remove some body tissue to do some tests. The results of these tests will 
be given to you by your doctor and will be used to plan your care.   
 
If you do have cancer, one of your treatment options might be a clinical trial.  A clinical 
trial is a type of research study.  If your doctor thinks a clinical trial would be a good 
option for you, he or she will discuss everything that would be involved in taking part in 
the study, like what type of treatment you would get and what tests you will need to take 
part. 
 
Many clinical trials require that samples (specimens) of your bone marrow and blood be 
submitted before you start treatment.  The specimens are used for testing that is needed as 
part of the clinical trial.   
 
The purpose of this consent form is to ask your permission to draw extra blood and bone 
marrow at the same time they are being taken for your diagnosis to send to a central 
laboratory, so that if you decide to take part in a clinical trial you will not have to have 
another bone marrow and blood draw.  If you agree, you will have an extra 2 teaspoons 
of bone marrow and 1-2 tablespoons of blood taken.  The extra marrow and blood can 
usually be taken through the same needle stick and do not require extra procedures.  By 
taking the extra marrow and blood at the time of diagnosis, we hope to prevent the need 
for an extra marrow/blood draw if the clinical trial requires them. 
 
No tests will be done on any of your specimens without your permission.  If you and your 
doctor do not feel that a clinical trial is your best option after getting your diagnosis, or if 
you decide not to take part in the clinical trial for any reason, your specimens will not be 
used for testing.   
 
If you and your doctor decide a clinical trial is your best option, and the trial requires 
specimens before you start treatment, you will be told about any tests that will be done 
with your specimens as part of the clinical trial consent.  Your specimens will not be used 
unless you agree to take part in the clinical trial.   
 
By signing this consent form you are agreeing to allow extra bone marrow and 
blood to be drawn at the time specimens are being taken to get your diagnosis, and 
to allow these specimens to be sent to the central laboratory to be used as part of a 
clinical trial if you take part in one.  You are not consenting to take part in a clinical 
trial or to have your specimens used for any other research. 
 


 
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What are the risks? 
 
The bone marrow and blood draws are part of your regular cancer screening and 
care, so your doctor will discuss their risks with you.  The risks that are part of 
collecting extra specimens are unlikely, but are: 
 
• Extra pain during the bone marrow draw 
• A second needle stick might be needed to get enough bone marrow or blood 
 
Your name and identifying information will not be sent with your specimens, so 
there is little risk of anyone getting your identifying information.  Instead, your 
specimens will be labeled with a number that is assigned by the clinical trials 
registration system.  Your identifying information will be linked to the number in a 
secure database to help make sure it cannot be accessed. 
 
 
Signature 
 
I have been given a copy of all 2 pages of this form.  I have read it or it has been read to 
me.  I understand the information and have had my questions answered.  I agree to take 
part in this study. 
 
 
Participant (or legally authorized representative) _______________________________ 
 
Date _____________________________________