Conditions: Leukemia
Keywords: adult acute promyelocytic leukemia (M3) adult acute myeloid leukemia with t(15;17)(q22;q12) adult acute myeloid leukemia with inv(16)(p13;q22) adult acute myeloid leukemia with t(16;16)(p13;q22) untreated adult acute myeloid leukemia
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 78
Healthy volunteers: no

Brief summary:
RATIONALE: Drugs used in chemotherapy work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as gemtuzumab, can block cancer growth in different ways. Some find cancer cells and help kill them or carry cancer-killing substances to them. Others interfere with the ability of cancer cells to grow and spread. Gemtuzumab may also stop the growth of promyelocytic leukemia by blocking blood flow to the cancer. Giving gemtuzumab together with combination chemotherapy may be more effective in treating promyelocytic leukemia.

PURPOSE: This phase II trial is studying how well giving gemtuzumab together with combination chemotherapy works in treating patients with previously untreated promyelocytic leukemia.

Detailed description:
OBJECTIVES:

* To assess the event-free survival and death during the first six weeks in patients with previously untreated, high-risk acute promyelocytic leukemia treated with a combined regimen of tretinoin, arsenic trioxide, and gemtuzumab ozogamicin.
* To estimate the frequency and severity of toxicities of this regimen in this group of patients.
* To investigate the molecular response rate utilizing this regimen in high-risk patients.

OUTLINE:

* Induction chemotherapy: Patients receive oral tretinoin twice daily beginning on day 1 until CR (up to 90 days), gemtuzumab ozogamicin IV over 2 hours on day 1, and arsenic trioxide IV over 2 hours 5 days a week beginning on day 10 until CR (up to 60 days) in the absence of disease progression or unacceptable toxicity. Patients achieving A1 bone marrow, B1 peripheral blood, and C1 extramedullary disease status proceed to consolidation therapy after maintaining B1 peripheral blood status for ≥ 7 days.
* Consolidation therapy: Beginning between 2-8 weeks after documentation of complete response (CR), patients receive consolidation therapy.

  * Consolidation courses 1 and 2: Patients receive arsenic trioxide IV over 2 hours 5 days a week for 5 weeks. Treatment repeats every 7 weeks for up to 2 courses. Patients remaining in A1 bone marrow, B1 peripheral blood, and C1 extramedullary disease status continue with consolidation courses 3 and 4.
  * Consolidation courses 3 and 4: Within 4 weeks of completing consolidation course 2, patients receive oral tretinoin twice daily on days 1-7 and daunomycin IV bolus or over 1 hour on days 1-3. Within 2-8 weeks after recovery to B1 peripheral blood status, patients receive consolidation course 4 as in course 3. Patients who remain in B1 peripheral blood and C1 extramedullary disease status continue on consolidation courses 5 and 6.
  * Consolidation courses 5 and 6: Beginning between 2-8 weeks after recovery to B1 peripheral blood status, patients receive gemtuzumab IV over 2 hours on day 1. Between 2-8 weeks after recovery to B1 peripheral blood status, patients receive consolidation course 6 as in course 5. Patients who remain in A1 bone marrow, B1 peripheral blood, and C1 extramedullary disease status proceed to maintenance therapy.
* Maintenance therapy: Beginning 2-8 weeks after recovery of blood counts, patients receive oral tretinoin twice daily on days 1-7 every other week for 1 year, oral mercaptopurine once daily for 1 year, and oral methotrexate once weekly for 1 year.

Patients undergo bone marrow aspirates and biopsies periodically during study. Samples are analyzed for cytogenetics by fluorescence in situ hybridization (FISH) and for PML-RARα by polymerase chain reaction (PCR).

After completion of study treatment, patients are evaluated at 3, 6, 9, 12, 18, 24, and 36 months.

Arms:
arm 1: Induction:

ATRA 45mg/m2 PO D1-CR Gemtuzumab Ozogamicin 9 mg/m2 IV D1 Arsenic Trioxide 0.15 mg/kg/d IV 5days/wk D10-CR

Consolidation 1 and 2:

Arsenic Trioxide 0.15 mg/kg/d IV 5days/wk x 5 weeks, repeat after 2 weeks rest

Consolidation 2 and 3:

ATRA 45 mg/m2 PO D1-7 Daunomycin 50 mg/m2/d IV D1-3

Consolidation 5 and 6:

GO 9mg/m2 IV D1

Maintenance:

ATRA 45 mg/m2/d PO D1-7 every 14 days 6-MP 60 mg/m2/d PO daily for 1 year Methotrexate 20 mg/m2 PO once/wk for 1 year

Interventions: intervention 1: arsenic trioxide intervention 2: gemtuzumab ozogamicin intervention 3: mercaptopurine intervention 4: methotrexate intervention 5: tretinoin
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None intervention 4: None intervention 5: None

Protocol document:
Prot_SAP_ICF_000.pdf: 
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October 1, 2015 
 
 
TO: 
ALL NATIONAL CLINICAL TRIALS NETWORK (NCTN) MEMBERS 
 
FROM: 
Cara Laubach, MIIM, Protocol Coordinator (E-mail:  claubach@swog.org) 
 
RE: 
S0535, "A Phase II Study of ATRA, Arsenic Trioxide and Gemtuzumab 
Ozogamicin in Patients with Previously Untreated High-Risk Acute 
Promyelocytic Leukemia"  Study Chairs:  Drs. J.E. Lancet, R. Komrokji, J. 
Radich, M. Fang, and D. Roulston.  
 
MEMORANDUM 
 
Study Chair:  Jeffrey E. Lancet, M.D. 
Phone number:  813/745-6841 
E-mail:  lancetje@moffitt.usf.edu 
 
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 
 
 
MEMORANDUM 
 
The purpose of this memorandum is to clarify the intended timing of patient follow-up for 
S0535.  All patients must be followed until death or a maximum of 3 years from time of 
initial patient registration (as indicated in Section 7.13 of the protocol).   
 
There is a discrepancy in the follow-up language between the protocol (Section 7.13), 
which is correct, footnote (Ĭ) in Section 9.0,  and the Model Consent Form language on 
Page 6, under “How long will I be in the study?.” This discrepancy occurred due to a 
protocol change prior to the initial activation of the protocol. At that time, the update was 
inadvertently omitted from the footnote in Section 9.0 and the Model Consent Form 
(MCF).  
 
The second sentence of footnote (Ĭ) in Section 9.0 indicates, that bone marrow aspirates 
should be obtained "Once maintenance is complete, every 3 months for the 1st year, 
then every 6 months for the 2nd year, then at the end of the 3rd year from registration." 
This was an oversight and the second word of this sentence should have been updated 
(at time of protocol activation) to reflect "treatment" in place of "maintenance", so that 
bone marrow aspirates should be obtained "Once treatment is complete, every 3 months 
for the 1st year, then every 6 months for the 2nd year, then at the end of the 3rd year 
from registration."  
 


 
S0535 
 
Memorandum (contd.) 
 
Page 2 
 
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Similarly, the Model Consent Form indicates, “After you are finished with these courses of 
treatment, the study doctor will ask you to visit the office for follow-up exams every 3 
months for the first year, every 6 months for the second year, then at 3 years from the 
time you finish treatment.” Although there were subsequent changes to the MCF, 
unfortunately it was not previously noted that the “After you are finished with these 
courses of treatment” and the “then at 3 years from the time you finish treatment” 
qualifiers preceding and following the timing of follow-up visits were incorrect. Therefore, 
the Model Consent Form language does not reflect the intent of the protocol.    
 
Patients still receiving treatment or who are still in follow-up may be notified, at the 
discretion of the treating physician and in a manner approved by the local IRB, that the 
follow-up period is 3 years from the time of initial patient registration.  
 
The S0535 study will be included on the no-follow list in June 2016, and is subject to 
SWOG-audit until that time. SWOG’s Quality Assurance Department has made note of 
this discrepancy and sites will not be cited for differences in follow-up period resultant 
from this discrepancy.  
 
This memorandum will serve as documentation for sites that may undergo audit by 
outside organizations or authorities. 
 
This memorandum serves to notify the NCI and SWOG Statistical Center. 
 
cc: 
PROTOCOL & INFORMATION OFFICE 
 
Megan Othus, Ph.D. 
 
Anna Moseley, M.S. 
 
Shannon McDonough, M.S. 
 
Tracy Maher, C.C.R.P. 
 
Louise Highleyman 
Laura Kingsbury, M.R.T.  
Samantha Sublett - Alliance 
Laura Gagnon - ECOG-ACRIN 
Daniel Matulich - Pfizer 
Elliot Lee - Biologics 
 
 


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July 1, 2015 
TO: 
ALL NATIONAL CLINICAL TRIALS NETWORK (NCTN) MEMBERS 
FROM: 
SWOG Operations Office 
RE: 
Updated Drug Order Form and Holiday Closure 
MEMORANDUM 
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 
MEMORANDUM
The purpose of this memorandum is to inform sites that Biologics, Inc has updated all 
SWOG Drug Order Forms to clarify that the  prescriber's signature is required.  
The updated Drug Order Form pertains to the following studies: 
S1313 (Gastrointestinal) 
S0635 (Lung 
S1406 (Gastrointestinal) 
S1300 (Lung) 
S1014 (Genitourinary) 
S1403 (Lung) 
S1216 (Genitourinary) 
S1304 (Myeloma) 
Please also note that Biologics, Inc will be closed Friday, July 3, 2015 in observance of 
Independence Day.  Biologics, Inc. will resume regular business hours (M-F, 9-6 ET) on 
Monday July 6, 2015. 
Please contact the Biologics Clinical Research Services team (800/693-4906; 
clinicaltrials@biologicsinc.com) with any questions or concerns. 


 
Memorandum (contd.) 
Page 2 
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This Holiday Closure pertains to the following studies: 
S1202 (Cancer Control – Symptomatic) 
S0635 (Lung) 
S1313 (Gastrointestinal) 
S0709 (Lung) 
S1406 (Gastrointestinal) 
S1300 (Lung) 
S1014 (Genitourinary) 
S1403 (Lung) 
S1216 (Genitourinary) 
S1304 (Myeloma) 
S0535 (Leukemia) 
 
This memorandum serves to notify the NCI and the SWOG Statistical Center. 
cc: PROTOCOL & INFORMATION OFFICE 
Mary Alice Norrison - Boehringer Ingelheim 
Laura Kingsbury, M.R.T. 
Linda Fischer - Bristol-Myers Squibb 
 
Tracy Maher, C.C.R.P. 
Becky Fillingham – ECOG-ACRIN 
Amy Johnson 
Laura Gagnon – ECOG-ACRIN 
Austin Hamm. 
Mary Bonds – ECOG-ACRIN 

Brian Zeller 
April Noska – Genentech  
Christine McLeod 
NCI Coop Coverage - Genentech 
Jean Barce 
Leta Truett, Ph.D., M.N. – Janssen Services, LLC 
Jeri Jardine 
Mohan Chelladurai, Ph.D. M.S.A. – 
Larry Kaye 
 
Janssen Services, LLC
Louise Highleyman 
Royce-Ann Adkins, Janssen Services, LLC 
Monica Yee 
William Heckman - Lilly 
Stephanie Edwards 
Theresa Bucher, R.N., Millennium 
Vicki Green 
Mark Showers – Onyx 
Guadalupe Aquino – Alliance 
Kellis Snodgrass – Pfizer  
Samantha Sublett – Alliance 
Afrouz Bazmi – Quintiles, Inc. 
 
Elliott Lee, Biologics, Inc. 
Steve Shuey – Halozyme Therapeutics


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Distribution Date: 
June 1, 2015 
E-Mailed Date: 
May 19, 2015 
TO: 
ALL NATIONAL CLINICAL TRIALS NETWORK (NCTN) MEMBERS 
FROM: 
SWOG Operations Office 
RE: 
Holiday Closure for Monday, May 25, 2015 in Observance of Memorial Day 
MEMORANDUM 
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 
MEMORANDUM
The purpose of this memorandum is to inform sites that Biologics, Inc. Clinical Trials 
Services will be closed Monday, May 25, 2015 in observance of Memorial Day. 
Regular business hours will resume on Tuesday, May 26, 2015. Regular business hours 
are Monday through Friday, 9:00 a.m. - 6:00 p.m. Eastern. 
Please contact the Biologics Clinical Research Services team (800/693-4906; 
clinicaltrials@biologicsinc.com) with any questions or concerns. 
This Holiday Closure pertains to the following studies: 
S1202 (Cancer Control – Symptomatic) 
S0635 (Lung) 
S1313 (Gastrointestinal) 
S0709 (Lung) 
S1406 (Gastrointestinal) 
S1300 (Lung) 
S1014 (Genitourinary) 
S1403 (Lung)
S1216 (Genitourinary) 
S1304 (Myeloma - Active)
S0535 (Leukemia) 
 
This memorandum serves to notify the NCI and the SWOG Statistical Center. 


 
Memorandum (contd.) 
Page 2 
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cc: PROTOCOL & INFORMATION OFFICE Mary Alice Norrison - Boehringer Ingelheim 
Laura Kingsbury, M.R.T. 
Linda Fischer - Bristol-Myers Squibb 
 
Tracy Maher, C.C.R.P. 
Becky Fillingham – ECOG-ACRIN 

Amy Johnson 
Laura Gagnon – ECOG-ACRIN 
Austin Hamm. 
Mary Bonds – ECOG-ACRIN 
Brian Zeller 
April Noska – Genentech 
 
Christine McLeod 
NCI Coop Coverage - Genentech 
Jean Barce 
Leta Truett, Ph.D., M.N. – Janssen Services, LLC 
Jeri Jardine 
Mohan Chelladurai, Ph.D. M.S.A. – Janssen Services, LLC
Larry Kaye 
Royce-Ann Adkins, Janssen Services, LLC
Louise Highleyman 
William Heckman - Lilly 
Monica Yee 
Theresa Bucher, R.N., Millennium 
Stephanie Edwards 
Mark Showers – Onyx 
Vicki Green 
Kellis Snodgrass – Pfizer 
 
Guadalupe Aquino – Alliance 
Afrouz Bazmi – Quintiles, Inc.  
Samantha Sublett – Alliance 
Steve Shuey – Halozyme Therapeutics 
Elliott Lee, Biologics, Inc. 
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Distribution Date: 
January 15, 2015 
CTEP Submission Date: 
December 26, 2014 
 
 
 
TO: 
ALL NATIONAL CLINICAL TRIALS NETWORK (NCTN) MEMBERS 
 
FROM: 
Sandi Jo Fredette, Protocol Coordinator (E-mail:  sfredette@swog.org) 
 
RE: 
S0535, "A Phase II Study of ATRA, Arsenic Trioxide and Gemtuzumab 
Ozogamicin in Patients with Previously Untreated High-Risk Acute 
Promyelocytic Leukemia"  Study Chairs:  Drs. J.E. Lancet, R. Komrokji, J. 
Radich, M. Fang, and D. Roulston.  
 
REVISION #14 
 
Study Chair:  Jeffrey E. Lancet, M.D. 
Phone number:  813/745-6841 
E-mail:  lancetje@moffitt.usf.edu 
 
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 #14
 
The above-referenced protocol has been revised as follows: 
 
1. 
Pages 1-2, Title Page:  The Version Date of the protocol and Model Consent Form 
have been updated.  The participant list has been moved from Page 1 to Page 2 
and revised to be consistent with the new NCTN/CTSU guidelines. Page 2 has 
been added and subsequent pages have been repaginated. 
 
This memorandum serves to notify the NCI and SWOG Statistical Center. 
 
cc: 
PROTOCOL & INFORMATION OFFICE 
Louise Highleyman 
Megan Othus, Ph.D. 
Laura Kingsbury, M.R.T.  
Hongli Li, M.S. 
Samantha Sublett - Alliance 
Shannon McDonough, M.S. 
Laura Gagnon - ECOG-ACRIN 
Tracy Maher, C.C.R.P. 
Kellis Snodgrass - Pfizer 
Jean Barce 
Elliot Lee - Biologics 
 


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January 1, 2015 
TO: 
ALL NATIONAL CLINICAL TRIALS NETWORK (NCTN) MEMBERS; CTSU 
FROM: 
SWOG Operations Office 
RE: 
IND Safety Reports for Gemtuzumab Ozogamicin 
MEMORANDUM 
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 
MEMORANDUM
The following new safety reports have been posted regarding adverse events that 
occurred in association with the drug gemtuzumab ozogamicin. Please access these 
safety reports via the study’s abstract page or the safety report link on the SWOG 
website (https://swog.org/safetyreports/safetyreports.asp).
These safety reports pertain to the 
following studies: 
 
S0535 Leukemia 
S0703 Leukemia 
Reports: 
Nov. 14, 2014 Mfr Rpt #2014169108 FU 
Dec. 3, 2014 Mfr Rpt #FRWYEG01649708 FU
Protocol amendments are not necessary at this time, but your consent form may be 
revised to include the information provided in these reports if it is deemed necessary by 
your institution.  Please append this notice and these reports to your copy of the protocol 
and forward copies to your Institutional Review Board (IRB) as required by your local 
policies and procedures. Should any further information regarding these adverse events 
be made available, it will be forwarded to you. 
This memorandum serves to notify the NCI and the SWOG Statistical Center. 
cc: PROTOCOL & INFORMATION OFFICE 
Samantha Sublett – Alliance 
 
Megan Othus, Ph.D. 
Laura Gagnon – ECOG-ACRIN 
 
Hongli Li, M.S. 
Becky Fillingham – ECOG-ACRIN 
 
Shannon McDonough, M.S. 
Kellis Snodgrass – Pfizer 
 
Tracy Maher, C.C.R.P. 
Elliot Lee – Biologics 
 
Jean Barce 
 
Laura Kingsbury, M.R.T. 
 
Louise Highleyman 


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December 15, 2014 
 
TO: 
ALL SWOG GROUP MEMBER, NCORP, AND AFFILIATE MEDICAL 
ONCOLOGISTS AND PATHOLOGISTS; CTSU 
 
FROM: 
Sandi Jo Fredette, Protocol Coordinator (sfredette@swog.org) 
 
RE: 
S0535, "A Phase II Study of ATRA, Arsenic Trioxide and Gemtuzumab 
Ozogamicin in Patients with Previously Untreated High-Risk Acute 
Promyelocytic Leukemia"  Study Coordinators:  Drs. J.E. Lancet, R. 
Komrokji, J. Radich, M. Fang, and D. Roulston.  
 
MEMORANDUM 
 
Study Coordinator:  Jeffrey E. Lancet, M.D. 
Phone number:  813/745-6841 
E-mail:  lancetje@moffitt.usf.edu 
 
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 
 
 
MEMORANDUM
 
The purpose of this memorandum is to inform sites that Biologics, Inc. Clinical Trials 
Services will be closed Wednesday, December 24, 2014, Thursday, December 25, 
2014, and Thursday, January 1, 2015, in observance of the seasonal holidays. 
 
Regular business hours will continue on December 26 and January 2 from 9:00 a.m. 
– 6:00 p.m. Eastern. 
 
If you have questions or need to coordinate shipments in advance, please contact 
your Clinical Research Services team at 800/693-4906 or via e-mail at 
clinicaltrials@biologicsinc.com. 

This memorandum serves to notify the NCI and SWOG Statistical Center. 
 
cc: 
PROTOCOL & INFORMATION OFFICE 
Samantha Sublett - Alliance 
Megan Othus, Ph.D. 
Mary Bonds – ECOG - ACRIN 
Shannon McDonough, M.S. 
Kellis Snodgrass - Pfizer 
Hongli Li, M.S. 
Elliott Lee - Biologics 
Tracy Maher, C.C.R.P. 
 
Jean Barce 


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November 15, 2014 
TO: 
ALL SWOG MEMBER, CCOP AND AFFILIATE MEDICAL ONCOLOGISTS 
FROM: 
SWOG Operations Office 
RE: 
IND Safety Report for Gemtuzumab Ozogamicin 
MEMORANDUM 
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 
MEMORANDUM
The following new safety report has been posted regarding an adverse event that 
occurred in association with the drug gemtuzumab ozogamicin. Please access this safety 
report via the study’s abstract page or the safety report link on the SWOG website 
(https://swog.org/safetyreports/safetyreports.asp). 
This safety report pertains to the following 
studies:
 
S0535 Leukemia 
S0703 Leukemia 
Report:
Oct. 28, 2014 Mfr Rpt #2014169108 FU
Protocol amendments are not necessary at this time, but your consent form may be 
revised to include the information provided in this report if it is deemed necessary by your 
institution.  Please append this notice and this report to your copy of the protocol and 
forward a copy to your Institutional Review Board (IRB) as required by your local policies 
and procedures. Should any further information regarding this adverse event be made 
available, it will be forwarded to you. 
This memorandum serves to notify the NCI and the SWOG Statistical Center. 
cc: PROTOCOL & INFORMATION OFFICE 
Samantha Sublett – Alliance 
 
Megan Othus, Ph.D. 
Laura Gagnon – ECOG-ACRIN 
 
Hongli Li, M.S. 
Becky Fillingham – ECOG-ACRIN 
 
Tracy Maher, C.C.R.P. 
Kellis Snodgrass – Pfizer 
 
Jean Barce 
Elliot Lee – Biologics 
 
Laura Kingsbury, M.R.T. 


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
 
 
 
November 1, 2014 
 
TO: 
ALL 
SWOG 
GROUP 
MEMBER, 
CCOP 
AND 
AFFILIATE 
MEDICAL 
ONCOLOGISTS AND PATHOLOGISTS; CTSU 
 
FROM: 
Sandi Jo Fredette, Protocol Coordinator (sfredette@swog.org) 
 
RE: 
S0535, "A Phase II Study of ATRA, Arsenic Trioxide and Gemtuzumab 
Ozogamicin in Patients with Previously Untreated High-Risk Acute Promyelocytic 
Leukemia"  Study Coordinators:  Drs. J.E. Lancet, R. Komrokji, J. Radich, M. 
Fang, and D. Roulston.  
 
MEMORANDUM 
 
Study Coordinator:  Jeffrey E. Lancet, M.D. 
Phone number:  813/745-6841 
E-mail:  lancetje@moffitt.usf.edu 
 
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 
 
 
MEMORANDUM
 
The purpose of this memorandum is to inform sites that Biologics, Inc. Clinical Trials Services 
will be closed Thursday, November 27 and Friday, November 28, 2014 in observance of the 
Thanksgiving holiday. 
 
Regular business hours will resume on Monday, December 1, 2014.  Regular business hours 
are Monday through Friday, 9:00 a.m. – 6:00 p.m. Eastern. 
 
For additional information, please access Biologics’ website at www.biologicsinc.com. 
 
If you have questions or need to coordinate shipments in advance, please contact your 
Clinical Trial Project Manager at 800/693-4906 or via email at clinicaltrials@biologicsinc.com. 

This memorandum serves to notify the NCI and SWOG Statistical Center. 
 
cc: 
PROTOCOL & INFORMATION OFFICE 
Samantha Sublett - Alliance 
Megan Othus, Ph.D. 
Mary Bonds – ECOG - ACRIN 
Shannon McDonough, M.S. 
Kellis Snodgrass - Pfizer 
Hongli Li, M.S. 
Elliott Lee - Biologics 
Tracy Maher, C.C.R.P. 
 
Jean Barce 


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
October 1, 2014 
TO: 
ALL SWOG MEMBER, CCOP AND AFFILIATE MEDICAL ONCOLOGISTS 
FROM: 
SWOG Operations Office 
RE: 
IND Safety Report for Gemtuzumab Ozogamicin 
MEMORANDUM 
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 
MEMORANDUM
The following new safety report has been posted regarding an adverse event that 
occurred in association with the drug gemtuzumab ozogamicin. Please access this safety 
report via the study’s abstract page or the safety report link on the SWOG website 
(https://swog.org/safetyreports/safetyreports.asp). 
This safety report pertains to the following 
studies:
 
S0535 Leukemia 
S0703 Leukemia 
Report:
Aug. 6, 2014 Mfr Rpt #2014211874 
Protocol amendments are not necessary at this time, but your consent form may be 
revised to include the information provided in this report if it is deemed necessary by your 
institution.  Please append this notice and this report to your copy of the protocol and 
forward a copy to your Institutional Review Board (IRB) as required by your local policies 
and procedures. Should any further information regarding this adverse event be made 
available, it will be forwarded to you. 
This memorandum serves to notify the NCI and the SWOG Statistical Center. 
cc: PROTOCOL & INFORMATION OFFICE 
Samantha Sublett – Alliance 
 
Megan Othus, Ph.D. 
Laura Gagnon – ECOG-ACRIN 
 
Hongli Li, M.S. 
Becky Fillingham – ECOG-ACRIN 
 
Tracy Maher, C.C.R.P. 
Kellis Snodgrass – Pfizer 
 
Jean Barce 
Elliot Lee – Biologics 
 
Laura Kingsbury, M.R.T. 


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August 15, 2014 
 
TO: 
ALL NATIONAL CLINICAL TRIALS NETWORK (NCTN) MEMBERS; CTSU 
 
FROM: 
Sandi Jo Fredette, Protocol Coordinator (E-mail:  sfredette@swog.org) 
 
RE: 
S0535, "A Phase II Study of ATRA, Arsenic Trioxide and Gemtuzumab 
Ozogamicin in Patients with Previously Untreated High-Risk Acute 
Promyelocytic Leukemia"  Study Chairs:  Drs. J.E. Lancet, R. Komrokji, J. 
Radich, M. Fang, and D. Roulston.  
 
MEMORANDUM 
 
Study Chair:  Jeffrey E. Lancet, M.D. 
Phone number:  813/745-6841 
E-mail:  lancetje@moffitt.usf.edu 
 
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 
 
 
MEMORANDUM
 
The purpose of this memorandum is to inform sites that Biologics, Inc. Clinical Trials 
Services will be closed Monday, September 1, 2014, in observance of Labor Day. 
 
Regular business hours will resume on Tuesday, September 2, 2014. Regular business 
hours are Monday through Friday, 9:00 a.m. - 6:00 p.m. Eastern. 
 
Please contact the Biologics Clinical Research Services team (800/693-4906; 
clinicaltrials@biologicsinc.com)  with any questions or concerns. 

This memorandum serves to notify the NCI and the SWOG Statistical Center. 
 
cc: 
PROTOCOL & INFORMATION OFFICE 
Samantha Sublett - Alliance 
Megan Othus, Ph.D. 
Laura Gagnon – ECOG-ACRIN 
Hongli Li, M.S. 
Becky Fillingham – ECOG-ACRIN 
Shannon McDonough, M.S. 
Kellis Snodgrass - Pfizer 
Tracy Maher, C.C.R.P. 
Elliot Lee - Biologics 
Jean Barce 
 
Laura Kingsbury, M.R.T.  
 
 
 





 
 
 
 
June 15, 2014 
 
TO: 
ALL NATIONAL CLINICAL TRIALS NETWORK (NCTN) MEMBERS; CTSU 
 
FROM: 
Sandi Jo Fredette, Protocol Coordinator (E-mail:  sfredette@swog.org) 
 
RE: 
S0535, "A Phase II Study of ATRA, Arsenic Trioxide and Gemtuzumab 
Ozogamicin in Patients with Previously Untreated High-Risk Acute 
Promyelocytic Leukemia"  Study Chairs:  Drs. J.E. Lancet, R. Komrokji, J. 
Radich, M. Fang, and D. Roulston.  
 
MEMORANDUM 
 
Study Chair:  Jeffrey E. Lancet, M.D. 
Phone number:  813/745-6841 
E-mail:  lancetje@moffitt.usf.edu 
 
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 
 
 
MEMORANDUM
 
The purpose of this memorandum is to inform sites that Biologics, Inc. Clinical Trials 
Services will be closed Friday, July 4, 2014 in observance of Independence Day. 
 
Regular business hours will resume on Monday, July 7, 2014.  Regular business hours 
are Monday through Friday, 9:00 a.m. - 6:00 p.m. Eastern. 
 
Please contact the Biologics Clinical Research Services team (800/693-4906; 
clinicaltrials@biologicsinc.com) with any questions or concerns. 

This memorandum serves to notify the NCI and SWOG Statistical Center. 
 
cc: 
PROTOCOL & INFORMATION OFFICE 
Samantha Sublett - Alliance 
Megan Othus, Ph.D. 
Laura Gagnon – ECOG-ACRIN 
Hongli Li, M.S. 
Becky Fillingham – ECOG-ACRIN 
Shannon McDonough, M.S. 
Alison Randall - Pfizer 
Tracy Maher, C.C.R.P. 
Elliot Lee - Biologics 
Jean Barce 
 
Laura Kingsbury, M.R.T.  
 
 
 


May 15, 2014 
TO: 
ALL NATIONAL CLINICAL TRIALS NETWORK (NCTN) MEMBERS; CTSU 
FROM: 
Sandi Jo Fredette, Protocol Coordinator (E-mail:  sfredette@swog.org) 
RE: 
S0535, "A Phase II Study of ATRA, Arsenic Trioxide and Gemtuzumab 
Ozogamicin in Patients with Previously Untreated High-Risk Acute 
Promyelocytic Leukemia"  Study Chairs:  Drs. J.E. Lancet, R. Komrokji, J. 
Radich, M. Fang, and D. Roulston.  
 
MEMORANDUM 
 
Study Chair:  Jeffrey E. Lancet, M.D. 
Phone number:  813/745-6841 
E-mail:  lancetje@moffitt.usf.edu 
 
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 
 
 
MEMORANDUM
 
The purpose of this memorandum is to inform sites that Biologics, Inc. Clinical Trials 
Services will be closed Monday, May 26, 2014 in observance of Memorial Day.   
 
Regular business hours will resume on Tuesday, May 27, 2014.  Regular business hours 
are Monday through Friday, 9:00 a.m. - 6:00 p.m. Eastern. 
 
This memorandum serves to notify the NCI and SWOG Statistical Center. 
 
cc: 
PROTOCOL & INFORMATION OFFICE 
 
Megan Othus, Ph.D. 
 
Hongli Li, M.S. 
Shannon McDonough, M.S. 
 
Tracy Maher, C.C.R.P. 
 
Jean Barce 
 
Laura Kingsbury, M.R.T.  
 
Samantha Sublett - Alliance 
Laura Gagnon – ECOG-ACRIN 
Becky Fillingham – ECOG-ACRIN 
Alison Randall - Pfizer 
Elliot Lee - Biologics 
ED EFFECTIVE 06/01/2013
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Distribution Date: 
May 1, 2014 
CTEP Submission Date: 
April 16, 2014 
TO: 
ALL NATIONAL CLINICAL TRIALS NETWORK MEMBERS; CTSU 
FROM: 
Sandi Jo Fredette, Protocol Coordinator (E-mail:  sfredette@swog.org) 
RE: 
S0535, "A Phase II Study of ATRA, Arsenic Trioxide and Gemtuzumab 
Ozogamicin in Patients with Previously Untreated High-Risk Acute 
Promyelocytic Leukemia"  Study Chairs:  Drs. J.E. Lancet, R. Komrokji, J. 
Radich, M. Fang, and D. Roulston.  
 
REVISION #13 
 
Study Chair:  Jeffrey E. Lancet, M.D. 
Phone number:  813/745-6841 
E-mail:  lancetje@moffitt.usf.edu 
 
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 #13
 
1. 
The Version Date of the protocol and Model Consent Form have been updated. 
 
2. 
Throughout the protocol, “Study Coordinator” has been updated to “Study Chair”.  
This change takes place on the Title Page (Page 1) and in Sections 7.0 (Page 
23), 7.2g and 7.3b (Page 24), 7.5d (Page 25), 7.6c (Page 26), 8.4a (Page 34), 
8.4c (Page 35), 8.5 (Page 36), 8.7 (Page 37), 11.4 (Page 44) and 18.2 (Page 64).   
 
3. 
Throughout the protocol, NCI’s Adverse Event Expedited Reporting System 
(AdEERS) has been updated to CTEP’s Adverse Event Reporting System (CTEP-
AERS).  This change takes place in Sections 3.2b (Page 8), 16.1 (Pages 55-58) 
and 18.4 (Page 69).  Associated web links on these pages have also been 
updated. 
 
4. 
Pages 1-3, Title Pages:  The participant list, Study Chair, Biostatistician and Agent 
information have been moved to Page 1.  The Table of Contents has been moved 
to Pages 2-3.   
 
ED EFFECTIVE 06/01/2013
CTSU 
CTSU 
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. J.E. Lancet,
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 activation (s
creased risk to
creased risk 
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) Addition o
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2.


S0535 
 
Revision #13 (contd.) 
Page 2 
 
5. 
Page 37, Section 8.8:  Information in this section has been reworded and 
reorganized for clarity. 
6. 
Page 39, Section 9.0:  The “Ĭ” footnote has been updated to clarify that marrows 
are obtained until the 3rd year “from registration”. 
 
7. 
Page 45, Section 13.3a:  The SWOG phone number has been updated in the last 
paragraph. 
 
8. 
Page 54, Section 16.0:  The information in the Drug Accountability section has 
been updated to the current standard referencing the Code of Federal Regulations 
21 CFR 312.  The new standard confidentiality statement has been added. 
 
9. 
Page 55, Section 16.1d:  Information in this section has been reworded and 
reorganized for clarity. 
 
10. 
Page 56, Table 16.1 and Section 16.1e:  The table and related information below 
it have been updated to the current standard. 
 
11. 
Pages 58-59, Sections 16.1h and 16.1i:  The information for reporting secondary 
AML/ALL/MDS has been updated to the current standard in Section 16.1h.  
Section 16.1i has been add to include reporting requirements for pregnancy, fetal 
death and neonatal death.  This addition has caused the addition of a new Page 
59.  Subsequent pages have been renumbered accordingly. 
 
This memorandum serves to notify the NCI and SWOG Statistical Center. 
 
cc: 
PROTOCOL & INFORMATION OFFICE 
 
Megan Othus, Ph.D. 
 
Shannon McDonough, M.S. 
 
Tracy Maher, C.C.R.P. 
 
Jean Barce 
 
Laura Kingsbury, M.R.T.  
 
Samantha Sublett - Alliance 
Laura Gagnon – ECOG-ACRIN 
Becky Fillingham – ECOG-ACRIN 
Alison Randall - Pfizer 
Elliot Lee - Biologics 
 
 
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 NCI and SW
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


 
 
 
 
December 15, 2013 
 
TO: 
ALL SWOG GROUP MEMBER, CCOP AND AFFILIATE MEDICAL 
ONCOLOGISTS AND PATHOLOGISTS; CTSU 
 
FROM: 
Sandi Jo Fredette, Protocol Coordinator 
 
RE: 
S0535, "A Phase II Study of ATRA, Arsenic Trioxide and Gemtuzumab 
Ozogamicin in Patients with Previously Untreated High-Risk Acute 
Promyelocytic Leukemia"  Study Chairs:  Drs. J.E. Lancet, R. Komrokji, J. 
Radich, M. Fang, and D. Roulston.  
 
MEMORANDUM 
 
Study Chair:  Jeffrey E. Lancet, M.D. 
Phone number:  813/745-6841 
E-mail:  lancetje@moffitt.usf.edu 
 
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 
 
 
MEMORANDUM
 
The purpose of this memorandum is to inform sites that Biologics, Inc. Clinical Trials 
Services will be closed Tuesday, December 24, 2013, Wednesday, December 25, 2013, 
and Wednesday, January 1, 2014, in observance of the seasonal holidays. 
 
Regular business hours will continue December 26-27 and December 30-31 from 9:00 
a.m. – 6:00 p.m. Eastern. 
 
If you have questions or need to coordinate shipments in advance, please contact your 
Clinical 
Research 
Services 
team 
at 
800/693-4906 
or 
via 
e-mail 
at 
clinicaltrials@biologicsinc.com. 
 
This memorandum serves to notify the NCI and SWOG Statistical Center. 
 
cc: 
PROTOCOL & INFORMATION OFFICE 
Samantha Sublett - CALGB 
Megan Othus, Ph.D. 
Laura Gagnon - ECOG/ACRIN 
Shannon McDonough, M.S. 
Becky Fillingham – ECOG/ACRIN 
Tracy Maher, C.C.R.P. 
Alison Randall - Pfizer 
Jean Barce 
Elliot Lee - Biologics 
Laura Kingsbury, M.R.T.  
 





 
 
 
November 1, 2013 
 
TO: 
ALL SWOG GROUP MEMBER, CCOP AND AFFILIATE MEDICAL 
ONCOLOGISTS AND PATHOLOGISTS; CTSU 
 
FROM: 
Sandi Jo Fredette, Protocol Coordinator 
 
RE: 
S0535, "A Phase II Study of ATRA, Arsenic Trioxide and Gemtuzumab 
Ozogamicin 
in 
Patients 
with 
Previously 
Untreated 
High-Risk 
Acute 
Promyelocytic Leukemia"  Study Chairs:  Drs. J.E. Lancet, R. Komrokji, J. 
Radich, M. Fang, and D. Roulston.  
 
MEMORANDUM 
 
Study Chair:  Jeffrey E. Lancet, M.D. 
Phone number:  813/745-6841 
E-mail:  lancetje@moffitt.usf.edu 
 
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 
 
 
MEMORANDUM
 
The purpose of this memorandum is to inform sites of a holiday closure of Biologics, Inc.  
Biologics, Inc. Clinical Trials Services is closed Thursday, November 28 and Friday, 
November 29, 2013 in observance of the Thanksgiving holiday. 
 
Regular business hours will resume on Monday, December 2, 2013.  Regular business 
hours are Monday through Friday, 9:00 a.m. – 6:00 p.m. Eastern. 
 
For additional information, please access Biologics’ website at www.biologicsinc.com. 
 
If you have questions or need to coordinate shipments in advance, please contact your 
Clinical Trial Project Manager at 800/693-4906. 
 
This memorandum serves to notify the NCI and SWOG Statistical Center. 
 
cc: 
PROTOCOL & INFORMATION OFFICE 
Jean Barce 
Megan Othus, Ph.D. 
Samantha Sublett - Alliance 
Shannon McDonough, M.S. 
Laura Gagnon - ECOG 
Tracy Maher, C.C.R.P. 
Alison Randall - Pfizer 
Laura Kingsbury, M.R.T. 
Elliott Lee - Biologics 





 
 
 
August 15, 2013 
 
TO: 
ALL SWOG GROUP MEMBER, CCOP AND AFFILIATE MEDICAL 
ONCOLOGISTS AND PATHOLOGISTS; CTSU 
 
FROM: 
Sandi Jo Fredette, Protocol Coordinator 
 
RE: 
S0535, "A Phase II Study of ATRA, Arsenic Trioxide and Gemtuzumab 
Ozogamicin 
in 
Patients 
with 
Previously 
Untreated 
High-Risk 
Acute 
Promyelocytic Leukemia"  Study Chairs:  Drs. J.E. Lancet, R. Komrokji, J. 
Radich, M. Fang, and D. Roulston.  
 
MEMORANDUM 
 
Study Chair:  Jeffrey E. Lancet, M.D. 
Phone number:  813/745-6841 
E-mail:  lancetje@moffitt.usf.edu 
 
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 
 
 
MEMORANDUM
 
The purpose of this memorandum is to inform sites of the Holiday closure of Biologics, Inc. 
Biologics, Inc. Clinical Trial Services is closed Monday, September 2, 2013 in observance 
of the Labor Day holiday. 
 
Regular business hours are Monday through Friday, 9:00 a.m. – 6:00 p.m. Eastern. 
 
For additional information, please access Biologics’ new website at www.biologicsinc.com. 
 
If you have questions or need to coordinate shipments in advance, please don’t hesitate to 
contact your Clinical Trial Project Manager at 800/693-4906. 
 
This memorandum serves to notify the NCI and SWOG Statistical Center. 
 
cc: 
PROTOCOL & INFORMATION OFFICE 
Jean Barce 
Megan Othus, Ph.D. 
Samantha Sublett - Alliance 
Shannon McDonough, M.S. 
Laura Gagnon - ECOG 
Tracy Maher, C.C.R.P. 
Alison Randall - Pfizer 
Laura Kingsbury, M.R.T. 
Elliott Lee - Biologics 





 
 
 
June 15, 2013 
 
TO: 
ALL SWOG GROUP MEMBER, CCOP AND AFFILIATE MEDICAL 
ONCOLOGISTS AND PATHOLOGISTS; CTSU 
 
FROM: 
Sandi Jo Fredette, Protocol Coordinator 
 
RE: 
S0535, "A Phase II Study of ATRA, Arsenic Trioxide and Gemtuzumab 
Ozogamicin 
in 
Patients 
with 
Previously 
Untreated 
High-Risk 
Acute 
Promyelocytic Leukemia"  Study Chairs:  Drs. J.E. Lancet, R. Komrokji, J. 
Radich, M. Fang, and D. Roulston.  
 
MEMORANDUM 
 
Study Chair:  Jeffrey E. Lancet, M.D. 
Phone number:  813/745-6841 
E-mail:  lancetje@moffitt.usf.edu 
 
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 
 
 
MEMORANDUM
 
The purpose of this memorandum is to inform sites of the Holiday closure of Biologics, Inc. 
Biologics, Inc. Clinical Trial Services is closed Thursday, July 4, 2013 in observance of 
the Independence Day holiday. 
 
Regular business hours are Monday through Friday, 9:00 a.m. – 6:00 p.m. Eastern. 
 
For additional information, please access Biologics’ new website at www.biologicsinc.com. 
 
If you have questions or need to coordinate shipments in advance, please don’t hesitate to 
contact your Clinical Trial Project Manager at 800/693-4906. 
 
This memorandum serves to notify the NCI and SWOG Statistical Center. 
 
cc: 
PROTOCOL & INFORMATION OFFICE 
Samantha Sublett - Alliance 
Megan Othus, Ph.D. 
Mary Bonds - ECOG 
Shannon McDonough, M.S. 
Alison Randall - Pfizer 
Tracy Maher, C.C.R.P. 
Elliott Lee - Biologics 
Jean Barce 
 





 
 
 
 
Distribution Date: 
June 1, 2013 
E-mailed Date: 
May 21, 2013 
 
TO: 
ALL SWOG GROUP MEMBER, CCOP AND AFFILIATE MEDICAL 
ONCOLOGISTS AND PATHOLOGISTS; CTSU 
 
FROM: 
Sandi Jo Fredette, Protocol Coordinator 
 
RE: 
S0535, "A Phase II Study of ATRA, Arsenic Trioxide and Gemtuzumab 
Ozogamicin in Patients with Previously Untreated High-Risk Acute 
Promyelocytic Leukemia"  Study Coordinators:  Drs. J.E. Lancet, R. 
Komrokji, J. Radich, M. Fang, and D. Roulston.  
 
MEMORANDUM 
 
Study Coordinator:  Jeffrey E. Lancet, M.D. 
Phone number:  813/745-6841 
E-mail:  lancetje@moffitt.usf.edu 
 
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 
 
 
MEMORANDUM
 
The purpose of this memorandum is to inform sites of the Holiday closure of 
Biologics, Inc.  Biologics, Inc. Clinical Trial Services is closed Monday, May 27, 
2013 in observance of the Memorial Day holiday. 
 
Regular business hours are Monday through Friday, 9:00 a.m. – 6:00 p.m. Eastern. 
 
For 
additional 
information, 
please 
access 
Biologics’ 
new 
website 
at 
www.biologicsinc.com. 
 
If you have questions or need to coordinate shipments in advance, please don’t 
hesitate to contact your Clinical Trial Project Manager at 800/693-4906. 
 
This memorandum serves to notify the NCI and SWOG Statistical Center. 
 
cc: 
PROTOCOL & INFORMATION OFFICE 
Samantha Sublett - CALGB 
Megan Othus, Ph.D. 
Mary Bonds - ECOG 
Shannon McDonough, M.S. 
Alison Randall - Pfizer 
Tracy Maher, C.C.R.P. 
Elliott Lee - Biologics 
Jean Barce 
 





 
 
 
 
Distribution Date: 
June 1, 2013 
E-mailed Date: 
May 21, 2013 
 
TO: 
ALL SWOG GROUP MEMBER, CCOP AND AFFILIATE MEDICAL 
ONCOLOGISTS AND PATHOLOGISTS; CTSU 
 
FROM: 
Sandi Jo Fredette, Protocol Coordinator 
 
RE: 
S0535, "A Phase II Study of ATRA, Arsenic Trioxide and Gemtuzumab 
Ozogamicin in Patients with Previously Untreated High-Risk Acute 
Promyelocytic Leukemia"  Study Coordinators:  Drs. J.E. Lancet, R. 
Komrokji, J. Radich, M. Fang, and D. Roulston.  
 
MEMORANDUM 
 
Study Coordinator:  Jeffrey E. Lancet, M.D. 
Phone number:  813/745-6841 
E-mail:  lancetje@moffitt.usf.edu 
 
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 
 
 
MEMORANDUM
 
The purpose of this memorandum is to inform investigators about a recall of the study 
drug methotrexate due to particulate matter in vials from two drug lots:  CL0996 
(expiration date 12/2013) and CJ4948 (expiration date 5/2013).   
ISSUE: Sandoz is conducting a voluntary nationwide recall to the hospital/user level 
of two lots of its Methotrexate Sodium, USP, 25 mg/mL, 40 mL vial injectable product 
in the US, due to the discovery of particulate matter in vials during routine quality 
examination of retention samples at the manufacturer. Parenteral injection of drug 
from the affected lots can lead to microembolisation in areas where the particles 
lodge. Clinical symptoms are not to be expected from these microemboli and Sandoz 
is not aware of any reports of related adverse events.
BACKGROUND: Methotrexate is an antimetabolite used in the treatment of 
neoplastic diseases, severe psoriasis, and rheumatoid arthritis, including polyarticular 
juvenile rheumatoid arthritis. The lot numbers and expiration dates of the two recalled 
lots are: CL0996 (expiration date 12/2013) and CJ4948 (expiration date 05/2013). 
These lots were distributed nationally across the US and to a single foreign country 
(Poland).


 
S0535 
 
Memorandum (contd.) 
 
Page 2 
 


RECOMMENDATION: In the event that a patient experiences an adverse reaction or 
quality problem involving this product, they should immediately contact their 
healthcare professional as well as Sandoz to report the finding. The Sandoz Drug 
Information Direct Line is open at 800-525-2492, 24 hours/day, seven days a week, 
or reports can be made via email at qa.druginfo@sandoz.com. 
 
Read the MedWatch alert, including a link to the Recall Notice, at: 
http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedica
lProducts/ucm353266.htm

This memorandum serves to notify the NCI and SWOG Statistical Center. 
 
cc: 
PROTOCOL & INFORMATION OFFICE 
 
Megan Othus, Ph.D. 
 
Shannon McDonough, M.S. 
Tracy Maher, C.C.R.P. 
 
Jean Barce 
 
Samantha Sublett - CALGB 
Mary Bonds - ECOG 
Alison Randall - Pfizer 
Katie Reitzel - Biologics 
 





 
 
 
 
May 15, 2013 
 
 
TO: 
ALL SWOG GROUP MEMBER, CCOP AND AFFILIATE MEDICAL 
ONCOLOGISTS AND PATHOLOGISTS; CTSU 
 
FROM: 
Sandi Jo Fredette, Protocol Coordinator 
 
RE: 
S0535, "A Phase II Study of ATRA, Arsenic Trioxide and Gemtuzumab 
Ozogamicin in Patients with Previously Untreated High-Risk Acute 
Promyelocytic Leukemia"  Study Coordinators:  Drs. J.E. Lancet, R. 
Komrokji, J. Radich, M. Fang, and D. Roulston.  
 
STATUS NOTICE 
 
Study Coordinator:  Jeffrey E. Lancet, M.D. 
Phone number:  813/745-6841 
E-mail:  lancetje@moffitt.usf.edu 
 
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 
 
 
PERMANENT CLOSURE
 
The above-referenced study has met its accrual goal and will permanently close to 
accrual effective June 1, 2013 at 11:59 p.m. Pacific. 

Because the study is being permanently closed prior to local implementation of Revision 
#12, sites do not need to update local consent forms per the requirement in the 
Revision #12 cover memorandum. 

This memorandum serves to notify the NCI and SWOG Statistical Center. 
 
cc: 
PROTOCOL & INFORMATION OFFICE 
 
Megan Othus, Ph.D. 
 
Shannon McDonough, M.S. 
Tracy Maher, C.C.R.P. 
 
Jean Barce 
 
Samantha Sublett - CALGB 
Mary Bonds - ECOG 
Alison Randall - Pfizer 
Katie Reitzel - Biologics 





 
 
 
 
 
Distribution Date: 
May 15, 2013 
CTEP Submission Date: 
April 25, 2013 
 
 
TO: 
ALL SWOG GROUP MEMBER, CCOP AND AFFILIATE MEDICAL 
ONCOLOGISTS AND PATHOLOGISTS; CTSU 
 
FROM: 
Sandi Jo Fredette, Protocol Coordinator 
 
RE: 
S0535, "A Phase II Study of ATRA, Arsenic Trioxide and Gemtuzumab 
Ozogamicin in Patients with Previously Untreated High-Risk Acute 
Promyelocytic Leukemia"  Study Coordinators:  Drs. J.E. Lancet, R. 
Komrokji, J. Radich, M. Fang, and D. Roulston.  
 
REVISION #12 
 
Study Coordinator:  Jeffrey E. Lancet, M.D. 
Phone number:  813/745-6841 
E-mail:  lancetje@moffitt.usf.edu 
 
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 #12
 
The above-referenced study has been revised as follows: 
 
1. 
The protocol has been reformatted and repaginated to meet the current 
requirements for electronic protocol submission. This includes addition of second 
level headings in instances where they were previously absent, reformatting the 
title page to include all second level headings, reformatting the protocol calendars 
into MS Word and removal of the consent form as Section 18.0. 
 
2. 
Study Coordinators List, Page 3:  Cheryl Willman has been replaced by Jerald 
Radich as the Surface Markers Studies Coordinator.  Marilyn Slovak has been 
replaced by Min Fang and Diane Roulston as the Cytogenetics/FISH Coordinator.  
Corresponding contact information has been updated accordingly. 
 


 
S0535 
 
Revision #12 (contd.) 
 
Page 2 



3. 
Biostatisticians List, Page 3:  Holly Gundacker has been replaced by Shannon 
McDonough.  Corresponding contact information has been updated accordingly. 
 
4. 
Sections 14.4a, 14.4b, 14.4d, 14.4i and 14.4l, Pages 46-48:  These sections have 
been updated to require that CALGB sites submit the RT-PCR report at the 
indicated timpoints. 
 
5. 
Section 15.2, Page 49:  A note has been added stating that no specimens will be 
banked for SWOG and other sites not affiliated with ECOG or CALGB. 
 
The Model Consent Form has been updated as outlined below. 
 
Institutions must update their local consent forms to include the changes to the Model 
Consent Form. 
 
SWOG considers that the Model Consent Form changes do not represent an alteration in 
risk-benefit ratio.  Therefore, local accrual does not need to be suspended pending 
implementation of these changes.   
 
Patients currently on protocol treatment and patients who sign a consent form prior to 
Institutional Review Board (IRB) approval and local implementation of the consent form 
changes need not be informed of these changes unless required by the local IRB.   
 
1. 
Page 19:  The website address for information on clinical trials and insurance 
coverage has been updated in the “What are the costs of taking part in this 
study?” section. 
 
2. 
Page 25:  The information stating that specimens will be kept at UNM Cancer 
Research Center for SWOG institutions and other institutions has been removed 
as banking for SWOG institutions is no longer part of this study. 

This memorandum serves to notify the NCI and SWOG Statistical Center. 
 
 
cc: 
PROTOCOL & INFORMATION OFFICE 
 
Megan Othus, Ph.D. 
 
Holly Gundacker, M.S. 
 
Tracy Maher 
 
Jean Barce 
 
Michele Seiler - CALGB 
Mary Bonds - ECOG 
Mary Voehl - Pfizer 
Katie Reitzel - Biologics 
 
 
 




January 1, 2013 
TO:  
ALL 
SWOG 
MEMBER, 
CCOP 
AND 
AFFILIATE 
MEDICAL 
INVESTIGATORS AND CLINICAL RESEARCH ASSOCIATES 
FROM:  
SWOG Operations Office 
RE:  
Eligibility Affirmation 
MEMORANDUM 
By signing the FDA 1572, every SWOG investigator has agreed to conduct studies in 
compliance with the protocol, and to personally conduct or supervise the 
investigation. A critical step in this process is verification of patient eligibility. 
Effective January 1st, 2013, every registering investigator or another SWOG 
investigator designate is required to sign a statement on the Registration Worksheet 
that the eligibility criteria have been confirmed. This worksheet will not be submitted 
to Data Operations Office but must be maintained at the local institution for review 
during audits. 
As part of this transition, forms are being removed from active studies and will be 
posted separately on the individual protocol abstract page for each study.  
Subsequent pages have been renumbered accordingly.  No other form, protocol, or 
consent form changes have been made as part of the transition.  
If you have any questions, please contact the SWOG Operations Office at 210/614-
8808. 


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
 
 
 
 
December 15, 2012 
 
 
TO: 
ALL SWOG MEMBER, CCOP AND AFFILIATE MEDICAL ONCOLOGISTS AND 
PATHOLOGISTS; CTSU 
 
FROM: 
Sandi Jo Fredette, Protocol Coordinator 
 
RE: 
S0535, "A Phase II Study of ATRA, Arsenic Trioxide and Gemtuzumab 
Ozogamicin in Patients with Previously Untreated High-Risk Acute Promyelocytic 
Leukemia"  Study Coordinators:  Drs. J.E. Lancet, R. Komrokji, C.L. Willman, 
and M.L. Slovak. 
 
MEMORANDUM 
 
Study Coordinator:  Jeffrey E. Lancet, M.D. 
Phone number:  813/745-6841 
E-mail:  lancetje@moffitt.usf.edu 
 
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 
 
 
MEMORANDUM
 
The purpose of this memorandum is to inform sites of the Holiday closure of Biologics, Inc. 
Biologics, Inc. Clinical Trial Services is closed Monday, December 24, 2012, Tuesday, 
December 25, 2012 and Tuesday, January 1, 2013 in observance of the holidays. 
 
Regular business hours are Monday through Friday, 9:00 a.m. – 6:00 p.m. Eastern.  
 
For additional information, please access Biologics’ new website at www.biologicsinc.com. 
 
If you have questions or need to coordinate shipments in advance, please don’t hesitate to 
contact your Clinical Trial Project Manager at 800/693-4906. 
 
This memorandum serves to notify the NCI and SWOG Statistical Center. 
 
cc: 
PROTOCOL & INFORMATION OFFICE 
Mike Kelly – CALGB 
Megan Othus, Ph.D. 
Morgen Alexander-Young - CALGB 
Shannon McDonough, M.S. 
Mary Bonds - ECOG 
Jean Barce 
Alison Randall - Pfizer 
Tracy Maher, C.C.R.P. 
Elliott Lee - Biologics 
 
 





 
 
 
 
November 15, 2012 
 
 
TO: 
ALL SWOG MEMBER, CCOP AND AFFILIATE MEDICAL ONCOLOGISTS 
AND PATHOLOGISTS; CTSU 
 
FROM: 
Sandi Jo Fredette, Protocol Coordinator 
 
RE: 
S0535, "A Phase II Study of ATRA, Arsenic Trioxide and Gemtuzumab 
Ozogamicin in Patients with Previously Untreated High-Risk Acute 
Promyelocytic Leukemia"  Study Coordinators:  Drs. J.E. Lancet, R. 
Komrokji, C.L. Willman, and M.L. Slovak. 
 
MEMORANDUM 
 
Study Coordinator:  Jeffrey E. Lancet, M.D. 
Phone number:  813/745-6841 
E-mail:  lancetje@moffitt.usf.edu 
 
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 
 
 
MEMORANDUM
 
The purpose of this memorandum is to inform sites of the Holiday closure of Biologics, 
Inc. Biologics, Inc. Clinical Trial Services is closed Thursday, November 22, 2012 and 
Friday, November 23, 2012 for the Thanksgiving holiday.  
 
Regular business hours will resume on Monday, November 26, 2012. Regular business 
hours are Monday through Friday, 9:00 a.m. – 6:00 p.m. Eastern.   
 
If you have questions or need to coordinate shipments in advance, please don’t hesitate 
to contact your Clinical Trial Project Manager at 800/693-4906. 
 
This memorandum serves to notify the NCI and SWOG Statistical Center. 
 
cc: 
PROTOCOL & INFORMATION OFFICE 
Mike Kelly – CALGB 
Megan Othus, Ph.D. 
Morgen Alexander-Young - CALGB 
Shannon McDonough, M.S. 
Mary Bonds - ECOG 
Jean Barce 
Alison Randall - Pfizer 
Tracy Maher, C.C.R.P. 
Elliott Lee - Biologics 
 
 





 
 
 
 
September 1, 2012 
 
TO: 
ALL SWOG MEMBER, CCOP AND AFFILIATE MEDICAL ONCOLOGISTS 
AND PATHOLOGISTS; CTSU 
 
FROM: 
Sandi Jo Fredette, Protocol Coordinator 
 
RE: 
S0535, "A Phase II Study of ATRA, Arsenic Trioxide and Gemtuzumab 
Ozogamicin in Patients with Previously Untreated High-Risk Acute 
Promyelocytic Leukemia"  Study Coordinators:  Drs. J.E. Lancet, R. 
Komrokji, C.L. Willman, and M.L. Slovak. 
 
MEMORANDUM 
 
Study Coordinator:  Jeffrey E. Lancet, M.D. 
Phone number:  813/745-6841 
E-mail:  lancetje@moffitt.usf.edu 
 
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 
 
 
MEMORANDUM
 
The purpose of this memorandum is to inform sites of an updated expiration date for the 
study drug gemtuzumab ozogamicin (Mylotarg).   
 
Pfizer, Inc., the drug’s manufacturer, has extended the expiration date for lot # 10-084666 
to November 30, 2013.  Note that Pfizer does not require that drug be relabeled; sites are 
to follow their own local requirement for drug relabeling. 
 
For questions, please contact Alison Randall (alison.randall@pfizer.com, 212/733-1765). 
 
This memorandum serves to notify the NCI and SWOG Statistical Center. 
 
cc: 
PROTOCOL & INFORMATION OFFICE 
Mike Kelly – CALGB 
Megan Othus, Ph.D. 
Morgen Alexander-Young - CALGB 
Shannon McDonough, M.S. 
Mary Bonds - ECOG 
Jean Barce 
Alison Randall - Pfizer 
Tracy Maher, C.C.R.P. 
Elliott Lee - Biologics 
 
 
 
 





 
 
 
 
 
Distribution Date: 
September 1, 2012 
E-mail Date: 
August 30, 2012 
 
 
 
TO: 
ALL SWOG MEMBER, CCOP AND AFFILIATE MEDICAL ONCOLOGISTS 
AND PATHOLOGISTS; CTSU 
 
FROM: 
Sandi Jo Fredette, Protocol Coordinator 
 
RE: 
S0535, "A Phase II Study of ATRA, Arsenic Trioxide and Gemtuzumab 
Ozogamicin in Patients with Previously Untreated High-Risk Acute 
Promyelocytic Leukemia"  Study Coordinators:  Drs. J.E. Lancet, R. 
Komrokji, C.L. Willman, and M.L. Slovak. 
 
MEMORANDUM 
 
Study Coordinator:  Jeffrey E. Lancet, M.D. 
Phone number:  813/745-6841 
E-mail:  lancetje@moffitt.usf.edu 
 
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 
 
 
MEMORANDUM
 
The purpose of this memorandum is to inform sites that Biologics, Inc. will be closed on 
Monday, September 3, 2012 in observance of the Labor Day holiday. 
 
If you have questions or need to coordinate shipments in advance, please don’t hesitate 
to contact your Clinical Trial Project Manager at 800/693-4906. 
 
This memorandum serves to notify the NCI and SWOG Statistical Center. 
 
cc: 
PROTOCOL & INFORMATION OFFICE 
Mike Kelly – CALGB 
Megan Othus, Ph.D. 
Morgen Alexander-Young - CALGB 
Shannon McDonough, M.S. 
Mary Bonds - ECOG 
Jean Barce 
Alison Randall - Pfizer 
Tracy Maher, C.C.R.P. 
Elliott Lee - Biologics 
 
 





August 15, 2012 
TO: 
ALL SWOG MEMBER, CCOP AND AFFILIATE MEDICAL ONCOLOGISTS 
FROM: 
SWOG Operations Office 
RE: 
IND Safety Report for Gemtuzumab Ozogamicin 
MEMORANDUM 
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 
MEMORANDUM
The following new safety report has been posted regarding an adverse event that 
occurred in association with the drug gemtuzumab ozogamicin. Please access this safety 
report via the study’s abstract page or the safety report link on the SWOG website 
(https://swog.org/safetyreports/safetyreports.asp). 
This safety report pertains to the following 
studies:
S0106 Leukemia 
 
S0535 Leukemia 
S0703 Leukemia 
Report:
Aug. 3, 2012 Mfr Rpt #2012117176 
Protocol amendments are not necessary at this time, but your consent form may be 
revised to include the information provided in this report if it is deemed necessary by your 
institution.  Please append this notice and this report to your copy of the protocol and 
forward a copy to your Institutional Review Board (IRB) as required by your local policies 
and procedures. Should any further information regarding this adverse event be made 
available, it will be forwarded to you. 
This memorandum serves to notify the NCI and SWOG Statistical Center. 
cc: PROTOCOL & INFORMATION OFFICE 
Morgen Alexander-Young – CALGB 
 
Megan Othus, Ph.D. 
Michael Kelly – CALGB 
 
Shannon McDonough, M.S. 
Camilla Byström – GTO/Karolinska, Sweden 
 
Tracy Maher, C.C.R.P. 
Mary Bonds – ECOG 
 
Jean Barce 
Andrea Hiltz – NCIC CTG 
 
 
Alison Randall – Pfizer 
 
 
Elliot Lee – Biologics 





 
 
 
 
 
Distribution Date: 
August 1, 2012 
E-mailed Date: 
July 24, 2012 
 
 
TO: 
ALL SWOG MEMBER, CCOP AND AFFILIATE MEDICAL ONCOLOGISTS 
AND PATHOLOGISTS; CTSU 
 
FROM: 
Sandi Jo Fredette, Protocol Coordinator 
 
RE: 
S0535, "A Phase II Study of ATRA, Arsenic Trioxide and Gemtuzumab 
Ozogamicin in Patients with Previously Untreated High-Risk Acute 
Promyelocytic Leukemia"  Study Coordinators:  Drs. J.E. Lancet, R. 
Komrokji, C.L. Willman, and M.L. Slovak. 
 
MEMORANDUM 
 
Study Coordinator:  Jeffrey E. Lancet, M.D. 
Phone number:  813/745-6841 
E-mail:  lancetje@moffitt.usf.edu 
 
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 
 
 
MEMORANDUM
 
The purpose of this memorandum is to inform investigators about a recall of the study 
drug methotrexate due to particles embedded in the glass at the neck of the vial. 
 
There may be potential for product to come into contact with the embedded particles and 
the particles may become dislodged into the solution. In the event in which particulate 
matter could be injected into a patient, there may be the potential for patient injury where 
medical intervention may be required. Signs and symptoms might include bleeding, 
bruising, inflammation, itching, rash, chest pain and respiratory symptoms. 
See the Press Release for a listing of affected product lot numbers and expiration dates. 
BACKGROUND: These products were distributed nationwide to wholesalers and direct 
customers. Hospira completed an investigation and attributed the root cause to a supplier 
glass defect. Hospira is arranging for return/replacement etc. of all recalled products. 
Formal recall letters have been distributed within the US along with notification to safety 
organizations.


 
S0535 
 
Memorandum (contd.) 
 
Page 2 



RECOMMENDATION: Anyone with an existing inventory in the United States should stop 
use and distribution, quarantine the product immediately, and call Stericycle at 1-888-
628-0734 between the hours of 8am to 5pm EDT, Monday through Friday, to arrange for 
the return of the product.
Read the MedWatch safety alert, including a link to the Press Release, at:
http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalPro
ducts/ucm312048.htm. 
 
This memorandum serves to notify the NCI and SWOG Statistical Center. 
 
 
 
cc: 
PROTOCOL & INFORMATION OFFICE 
 
Megan Othus, Ph.D. 
 
Shannon McDonough, M.S. 
 
Jean Barce 
 
Tracy Maher, C.C.R.P. 
Michele Seiler - CALGB 
Mary Bonds - ECOG 
Alison Randall - Pfizer 
Elliott Lee - Biologics 
 
 
 





 
 
 
 
 
June 15, 2012 
 
 
 
TO: 
ALL SWOG MEMBER, CCOP AND AFFILIATE MEDICAL ONCOLOGISTS 
AND PATHOLOGISTS; CTSU 
 
FROM: 
Sandi Jo Fredette, Protocol Coordinator 
 
RE: 
S0535, "A Phase II Study of ATRA, Arsenic Trioxide and Gemtuzumab 
Ozogamicin in Patients with Previously Untreated High-Risk Acute 
Promyelocytic Leukemia"  Study Coordinators:  Drs. J.E. Lancet, R. 
Komrokji, C.L. Willman, and M.L. Slovak. 
 
MEMORANDUM 
 
Study Coordinator:  Jeffrey E. Lancet, M.D. 
Phone number:  813/745-6841 
E-mail:  lancetje@moffitt.usf.edu 
 
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 
 
 
MEMORANDUM
 
The purpose of this memorandum is to inform sites that Biologics, Inc. will be closed on 
Wednesday, July 4, 2012 in observance of the Independence Day holiday.   
 
If you have questions or need to coordinate shipments in advance, please don’t hesitate 
to contact your Clinical Trial Project Manager at 800/693-4906. 
 
This memorandum serves to notify the NCI and SWOG Statistical Center. 
 
 
 
cc: 
PROTOCOL & INFORMATION OFFICE 
Tracy Maher, C.C.R.P. 
Kenneth J. Kopecky, Ph.D. 
Michele Seiler - CALGB 
Megan Othus, Ph.D. 
Mary Bonds - ECOG 
Shannon McDonough, M.S. 
Mary Voehl - Pfizer 
Jean Barce 
Elliot Lee - Biologics 
 





 
 
 
 
 
May 1, 2012 
 
 
 
TO: 
ALL SWOG MEMBER, CCOP AND AFFILIATE MEDICAL ONCOLOGISTS 
AND PATHOLOGISTS; CTSU 
 
FROM: 
Sandi Jo Fredette, Protocol Coordinator 
 
RE: 
S0535, "A Phase II Study of ATRA, Arsenic Trioxide and Gemtuzumab 
Ozogamicin in Patients with Previously Untreated High-Risk Acute 
Promyelocytic Leukemia"  Study Coordinators:  Drs. J.E. Lancet, R. 
Komrokji, C.L. Willman, and M.L. Slovak. 
 
MEMORANDUM 
 
Study Coordinator:  Jeffrey E. Lancet, M.D. 
Phone number:  813/745-6841 
E-mail:  lancetje@moffitt.usf.edu 
 
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 
 
 
MEMORANDUM
 
The purpose of this memorandum is to inform sites that Biologics, Inc. will be closed on 
Monday, May 28, 2012 in observance of the Memorial Day holiday.   
 
If you have questions or need to coordinate shipments in advance, please don’t hesitate 
to contact your Clinical Trial Project Manager at 800/693-4906. 
 
This memorandum serves to notify the NCI and SWOG Statistical Center. 
 
 
 
cc: 
PROTOCOL & INFORMATION OFFICE 
Tracy Maher 
Kenneth J. Kopecky, Ph.D. 
Michele Seiler - CALGB 
Megan Othus, Ph.D. 
Maury Bonds - ECOG 
Holly Gundacker, M.S. 
Mary Voehl - Pfizer 
Jean Barce 
Katie Reitzel - Biologics 
 





 
 
 
 
January 1, 2012 
 
 
TO: 
ALL SWOG MEMBER, CCOP AND AFFILIATE MEDICAL ONCOLOGISTS 
AND PATHOLOGISTS; CTSU 
 
FROM: 
Sandi Jo Fredette, Protocol Coordinator 
 
RE: 
S0535, "A Phase II Study of ATRA, Arsenic Trioxide and Gemtuzumab 
Ozogamicin in Patients with Previously Untreated High-Risk Acute 
Promyelocytic Leukemia"  Study Coordinators:  Drs. J.E. Lancet, R. 
Komrokji, C.L. Willman, and M.L. Slovak. 
 
MEMORANDUM 
 
Study Coordinator:  Jeffrey E. Lancet, M.D. 
Phone number:  813/745-6841 
E-mail:  lancetje@moffitt.usf.edu 
 
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 
 
 
MEMORANDUM
 
The purpose of this memorandum is to inform sites of an Investigator Letter that was 
released by Pfizer on December 19, 2011 regarding the recommendation to visually inspect 
the study drug gemtuzumab ozogamicin after reconstitution and prior to use.  The 
Investigator Letter is attached. 
 
This memorandum serves to notify the NCI and SWOG Statistical Center. 
 
cc: 
PROTOCOL & INFORMATION OFFICE 
 
Kenneth J. Kopecky, Ph.D. 
 
Megan Othus, Ph.D. 
 
Holly Gundacker, M.S. 
 
Jean Barce 
 
Tracy Maher 
Michele Seiler - CALGB 
Maury Bonds - ECOG 
Mary Voehl - Pfizer 
Katie Reitzel - Biologics 


Pfizer, Inc. 
 235 East 42 Street 
ical Affairs
New York, NY 10017 
 
 
linical Development & Med
C
 
 
 
 
December 19, 2011 
 
 
 
 that investigators visually inspect MYLOTARG® (gentuzumab 
reconstitution with 5ml Sterile Water For Injection prior to 
dministration to ensure the absence of particulate matter. 
This letter is to reinforce the importance of visually inspecting MYLOTARG vials after 
ls Sterile Water For Injection prior to mixing in the preparation of the 
travenous solution. This communication has been triggered based on Good Manufacturing 
) 
 Healthcare professionals should visually inspect the MYLOTARG vials after 
For Injection in order to ensure the absence 
of particulate matter prior to administration of the reconstituted medicinal product, 
d solution should be free from visible particulates
 
 
 
Pfizer recommends
ozogamicin (GO)) vials after 
a
Dear Investigator:  
 
reconstitution with 5m
in
Practice (GMP) issues identified at the manufacturing site (Ben Venue Laboratories, BVL
where vials of MYLOTARG Powder for Solution for Injection have been produced. There is 
currently no evidence that the safety or efficacy of MYLOTARG is impacted by the issues 
identified at the BVL facility.  
 
Recommendation to healthcare professionals 
 
reconstitution with 5mls Sterile Water 
in order to minimize relevant risk. 
 
 MYLOTARG is a Powder for Solution for Injection that is reconstituted with Sterile 
Water For Injection. The reconstitute
. 
arg vials after reconstitution should be 
reported. To report a product issue or speak to a member of  Pfizer US Medical 
 
 Always carefully follow the administration instructions provided in the MYLOTARG 
dosage and administration instructions.   
 
 If you note particles in the vial after reconstitution please do not use the vial. Any 
evidence of particulate matter noted in Mylot
Information Team, please call 1-800-438-1985.  
 
Further information  
 


In November 2011, the European Medicines Agency carried out an inspection of a BVL site that 
ncluding Mylotarg. The inspection resulted in observations relating to 
e presence of particulate matter in certain products. No product-specific details have been 
 the 
cility. 
YLOTARG is a medicinal product containing Gentuzumab Ozogamicin. MYLOTARG has no 
rketing authorization in the USA (NDA) was 
ithdrawn in 2010 when an important phase 3 study failed to confirm clinical benefit, but it is 
lease report any adverse events associated with the use of MYLOTARG via the Pfizer Serious 
 for Investigator Initiated Research studies.  Additionally, this 
formation may be reported to your local Health Authority and Institutional Review Board or 
 
Mark Shapiro, MD, PhD 
Global Medical Affairs 
Pfizer Oncology 
manufactures products i
th
provided relating to any Pfizer products. 
 
There is currently no evidence that the safety or efficacy of MYLOTARG is impacted by
adverse inspection findings of the BVL fa
 
Background information on MYLOTARG 
 
M
Marketing Authorization in the EU and the ma
w
supplied for investigator-initiated studies and on a compassionate use basis for certain patients 
with Acute Myeloid Leukemia. 
 
Reporting recommendations 
 
P
Adverse Event Reporting policy
in
Ethics Committee, as appropriate. 
 
For further information or any questions on MYLOTARG, please contact Pfizer US Medical 
Information at 1-800-438-1985. 
 
Sincerely, 
 
 
 
 
 
 
 
 
 
 





 
 
 
 
December 15, 2011 
 
TO: 
ALL SWOG MEMBER, CCOP AND AFFILIATE MEDICAL ONCOLOGISTS 
AND PATHOLOGISTS; CTSU 
 
FROM: 
Sandi Jo Fredette, Protocol Coordinator 
 
RE: 
S0535, "A Phase II Study of ATRA, Arsenic Trioxide and Gemtuzumab 
Ozogamicin in Patients with Previously Untreated High-Risk Acute 
Promyelocytic Leukemia"  Study Coordinators:  Drs. J.E. Lancet, R. 
Komrokji, C.L. Willman, and M.L. Slovak. 
 
MEMORANDUM 
 
Study Coordinator:  Jeffrey E. Lancet, M.D. 
Phone number:  813/745-6841 
E-mail:  lancetje@moffitt.usf.edu 
 
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 
 
 
MEMORANDUM
 
The purpose of this memorandum is to inform sites of the New Year’s holiday shipment 
schedule for Biologics, Inc.  Biologics Inc. Clinical Trials Serves will be open on January 
2, 2012, but will not ship drug on that day.  Normal shipments will resume on January 3, 
2012.  If you have questions or need to coordinate shipments in advance please don’t 
hesitate to contact your Clinical Trials Project Manager at 800/693-4906. 
 
This memorandum serves to notify the NCI and SWOG Statistical Center. 
 
cc: 
PROTOCOL & INFORMATION OFFICE 
 
Kenneth J. Kopecky, Ph.D. 
 
Megan Othus, Ph.D. 
 
Holly Gundacker, M.S. 
 
Jean Barce 
 
Tracy Maher 
Michele Seiler - CALGB 
Maury Bonds - ECOG 
Mary Voehl - Pfizer 
Katie Reitzel - Biologics 





 
 
 
 
December 1, 2011 
 
TO: 
ALL SWOG MEMBER, CCOP AND AFFILIATE MEDICAL ONCOLOGISTS 
AND PATHOLOGISTS; CTSU 
 
FROM: 
Sandi Jo Fredette, Protocol Coordinator 
 
RE: 
S0535, "A Phase II Study of ATRA, Arsenic Trioxide and Gemtuzumab 
Ozogamicin in Patients with Previously Untreated High-Risk Acute 
Promyelocytic Leukemia"  Study Coordinators:  Drs. J.E. Lancet, R. 
Komrokji, C.L. Willman, and M.L. Slovak. 
 
MEMORANDUM 
 
Study Coordinator:  Jeffrey E. Lancet, M.D. 
Phone number:  813/745-6841 
E-mail:  lancetje@moffitt.usf.edu 
 
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 
 
 
MEMORANDUM
 
The purpose of this memorandum is to inform sites of the Holiday closure of Biologics, 
Inc.  Biologics, Inc. Clinical Trial Services is closed Friday, December 23, 2011 through 
Sunday December 25, 2011 for the holidays. Regular business hours will resume on 
Monday, December 26, 2011. If you have questions or need to coordinate shipments in 
advance, please don’t hesitate to contact your Clinical Trial Project Manager at 800/693-
4906. 
 
This memorandum serves to notify the NCI and SWOG Statistical Center. 
 
cc: 
PROTOCOL & INFORMATION OFFICE 
 
Kenneth J. Kopecky, Ph.D. 
 
Megan Othus, Ph.D. 
 
Holly Gundacker, M.S. 
 
Jean Barce 
 
Tracy Maher 
Michele Seiler - CALGB 
Maury Bonds - ECOG 
Mary Voehl - Pfizer 
Katie Reitzel - Biologics 


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

 
 
 
 
 
Distribution Date: 
November 15, 2011 
CTEP Submission Date: 
November 1, 2011 
 
 
TO: 
ALL SWOG GROUP MEMBER, CCOP AND AFFILIATE MEDICAL 
ONCOLOGISTS AND PATHOLOGISTS; CTSU 
 
FROM: 
Sandi Jo Fredette, Protocol Coordinator 
 
RE: 
S0535, "A Phase II Study of ATRA, Arsenic Trioxide and Gemtuzumab 
Ozogamicin in Patients with Previously Untreated High-Risk Acute 
Promyelocytic Leukemia"  Study Coordinators:  Drs. J.E. Lancet, R. 
Komrokji, C.L. Willman, and M.L. Slovak. 
 
REVISION #11 
 
Study Coordinator:  Jeffrey E. Lancet, M.D. 
Phone number:  813/745-6841 
E-mail:  lancetje@moffitt.usf.edu 
 
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 #11
 
Institutions should update their local consent forms to include the changes to the Model 
Consent Form.  
 
SWOG considers that the Model Consent Form changes do not represent an alteration in 
risk-benefit ratio.  Therefore, local accrual does not need to be suspended pending 
implementation of these changes. 
 
Patients currently receiving protocol therapy, and patients who have signed a consent 
form but not yet started treatment need not be informed of these changes unless 
required by the local Institutional Review Board (IRB). 
 
The above-referenced study has been revised as follows: 
 
1. 
Title Page:  The Version Date has been updated.  “Southwest Oncology Group” 
has been updated to “SWOG” above the title and in the participants list. 


 
S0535 
 
Revision #11 (contd.) 
 
Page 2 



 
2. 
Page 14, Section 5.1e:  The window for ATRA allowance prior to registration has 
been updated from 3 days to 5 days. 
 
3. 
Page 19, Section 7.3:  The “¿” footnote reference has been added to ATRA in the 
treatment table with associated “¿” footnote indicating that Day 1 of treatment will 
be the first day the patient is treated with ATRA, regardless of patient’s 
registration status.  The ʌ footnote below the treatment table has been updated 
to indicate that gemtuzumab ozogamicin may be delayed until Day 6 (previously 
Day 5).   
 
4. 
Page 22, Section 7.8a:  This section has been updated to clarify that subsequent 
bone marrow and biopsies will not be submitted centrally for cytogenetics and 
RT-PCR, but that these tests are still performed locally. 
 
5. 
Page 28, Section 8.3b:  A new bullet was added as follows: 
 
Other Arsenic Trioxide-Related Toxicity: If grade  3, then hold treatment until 
clear clinical evidence of resolution to  Grade 1 and then resume treatment with 
a 50% dose reduction (0.075 mg/kg/day). If toxicity persists for more than 14 
days after holding treatment or recurrent toxicity occurs despite dose reduction, 
then discontinue As2O3. 
 
6. 
Page 31, Section 8.5a:  A new bullet was added as follows: 
 
Other 6-MP or MTX-Related Toxicities: If grade  3, then hold treatment.  
Treatment may resume after a 50% dose reduction when toxicity resolves to  
Grade 1.  If toxicity reoccurs after a first dose reduction, treatment may resume 
again after another 50% dose reduction (i.e., 25% of original dose) when toxicity 
resolves to  Grade 1.  If toxicity reoccurs after a second dose reduction then 
discontinue drug(s). 
 
7. 
Page 32, Section 9.0:  The “ƒ” footnote has been updated to be consistent with 
the updated 5 day ATRA allowance.  The “ü” footnote has been updated to clarify 
the subsequent specimen submission requirements and to reference Section 
7.8a. 
 
8. 
Page 51a, Model Consent Form:  The timeline for follow up visits has been 
updated to be consistent with the protocol, updating from every 3 months for 3 
years to “every 3 months for the first year, every 6 months for the second year 
and at 3 years from the time you finish treatment”. 
 
This memorandum serves to notify the NCI and SWOG Statistical Center. 
 
 
cc: 
PROTOCOL & INFORMATION OFFICE 
 
Megan Othus, Ph.D. 
 
Holly Gundacker, M.S. 
 
Tracy Maher 
 
Jean Barce 
 
Michele Seiler - CALGB 
Mary Bonds - ECOG 
Mary Voehl - Pfizer 
Katie Reitzel - Biologics 
 
 
 


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November 1, 2011 
 
 
TO: 
ALL SWOG MEMBER, CCOP AND AFFILIATE MEDICAL ONCOLOGISTS 
AND PATHOLOGISTS; CTSU 
 
FROM: 
Sandi Jo Fredette, Protocol Coordinator 
 
RE: 
S0535, "A Phase II Study of ATRA, Arsenic Trioxide and Gemtuzumab 
Ozogamicin in Patients with Previously Untreated High-Risk Acute 
Promyelocytic Leukemia"  Study Coordinators:  Drs. J.E. Lancet, R. 
Komrokji, C.L. Willman, and M.L. Slovak. 
 
MEMORANDUM 
 
Study Coordinator:  Jeffrey E. Lancet, M.D. 
Phone number:  813/745-6841 
E-mail:  lancetje@moffitt.usf.edu 
 
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 
 
 
MEMORANDUM
 
The purpose of this memorandum is to inform sites of the Thanksgiving holiday closure of 
Biologics, Inc. Biologics, Inc. Clinical Trial Services will be closed Thursday, November 
24, 2011 and Friday, November 25, 2011 for the Thanksgiving holiday. Regular 
business hours will resume on Monday, November 28, 2011. If you have questions or 
need to coordinate shipments in advance, please don’t hesitate to contact your Clinical 
Trial Project Manager at 800/693-4906. 
 
This memorandum serves to notify the NCI and SWOG Statistical Center. 
 
 
cc: 
PROTOCOL & INFORMATION OFFICE 
Michele Seiler - CALGB 
Megan Othus, Ph.D. 
Mary Bonds - ECOG 
Holly Gundacker, M.S. 
Mary Voehl - Pfizer 
Tracy Maher 
Katie Reitzel - Biologics 
Jean Barce 
 
 
 


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
 
 
 
 
August 15, 2011 
 
TO: 
ALL SWOG MEMBER, CCOP AND AFFILIATE MEDICAL ONCOLOGISTS 
AND PATHOLOGISTS; CTSU 
 
FROM: 
Sandi Jo Fredette, Protocol Coordinator 
 
RE: 
S0535, "A Phase II Study of ATRA, Arsenic Trioxide and Gemtuzumab 
Ozogamicin in Patients with Previously Untreated High-Risk Acute 
Promyelocytic Leukemia"  Study Coordinators:  Drs. J.E. Lancet, R. 
Komrokji, C.L. Willman, and M.L. Slovak. 
 
MEMORANDUM 
 
Study Coordinator:  Jeffrey E. Lancet, M.D. 
Phone number:  813/745-6841 
E-mail:  lancetje@moffitt.usf.edu 
 
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 
 
 
MEMORANDUM
 
The purpose of this memorandum is to inform sites of the Labor Day Holiday closure of 
Biologics, Inc.  Biologics, Inc. Clinical Trial Services is closed Monday, September 5, 
2011 for the Labor Day holiday. Regular business hours will resume on Tuesday, 
September 6, 2011. If you have questions or need to coordinate shipments in advance, 
please don’t hesitate to contact your Clinical Trial Project Manager at 800/693-4906 
 
This memorandum serves to notify the NCI and SWOG Statistical Center. 
 
cc: 
PROTOCOL & INFORMATION OFFICE 
 
Kenneth J. Kopecky, Ph.D. 
 
Megan Othus, Ph.D. 
 
Holly Gundacker, M.S. 
 
Jean Barce 
 
Tracy Maher 
Camille White, C.C.R.P 
Michele Seiler - CALGB 
Hayley Dorfman - ECOG 
Mary Voehl - Pfizer 
Katie Reitzel - Biologics 





 
 
 
 
June 15, 2011 
 
TO: 
ALL SWOG MEMBER, CCOP AND AFFILIATE MEDICAL ONCOLOGISTS 
AND PATHOLOGISTS; CTSU 
 
FROM: 
Sandi Jo Fredette, Protocol Coordinator 
 
RE: 
S0535, "A Phase II Study of ATRA, Arsenic Trioxide and Gemtuzumab 
Ozogamicin in Patients with Previously Untreated High-Risk Acute 
Promyelocytic Leukemia"  Study Coordinators:  Drs. J.E. Lancet, R. 
Komrokji, C.L. Willman, and M.L. Slovak. 
 
MEMORANDUM 
 
Study Coordinator:  Jeffrey E. Lancet, M.D. 
Phone number:  813/745-6841 
E-mail:  lancetje@moffitt.usf.edu 
 
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 
 
 
MEMORANDUM
 
The purpose of this memorandum is to inform sites of the Independence Day Holiday 
closure of Biologics, Inc.  Biologics, Inc. Clinical Trial Services is closed Monday, July 4, 
2011 for the Independence Day holiday. Regular business hours will resume on Tuesday, 
July 5, 2011. If you have questions or need to coordinate shipments in advance, please 
don’t hesitate to contact your Clinical Trial Project Manager at 800/693-4906 
 
Additionally, please note that the gemtuzumab ozogamicin drug order form has been 
updated.  The updated form can be downloaded from the protocol abstract page on the 
SWOG website (www.swog.org).  Sites are instructed to begin using the updated order 
form immediately. 
 
This memorandum serves to notify the NCI and SWOG Statistical Center. 
 
cc: 
PROTOCOL & INFORMATION OFFICE 
Camille White, C.C.R.P 
Kenneth J. Kopecky, Ph.D. 
Michele Seiler - CALGB 
Megan Othus, Ph.D. 
Hayley Dorfman - ECOG 
Holly Gundacker, M.S. 
Mary Voehl - Pfizer 
Jean Barce 
Katie Reitzel - Biologics 
Tracy Maher 


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

 
 
 
 
 
May 15, 2011 
 
 
TO: 
ALL 
SOUTHWEST 
ONCOLOGY 
GROUP 
MEMBER, 
CCOP 
AND 
AFFILIATE MEDICAL ONCOLOGISTS AND PATHOLOGISTS; CTSU 
 
FROM: 
Sandi Jo Fredette, Protocol Coordinator 
 
RE: 
S0535, "A Phase II Study of ATRA, Arsenic Trioxide and Gemtuzumab 
Ozogamicin in Patients with Previously Untreated High-Risk Acute 
Promyelocytic Leukemia"  Study Coordinators:  Drs. J.E. Lancet, R. 
Komrokji, C.L. Willman, and M.L. Slovak. 
 
MEMORANDUM 
 
Study Coordinator:  Jeffrey E. Lancet, M.D. 
Phone number:  813/745-6841 
E-mail:  lancetje@moffitt.usf.edu 
 
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 
 
 
MEMORANDUM
 
The purpose of this memorandum is to inform sites that Biologics, Inc. Clinical Trial 
Services will be closed on Monday, May 30, for the Memorial Day holiday. Regular 
business hours will resume on Tuesday, May 31.  Please plan drug orders accordingly.  If 
you have questions or need to coordinate shipments in advance, please contact your 
Clinical Trial Project Manager at 800/693-4906. 
 
This memorandum serves to notify the NCI and SWOG Statistical Center. 
 
 
 
cc: 
PROTOCOL & INFORMATION OFFICE 
Camille White, C.C.R.P 
Kenneth J. Kopecky, Ph.D. 
Michele Seiler - CALGB 
Megan Othus, Ph.D. 
Hayley Dorfman - ECOG 
Holly Gundacker, M.S. 
Mary Voehl - Pfizer 
Jean Barce 
Katie Reitzel - Biologics 
Tracy Maher 


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

 
 
 
 
 
May 1, 2011 
 
 
TO: 
ALL 
SOUTHWEST 
ONCOLOGY 
GROUP 
MEMBER, 
CCOP 
AND 
AFFILIATE MEDICAL ONCOLOGISTS AND PATHOLOGISTS; CTSU 
 
FROM: 
Sandi Jo Fredette, Protocol Coordinator 
 
RE: 
S0535, "A Phase II Study of ATRA, Arsenic Trioxide and Gemtuzumab 
Ozogamicin in Patients with Previously Untreated High-Risk Acute 
Promyelocytic Leukemia"  Study Coordinators:  Drs. J.E. Lancet, R. 
Komrokji, C.L. Willman, and M.L. Slovak. 
 
MEMORANDUM 
 
Study Coordinator:  Jeffrey E. Lancet, M.D. 
Phone number:  813/745-6841 
E-mail:  lancetje@moffitt.usf.edu 
 
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 
 
 
MEMORANDUM
 
The purpose of this memorandum is to instruct sites on pre-ordering gemtuzumab 
ozogamicin.  In order to avoid treatment delay, gemtuzumab ozogamicin may be pre-
ordered at the time a patient is being screened for study enrollment. In the space for 
patient ID, sites should write "pre-order".  If a drug is pre-ordered and the patient is not 
enrolled, the site is instructed NOT to return the pre-ordered supply, but instead to keep it 
on hand for the next potential patient.  Section 3.5c will be updated to reflect this during 
the next protocol revision. 
 
This memorandum serves to notify the NCI and SWOG Statistical Center. 
 
 
cc: 
PROTOCOL & INFORMATION OFFICE 
Camille White, C.C.R.P 
Kenneth J. Kopecky, Ph.D. 
Michele Seiler - CALGB 
Megan Othus, Ph.D. 
Hayley Dorfman - ECOG 
Holly Gundacker, M.S. 
Mary Voehl - Pfizer 
Jean Barce 
Katie Reitzel - Biologics 
Tracy Maher 


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

 
 
 
 
 
Distribution Date: 
April 15, 2011 
CTEP Submission Date: 
April 7, 2011 
 
 
TO: 
ALL 
SOUTHWEST 
ONCOLOGY 
GROUP 
MEMBER, 
CCOP 
AND 
AFFILIATE MEDICAL ONCOLOGISTS AND PATHOLOGISTS; CTSU 
 
FROM: 
Sandi Jo Fredette, Protocol Coordinator 
 
RE: 
S0535, "A Phase II Study of ATRA, Arsenic Trioxide and Gemtuzumab 
Ozogamicin in Patients with Previously Untreated High-Risk Acute 
Promyelocytic Leukemia"  Study Coordinators:  Drs. J.E. Lancet, R. 
Komrokji, C.L. Willman, and M.L. Slovak. 
 
REVISION #10 
 
Study Coordinator:  Jeffrey E. Lancet, M.D. 
Phone number:  813/745-6841 
E-mail:  lancetje@moffitt.usf.edu 
 
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 #10
 
Institutions should update their local consent forms to include the changes to the Model 
Consent Form.  
 
The SWOG considers that the Model Consent Form changes do not represent an 
alteration in risk-benefit ratio.  Therefore, local accrual does not need to be suspended 
pending implementation of these changes. 
 
Patients currently on treatment need not be informed of these changes unless required 
by the local Institutional Review Board (IRB). 
  
1. 
Title Page:  The Version Date has been updated. 


 
S0535 
 
Revision #10 (contd.) 
 
Page 2 



 
2. 
Pages 11-11a, Section 3.4c:  The supplier has been updated from Wyeth, Corp. 
to Pfizer, Inc.  Drug ordering information has been updated to allow orders by the 
signature of the investigator or an authorized designate (previously required 
oncologist’s signature).  Information regarding use of commercial supplies to 
avoid treatment delays has been replaced by information allowing pre-orders for 
patients who are planned to be enrolled.  Drug return and accountability 
information has been added. Information from Page 11 has been displaced to 
Page 11a. 
 
3. 
Page 32, Section 9.0:  The ¥ footnote has been updated to require the indicated 
items after the patient is off treatment at the remaining of months 3, 6, 9, 12, 18, 
24 and 36 from the time of initial registration (previously every 3 months until 3 
years from initial registration). 
 
4. 
Page 33, Section 10.1a:  The requirement for > 20% marrow cellularity has been 
removed from the A1 bone marrow status in order to be consistent with current 
guidelines. 
 
5. 
Page 39, Section 14.16:  This section has been updated to require submission of 
the Follow Up Form after off treatment at the remaining of of months 3, 6, 9, 12, 
18, 24 and 36 from the time of initial registration (previously every 3 months after 
off treatment for the first year, every 6 months for the second year, then at the 
end of the third year after patient entered the study). 
 
6. 
Page 59, Model Consent Form:  Wyeth Corp. has been updated to Pfizer Inc. in 
the list of organizations that may view patient medical records.  The fourth 
paragraph in the “What are the costs of taking part in this study” section has 
been updated to state that gemtuzumab ozogamicin is investigational and will be 
provided by Pfizer, Inc. (previously stated that it was commercially available but 
provided by Wyeth, Corp.). 
 
This memorandum serves to notify the NCI and Southwest Oncology Group Statistical 
Center. 
 
cc: 
PROTOCOL & INFORMATION OFFICE 
 
Kenneth J. Kopecky, Ph.D. 
 
Megan Othus, Ph.D. 
 
Holly Gundacker, M.S. 
 
Tracy Maher 
 
Camille White, C.C.R.P 
 
Jean Barce 
Michele Seiler - CALGB 
Hayley Dorfman - ECOG 
Mary Voehl - Pfizer 
Katie Reitzel - Biologics 




 
 
 
 
 
 
 
Distribution Date: 
January 15, 2011 
Effective Date: 
January 4, 2011 
E-mailed Date: 
January 4, 2011 
 
TO: 
ALL SOUTHWEST ONCOLOGY GROUP MEMBER, CCOP AND 
AFFILIATE MEDICAL ONCOLOGISTS AND PATHOLOGISTS; CTSU 
 
FROM: 
Sandi Jo Fredette, Protocol Coordinator 
 
RE: 
S0535, "A Phase II Study of ATRA, Arsenic Trioxide and Gemtuzumab 
Ozogamicin in Patients with Previously Untreated High-Risk Acute 
Promyelocytic Leukemia"  Study Coordinators:  Drs. J.E. Lancet, R. 
Komrokji, C.L. Willman, and M.L. Slovak. 
 
STATUS UPDATE 
 
Study Coordinator:  Jeffrey E. Lancet, M.D. 
Phone number:  813/745-6841 
E-mail:  lancetje@moffitt.usf.edu 
 
IRB Review Requirements 
 
(   ) 
Full board review required.  Reason: 
(   ) Initial activation  
(   ) 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 
 
 
RE-ACTIVATION
 
Investigational gemtuzumab ozogamicin (Mylotarg) is now available for distribution to 
sites; therefore, the above-referenced study will re-open to accrual effective 2:00 p.m. 
EST on January 4, 2011.  Note that prior to re-activation of this study, the local IRB must 
review and approve Revision #9, which changes gemtuzumab ozogamicin from 
commercial to investigational supply. 
 
This memorandum serves to notify the NCI and Southwest Oncology Group Statistical 
Center. 
 
 
cc: 
PROTOCOL & INFORMATION OFFICE 
Camille White, C.C.R.P. 
Kenneth J. Kopecky, Ph.D. 
Michael Kelly - CALGB 
Megan Othus, Ph.D. 
Michele Seiler - CALGB 
Holly Gundacker, M.S. 
Hayley Dorfman - ECOG 
Jean Barce 
Mary Voehl - Pfizer 
Tracy Maher 
Karl Buer - Biologics 
 
 





 
 
 
 
Distribution Date: 
January 15, 2011 
E-mailed Date: 
January 4, 2011 
CTEP Submission Date: 
October 5, 2010 
 
TO: 
ALL 
SOUTHWEST 
ONCOLOGY 
GROUP 
MEMBER, 
CCOP 
AND 
AFFILIATE MEDICAL ONCOLOGISTS AND PATHOLOGISTS; CTSU 
 
FROM: 
Sandi Jo Fredette, Protocol Coordinator 
 
RE: 
S0535, "A Phase II Study of ATRA, Arsenic Trioxide and Gemtuzumab 
Ozogamicin in Patients with Previously Untreated High-Risk Acute 
Promyelocytic Leukemia"  Study Coordinators:  Drs. J.E. Lancet, R. 
Komrokji, C.L. Willman, and M.L. Slovak. 
 
REVISION #9 
 
Study Coordinator:  Jeffrey E. Lancet, M.D. 
Phone number:  813/745-6841 
E-mail:  lancetje@moffitt.usf.edu 
 
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 #9
 
The above referenced protocol has been updated as follows: 
 
1. 
Title Page:  IND #66,366 has been added to gemtuzumab ozogamicin.  This 
change has also been made in Section 3.4 (Page 9).  The Version Date has been 
updated.   
 
2. 
Page 11, Section 3.4d:  Information has been updated in the “Supplier” section to 
state that gemtuzumab ozogamicin is considered investigational for this study 
(previously commercial). 
 
3. 
Page 21, Section 7.7a:  The ANC requirement of 1.5 x 109/L has been updated to 
1.0 x 109/L to correct a typographical error. 
 
4. 
Page 49, Model Consent Form:  A sentence has been added to the end of the 
“Why is this study being done?” section to indicate that one of the chemotherapy 
drugs, gemtuzumab ozogamicin, is experimental. 


 
S0535 
 
Revision #9 (contd.) 
 
Page 2 

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

 
5. 
Pages 42e-44b, Sections 16.0-16.1g:  These sections have been updated/added 
to include adverse event reporting information for investigational drug in addition 
to the commercial drug reporting information.  Pages 44a-b have been added to 
prevent extensive repagination. 
 
 
6. 
Page 57, Model Consent Form:  A note regarding the increased death rate and 
lack of efficacy of gemtuzumab ozogamicin based on a previous study has been 
added to the risks/side effects section.  Institutions must update their local 
consent forms to include the changes to the Model Consent Form prior to 
enrolling new patients on this study. 
 
This revision may undergo expedited review at the discretion of the local IRB chair. 
 
Patients currently on treatment need not be informed of these changes unless required 
by the local Institutional Review Board (IRB). 
 
This memorandum serves to notify the NCI and Southwest Oncology Group Statistical 
Center. 
 
cc: 
PROTOCOL & INFORMATION OFFICE 
 
Kenneth J. Kopecky, Ph.D. 
 
Megan Othus, Ph.D. 
 
Holly Gundacker, M.S. 
 
Tracy Maher 
 
Camille White, C.C.R.P 
 
Jean Barce 
Michael Kelly - CALGB 
Michele Seiler - CALGB 
Hayley Dorfman - ECOG 
Mary Voehl - Pfizer 
Karl Buer - Biologics 



 
 
 
 
 
 
November 1, 2010 
 
TO: 
ALL SOUTHWEST ONCOLOGY GROUP MEMBER, CCOP, AND AFFILIATE 
MEDICAL ONCOLOGISTS 
 
FROM: 
Southwest Oncology Group Operations Office 
 
RE: 
Biologics Inc. Holiday Schedule 
 
MEMORANDUM
 
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 
 
 
MEMORANDUM
 
The Biologics Inc. Clinical Trial Services will not be processing drug orders for shipment 
from November 25 to November 26, 2010 and Friday, December 24 and Friday, December 
31, 2010 due to the holidays. 
 
For the Thanksgiving holiday, the last shipment date will be Wednesday, November 24. 
Drug shipments will resume on Monday, November 29. For the Christmas holiday, the last 
shipment dates will be Thursday, December 23, with shipment resuming Monday, 
December 27. For the New Year’s holiday, the last shipment date will be Thursday, 
December 30, 2010. Drug shipments will resume Monday, January 3, 2011. 
 
This upcoming holiday closure schedule pertains to the following studies: 
 
 
S0535 Leukemia 
 
S0635 Lung 
 
S0636 Lung 
 
S0709 Lung 
 
S0800 Breast 
 
S0904 Gynecologic 
 
Please append this notice to the front of your copy of the protocol. 
 
This memorandum serves to notify the NCI and the Southwest Oncology Group Statistical 
Center. 
 
cc: PROTOCOL & INFORMATION OFFICE Camille White, C.C.R.P. Larry Kaye 
 
John Crowley, Ph.D. 
Jean Barce 
Janice Leaman 
 
William Barlow, Ph.D. 
Jennie Barrett 
Arthur Cannon – Genentech 
 
Mary Redman, Ph.D. 
Iris Buchanan 
Katie Reitzel – Biologics Inc. 
 
Danika Lew, M.A. 
Stephanie Edwards 
 
James Moon, M.S. 
Jeri Jardine 
 
 
Operations Office 
4201 Medical Drive (Suite 250) • San Antonio, TX 78229 • Telephone 210-614-8808 • FAX 210-614-0006 • http://swog.org 


 
 
 
 
 
Distribution Date: 
September 15, 2010 
CTEP Submission Date: August 30, 2010 
 
TO: 
ALL 
SOUTHWEST 
ONCOLOGY 
GROUP 
MEMBER, 
CCOP 
AND 
AFFILIATE MEDICAL ONCOLOGISTS AND PATHOLOGISTS; CTSU 
 
FROM: 
Sandi Jo McMillan, Protocol Coordinator 
 
RE: 
S0535, "A Phase II Study of ATRA, Arsenic Trioxide and Gemtuzumab 
Ozogamicin in Patients with Previously Untreated High-Risk Acute 
Promyelocytic Leukemia"  Study Coordinators:  Drs. J.E. Lancet, R. 
Komrokji, C.L. Willman, and M.L. Slovak. 
 
REVISION #8 
 
Study Coordinator:  Jeffrey E. Lancet, M.D. 
Phone number:  813/745-6841 
E-mail:  lancetje@moffitt.usf.edu 
 
IRB Review Requirements 
 
 (   ) Full board review required.  Reason: 
 
(   ) 
Initial activation  
 
(   ) 
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 #8
 
The above referenced protocol has been updated as follows: 
 
1. 
Title Page:  The Version Date has been updated.  The contact information for Dr. 
Jeffrey Lancet and Dr. Rami Komrokji has been updated. 
 
2. 
Pages 26-26a, Section 8.1:  The criteria for reporting Adverse Events have been 
updated.  Effective October 1, 2010 CTCAE Version 4.0 will be utilized for SAE 
reporting.  The CTCAE Version 3.0 will continue to be used for routine toxicity 
reporting.  Page 26a was added to prevent extensive repagination. 
 
This memorandum serves to notify the NCI and Southwest Oncology Group Statistical 
Center. 
 
cc: 
PROTOCOL & INFORMATION OFFICE 
Jean Barce 
Kenneth J. Kopecky, Ph.D. 
Michael Kelly - CALGB 
Megan Othus, Ph.D. 
Ryan Palmer - ECOG 
Holly Gundacker, M.S. 
Mary Voehl - Pfizer 
Tracy Maher 
Karl Buer - Biologics 
Camille White 
 
 
 
Operations Office 
4201 Medical Drive (Suite 250) •San Antonio, TX 78229 • Telephone 210-614-8808 • FAX 210-614-0006 • http://swog.org 


 
 
 
 
 
 
September 1, 2010 
 
 
TO: 
ALL 
SOUTHWEST 
ONCOLOGY 
GROUP 
MEMBER, 
CCOP 
AND 
AFFILIATE MEDICAL ONCOLOGISTS AND PATHOLOGISTS; CTSU 
 
FROM: 
Sandi Jo McMillan, Protocol Coordinator 
 
RE: 
S0535, "A Phase II Study of ATRA, Arsenic Trioxide and Gemtuzumab 
Ozogamicin in Patients with Previously Untreated High-Risk Acute 
Promyelocytic Leukemia"  Study Coordinators:  Drs. J.E. Lancet, R. 
Komrokji, C.L. Willman, and M.L. Slovak. 
 
MEMORANDUM
 
Study Coordinator:  Jeffrey E. Lancet, M.D. 
Phone number:  813/745-6841 
E-mail:  lancetje@moffitt.usf.edu 
 
IRB Review Requirements 
 
 (   ) Full board review required.  Reason: 
 
(   ) 
Initial activation  
 
(   ) 
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 
 
 
MEMORANDUM
 
The purpose of this memorandum is to clarify timing of doses for idarubicin used in place of 
daunorubicin during the national shortage. The memorandum dated January 15, 2010 
instructed that idarubicin should be administered on Days 1-2. Since that time, the study 
team has determined that idarubicin should more correctly be given on Days 1-3, so during 
Revision #5 the protocol was updated to reflect this timing. Please note that the protocol is 
correct in instructing sites to administer idarubicin on Days 1-3. 
 
This memorandum serves to notify the NCI and Southwest Oncology Group Statistical 
Center. 
 
cc: 
PROTOCOL & INFORMATION OFFICE 
 
Kenneth J. Kopecky, Ph.D. 
 
Megan Othus, Ph.D. 
 
Holly Gundacker, M.S. 
 
Tracy Maher 
 
Camille White 
 
Jean Barce 
Michael Kelly - CALGB 
Ryan Palmer - ECOG 
Mary Voehl - Pfizer 
Karl Buer - Biologics 
 
Operations Office 
4201 Medical Drive (Suite 250) •San Antonio, TX 78229 • Telephone 210-614-8808 • FAX 210-614-0006 • http://swog.org 


 
 
 
 
 
Distribution Date: 
July 1, 2010 
Effective Date: 
June 22, 2010 
E-mailed Date: 
June 22, 2010 
 
TO: 
ALL 
SOUTHWEST 
ONCOLOGY 
GROUP 
MEMBER, 
CCOP 
AND 
AFFILIATE MEDICAL ONCOLOGISTS AND PATHOLOGISTS; CTSU 
 
FROM: 
Sandi Jo McMillan, Protocol Coordinator 
 
RE: 
S0535, "A Phase II Study of ATRA, Arsenic Trioxide and Gemtuzumab 
Ozogamicin in Patients with Previously Untreated High-Risk Acute 
Promyelocytic Leukemia"  Study Coordinators:  Drs. J.E. Lancet, R. 
Komrokji, C.L. Willman, and M.L. Slovak. 
 
STATUS NOTICE 
 
Study Coordinator:  Jeffrey E. Lancet, M.D. 
Phone number:  813/745-6841 
E-mail:  lancetje@moffitt.usf.edu 
 
IRB Review Requirements 
 
 (   ) Full board review required.  Reason: 
 
(   ) 
Initial activation  
 
(   ) 
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 
 
 
TEMPORARY CLOSURE
 
Commercial gemtuzumab ozogamicin (Mylotarg) has been withdrawn from the market and 
will no longer be available to new patients.  Therefore, this study will be temporarily closed 
effective 5:00 p.m. EDT on June 22, 2010 while alternate drug supply is obtained. 
 
The FDA press release can be accessed at  
http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm216448.htm. 
 
Sites must forward this information to their local IRB.  With local IRB approval (and with 
implementation of any additional local IRB requirements), patients currently on treatment 
may continue treatment as planned with commercial drug supply.  Documentation of this 
approval must be kept in the protocol file.  Patients currently on treatment must be informed 
of the updated information.  This information regarding drug availability and patient 
information may be located on the FDA press release noted above. 
 
The study will be re-opened when the conversion to investigational drug supply for new 
patients has been completed.  A Re-Activation memorandum will be distributed at that time. 
 
This memorandum serves to notify the NCI and Southwest Oncology Group Statistical 
Center. 
 
cc: 
PROTOCOL & INFORMATION OFFICE 
Jean Barce 
Kenneth J. Kopecky, Ph.D. 
Michael Kelly - CALGB 
Megan Othus, Ph.D. 
Ryan Palmer - ECOG 
Holly Gundacker, M.S. 
Mary Voehl - Pfizer 
Tracy Maher 
Karl Buer - Biologics 
Camille White 
 
 
Operations Office 
4201 Medical Drive (Suite 250) •San Antonio, TX 78229 • Telephone 210-614-8808 • FAX 210-614-0006 • http://swog.org 


 
 
 
 
 
Distribution Date: 
July 1, 2010 
CTEP Submission Date: June 15, 2010 
 
TO: 
ALL 
SOUTHWEST 
ONCOLOGY 
GROUP 
MEMBER, 
CCOP 
AND 
AFFILIATE MEDICAL ONCOLOGISTS AND PATHOLOGISTS; CTSU 
 
FROM: 
Sandi Jo McMillan, Protocol Coordinator 
 
RE: 
S0535, "A Phase II Study of ATRA, Arsenic Trioxide and Gemtuzumab 
Ozogamicin in Patients with Previously Untreated High-Risk Acute 
Promyelocytic Leukemia"  Study Coordinators:  Drs. J.E. Lancet, R. 
Komrokji, C.L. Willman, and M.L. Slovak. 
 
REVISION #7 
 
Study Coordinator:  Jeffrey E. Lancet, M.D. 
Phone number:  813/745-6841 
E-mail:  lancetje@moffitt.usf.edu 
 
IRB Review Requirements 
 
 (   ) Full board review required.  Reason: 
 
(   ) 
Initial activation  
 
(   ) 
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
 
The above referenced protocol has been updated as follows: 
 
1. 
The Version Date has been updated. 
 
2. 
Page 11, Section 3.4c:  The drug ordering information for gemtuzumab ozogamicin 
has been updated to indicate that the drug order form may also be found on the 
protocol abstract page of the CTSU website (www.ctsu.org).  
 
3. 
Page 15, Section 5.1g:  The first bullet in this section has been updated to include 
the requirement that CALGB sites submit specimens to a CLIA-approved laboratory.  
A reference to Section 15.4 has been added.  The third bullet has been updated to 
remove the requirement that CALGB sites be registered to CALGB 9862 prior to 
registration (previously required for PCR specimen submission) and instead include 
the requirements that patients be offered participation on CALGB 9862, and that 
consenting patients be registered to CALGB 9862 prior to registration. 
 
4. 
Page 21, Section 7.5e: The “*” footnote reference has been added to “Daunomycin” 
in the treatment table.  The associated “*” footnote has been added advising that 
idarubicin, 12mg/m2/day may be used in place of daunomycin only if daunomycin is 
unavailable due to the national shortage, and that this must be documented on the 
treatment summary form. 
 
 
Operations Office 
4201 Medical Drive (Suite 250) •San Antonio, TX 78229 • Telephone 210-614-8808 • FAX 210-614-0006 • http://swog.org 


 
S0535 
 
Revision #7 (contd.) 
 
Page 2 
 
 
 
 
 
 
 
 
5. 
Page 41, Section 5.2b:  A sentence has been added indicating that CLIA 
certificates will be verified at the time of audit. 
 
6. 
Pages 42c-42e, Section 15.4a:  This section has been updated to include the 
specimen submission information for PCR testing (15.4a.1), CALGB-9862 
(15.4a.2) and the associated submission time points (15.4a.3).  Page 42e has 
been added to prevent extensive repagination. 
 
7. 
Master Forms Set:  The S0535 Consolidation Cycles 3 and 4 Treatment Summary 
Form has been updated to collect information regarding the usage of idarubicin. The 
form number has been updated from #19935 to #38269. The form number has also 
been updated in Section 14.8 (Page 39) and 18.2i (Page 46). 
 
8. 
Master Forms Set: The S0535 Adverse Event Summary Form has been updated to 
allow idarubicin as an option to be used during Consolidation Cycles 3 and 4. The 
form number and Version Date remain the same. 
 
9. 
Pages 96, 98 and 99, Appendix 19.4:  The CTSU website url has been updated to 
www.ctsu.org throughout this section. 
 
Additionally, please note that this study has met the criteria to proceed to the second stage 
of accrual.  The study will not be closed pending data analysis, but will continue to 
complete accrual. 
 
This memorandum serves to notify the NCI and Southwest Oncology Group Statistical 
Center. 
 
cc: 
PROTOCOL & INFORMATION OFFICE 
 
Kenneth J. Kopecky, Ph.D. 
 
Megan Othus, Ph.D. 
 
Holly Gundacker, M.S. 
 
Tracy Maher 
 
Camille White 
 
Jean Barce 
Michael Kelly - CALGB 
Ryan Palmer - ECOG 
Virginia Dixon-Lipscomb – Wyeth 
Karl Buer - Biologics 
 
 


 
 
 
 
 
 
 
Distribution Date: 
June 1, 2010 
CTEP Submission Date: May 26, 2010 
 
 
 
TO: 
ALL 
SOUTHWEST 
ONCOLOGY 
GROUP 
MEMBER, 
CCOP 
AND 
AFFILIATE MEDICAL ONCOLOGISTS AND PATHOLOGISTS; CTSU 
 
FROM: 
Sandi Jo McMillan, Protocol Coordinator 
 
RE: 
S0535, "A Phase II Study of ATRA, Arsenic Trioxide and Gemtuzumab 
Ozogamicin in Patients with Previously Untreated High-Risk Acute 
Promyelocytic Leukemia"  Study Coordinators:  Drs. J.E. Lancet, R. 
Komrokji, C.L. Willman, and M.L. Slovak. 
 
REVISION #6 
 
Study Coordinator:  Jeffrey E. Lancet, M.D. 
Phone number:  813/745-6841 
E-mail:  lancetje@moffitt.usf.edu 
 
IRB Review Requirements 
 
 (   ) Full board review required.  Reason: 
 
(   ) 
Initial activation  
 
(   ) 
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 #6
 
The above-referenced protocol has been revised as follows: 
 
1. 
Title Page:  The Version Date has been updated. 
 
2. 
Pages 6-8b, Section 3.2b:  The toxicity information for arsenic trioxide has been 
replaced by the CAEPR Version 2.0 (March 26, 2010). 
 
CTEP has issued an updated CAEPR for arsenic trioxide.  This study did not 
contain a CAEPR previously; therefore, a significant number of risks have been 
added.  However, this information is considered to be similar to the risk information 
already communicated to patients in the Model Consent Form. 
 
Pages 8a-8b have been added to prevent extensive repagination. 
 
 
 
 
Operations Office 
4201 Medical Drive (Suite 250) •San Antonio, TX 78229 • Telephone 210-614-8808 • FAX 210-614-0006 • http://swog.org 


 
S0535 
 
Revision #6 (contd.) 
 
Page 2 
 
 
 
 
 
 
 
 
3. 
Pages 52-54a, Model Consent Form:  The following changes have been made to 
the Induction Therapy risks and side effects section of the Model Consent Form in 
order to be consistent with the updated arsenic trioxide CAEPR.  Many omissions 
were noted in the previous version of the consent form.  Therefore, patients 
currently on treatment must be informed of the added information as outlined 
in bold below. 
 
In the Likely Section 
x 
“Lower white blood count that may lead to infection, which could be life-
threatening” has been updated to “Decreased number of a type of white blood 
cell (neutrophil/granulocyte)” 
x 
“Lower platelets, which may lead to bruising or bleeding and which could be 
life-threatening.  This side effect may require you to receive a transfer of blood 
platelets from a donor.” has been updated to “Decreased number of a type of 
blood cell that help to clot blood (platelet)” 
x 
“Lower red blood counts, which may cause you to feel tired or have shortness 
of breath and require a transfer of red blood cells from a donor.  Low red blood 
counts could be life-threatening.”) has been updated to “Lack of enough red 
blood cells (anemia)” 
x 
“Fever, chills, headache” has been updated to “Fever”, “Chills” and “Headache 
or head pain” 
x 
“Nausea, vomiting, diarrhea” has been updated to “Nausea or the urge to 
vomit”, “Vomiting” and “Diarrhea” 
x 
“Loss of appetite, abdominal pain” has been updated to “Loss of appetite” and 
“Belly pain” 
x 
“Sores in the mouth” has been updated to “Irritation or sores in the lining of the 
mouth” 
x 
“Pain at the site of injection/local reaction” has been updated to “Inflammation 
(swelling and redness) or damage to the tissue surrounding where a drug was 
injected” 
x 
“Weakness” has been updated to “Muscle weakness” 
x 
“Difficulty breathing, shortness of breath” has been updated to “Shortness of 
breath” 
x 
“Fatigue” has been updated to “Fatigue or tiredness” 
x 
“Difficulty sleeping” has been updated to “Difficulty sleeping or falling asleep” 
x 
“Rash” has been updated to “Skin rash with the presence of macules (flat 
discolored area) and papules (raised bump)” 
x 
“Changes in blood pressure” has been updated to “High blood pressure” and 
“Low blood pressure” 
x 
“Dizziness” has been updated to “Dizziness (or sensation of lightheadedness, 
unsteadiness, or giddiness)” 
x 
“High blood sugar” has been updated to “Increased blood sugar level” 
x 
“”Headache” has been deleted to correct a duplication 
x 
“Low levels of potassium in the blood, which may cause: an irregular heartbeat; 
muscle weakness, cramping, or flaccid paralysis (limpness); leg discomfort; 
extreme thirst; frequent urination; confusion” has been updated to “Decreased 
blood level of potassium” 
x 
“Chest pain” has been updated to “Chest pain not heart related” 
x 
“Dryness of the skin and lips” has been updated to “Dryness of the lips” and 
“Dry skin” 
x 
“Damage to the kidneys, which could result in the need for dialysis” has been 
updated to “Sudden or traumatic injury to the kidney” 
x 
“Infection” has been added 
x 
“Itching” has been added (moved from Less Likely; previously “Itchy skin”) 


 
S0535 
 
Revision #6 (contd.) 
 
Page 3 
 
 
 
 
 
 
 
 
In the Less Likely Section 
x 
“Dry nose and mouth” has been updated to “Dry nose” and “Dry mouth” 
x 
“Fever associated with dangerously low levels of a type of white blood 
cell (neutrophils)” has been added 
x 
“Decreased number of all blood cell types” has been added” 
x 
“Unpleasant sensation of irregular and/or forceful beating of the heart” 
has been added 
x 
“Fast heartbeat; regular rhythm” has been added 
x 
“Irregular heartbeat resulting from an abnormality in one of the lower 
chambers of the heart (ventricle)” has been added 
x 
“Noise in the ears, such as ringing, buzzing, roaring, clicking” has been 
added 
x 
“Swelling or feeling of fullness and tightness in the abdomen (belly)” has 
been added 
x 
“Irritation or sores in the lining of the anus” has been added 
x 
“Heartburn ” has been added 
x 
“Inflammation (swelling and redness) of the pancreas” has been added 
x 
“Irritation or sores in the lining of the rectum” has been added 
x 
“Irritation or sores in the lining of the small bowel” has been added 
x 
“Swelling of the face” has been added 
x 
“Swelling of the extremities (arms and/or legs)” has been added 
x 
“Pain” has been added 
x 
“Infection associated with a decrease in a type of white blood cell 
(lymphocyte)” has been added 
x 
“Bruising” has been added 
x 
“Increased blood level of a liver enzyme (ALT/SGPT)” has been added 
x 
“Increased blood level of a liver enzyme (AST/SGOT)” has been added 
x 
“Increased blood level of a liver pigment (bilirubin) often a sign of liver 
problems” has been added 
x 
“Increased blood level of creatinine (a substance normally eliminated by 
the kidneys into the urine)” has been added 
x 
“Abnormal electrical conduction within the heart” has been added 
x 
“Increased blood level of a liver enzyme (GGT)” has been added 
x 
“Increased blood level of a fat-digesting enzyme (lipase)” has been added 
x 
“Increased blood level of a digestive enzyme (amylase)” has been added 
x 
“Weight loss” has been added 
x 
“Decrease in the total number of white blood cells (leukocytes)” has been 
added
x 
“More acid than normal in the blood” has been added 
x 
“Increased blood level of potassium” has been added 
x 
“Decreased blood level of magnesium” has been added 
x 
“Joint pain” has been added 
x 
“Bone pain” has been added 
x 
“Shrinking of the muscles” has been added 
x 
“Muscle pain” has been added 
x 
“Commonly known as “pins and needles”, where part of the body 
(typically a foot or hand) begins to tingle and becomes numb, or “falls 
asleep” ” has been added 
x 
“Weakness or paralysis (loss of muscle function) caused by damage to 
peripheral nerves (those nerves outside of brain and spinal cord)” has 
been added 
x 
“Inflammation (swelling and redness) or degeneration of the peripheral 
nerves (those nerves outside of brain and spinal cord) causing 
numbness, tingling, burning” has been added 
x 
“Anxiety, feelings of dread or danger” has been added 
x 
“More protein in the urine than usual, often a sign of kidney disease” has 
been added 


 
S0535 
 
Revision #6 (contd.) 
 
Page 4 
 
 
 
 
x 
“Stuffy or runny nose, sneezing” has been added 
x 
“Sudden constriction of the muscles in the walls of the bronchioles 
(small airways of the lung)” has been added 
x 
“Cough” has been added 
x 
“Irritation or sores in the lining of the voice box” has been added 
x 
“Irritation or sores in the lining of the throat” has been added 
x 
“Build up of a large amount of fluid between the layers of tissue that line 
the lungs and chest cavity” has been added 
x 
“A collection of symptoms including fever, difficulty breathing, chest 
pain, fluid in the lungs (seen on chest X-ray), fluid around the lungs and 
heart, and lack of oxygen first seen in patients receiving the drug retinoic 
acid” has been added 
x 
“Sore throat” has been added 
x 
“Irritation or sores in the lining of the windpipe” has been added 
x 
“Hair loss” has been added 
x 
“Excess sweating” has been added 
x 
“Area of bleeding within the skin causing a reddish purple discoloration” 
has been added 
x 
“Inflammation (swelling and redness) of the skin” has been added 
x 
“Thickening of the skin” has been added 
x 
“Darkening of the skin” has been added 
x 
“Hives” has been added 
x 
“Increase in the number and size of the pores in the capillaries (small 
blood vessels) which causes leakage of fluid from the blood to the tissue 
spaces resulting in dangerously low blood pressure, swelling and 
multiple organ failure” has been added 
x 
“Sudden reddening of the face and/or neck” has been added 
 
Page 54a has been added to prevent extensive repagination. 
 
4. 
Pages 54a-54e, Model Consent Form:  The following changes have been made to 
the Consolidation #1 and #2 Therapy risks and side effects section of the Model 
Consent Form in order to be consistent with the updated arsenic trioxide CAEPR.  
Many omissions were noted in the previous version of the consent form.  
Therefore, patients currently on treatment must be informed of the added 
information as outlined in bold below. 
 
 
In the Likely Section 
x 
“Fatigue” has been updated to “Fatigue or tiredness” 
x 
“Nausea” has been updated to “Nausea or the urge to vomit” 
x 
“Headache” has been updated to “Headache or head pain” 
x 
“Lower white blood count that may lead to infection, which could be life-
threatening” has been updated to “Decreased number of a type of white blood 
cell (neutrophil/granulocyte)” 
x 
“Lower platelets, which may lead to bruising or bleeding and which could be 
life-threatening.  This side effect may require you to receive a transfer of blood 
platelets from a donor.” has been updated to “Decreased number of a type of 
blood cell that help to clot blood (platelet)” 
x 
“Low blood oxygen levels” has been removed 
x 
“Vomiting” has been added 
x 
“Fever” has been added (moved from Less Likely) 
x 
“Infection” has been added 
x 
“Itching” has been added (moved from Less Likely) 
x 
“Skin rash with the presence of macules (flat discolored area) and 
papules (raised bump)” has been added 


 
S0535 
 
Revision #6 (contd.) 
 
Page 5 
 
 
 
 
In the Less Likely Section 
x 
“Fluid retention” has been removed 
x 
“Upper respiratory infection” has been removed 
x 
“Damage to the liver, which could cause yellowing of the skin and/or eyes” has 
been removed 
x 
“Heart problems (Abnormal electrical conduction within the heart and irregular 
heartbeat” has been updated to “Abnormal electrical conduction within the 
heart” 
x 
“Increased blood sugar level” has been added (moved from Likely; previously 
“High blood sugar”) 
x 
“Lack of enough red blood cells (anemia)” has been added (moved from Likely; 
previously Lower red blood counts that may cause you to feel tired or have 
shortness of breath and require a transfer of red blood cells from a donor.  Low 
red blood counts could be life-threatening.”) 
x 
“Belly pain” has been added (moved from Likely; previously “Abdominal pain”) 
x 
“Chest pain not heart-related” has been added (moved from Likely; previously 
“Chest pain”) 
x 
“Dry skin” and “Dry mouth” have been added (moved from Likely; previously 
“Dryness in the skin and lips”) 
x 
“Build up of a large amount of fluid between the layers of tissue that line the 
lungs and chest cavity” has been added (moved from Likely; previously “Fluid 
collection in the lungs”) 
x 
“Sudden or traumatic injury to the kidney” has been added (moved from Likely; 
previously “Damage to the kidneys, which could result in the need for dialysis”) 
x 
“Toothache” has been added (moved from Likely) 
x 
“Dizziness (or sensation of lightheadedness, unsteadiness, or giddiness)” has 
been added (moved from Likely; previously “Dizziness”) 
x 
“Fever associated with dangerously low levels of a type of white blood 
cell (neutrophils)” has been added 
x 
“Decreased number of all blood cell types” has been added 
x 
“Unpleasant sensation of irregular and/or forceful beating of the heart” 
has been added 
x 
“Fast heartbeat; regular rhythm” has been added 
x 
“Irregular heartbeat resulting from an abnormality in one of the lower 
chambers of the heart (ventricle)” has been added 
x 
“Noise in the ears, such as ringing, buzzing, roaring, clicking” has been 
added 
x 
“Swelling or feeling of fullness and tightness in the abdomen (belly)” has 
been added 
x 
“Irritation or sores in the lining of the anus” has been added 
x 
“Constipation” has been added 
x 
“Heartburn” has been added 
x 
“Irritation or sores in the lining of the mouth” has been added 
x 
“Inflammation (swelling and redness) of the pancreas” has been added 
x 
“Irritation or sores in the lining of the rectum” has been added 
x 
“Irritation or sores in the lining of the small bowel” has been added 
x 
“Swelling of the face” has been added 
x 
“Swelling of the extremities (arms and/or legs)” has been added 
x 
“Inflammation (swelling and redness) or damage to the tissue 
surrounding where a drug was injected” has been added 
x 
“Pain” has been added
x 
“Infection associated with a decrease in a type of white blood cell 
(lymphocyte)” has been added 
x 
“Bruising” has been added 
x 
“Increased blood level of a liver enzyme (ALT/SGPT)” has been added 
x 
“Increased blood level of a liver enzyme (AST/SGOT)” has been added 


 
S0535 
 
Revision #6 (contd.) 
 
Page 6 
 
 
 
 
x 
“Increased blood level of a liver pigment (bilirubin) often a sign of liver 
problems” has been added 
x 
“Increased blood level of creatinine (a substance normally eliminated by 
the kidneys into the urine)” has been added 
x 
“Increased blood level of a liver enzyme (GGT)” has been added 
x 
“Increased blood level of a fat-digesting enzyme (lipase)” has been added 
x 
“Increased blood level of a digestive enzyme (amylase)” has been added 
x 
“Weight loss” has been added 
x 
“Decrease in the total number of white blood cells (leukocytes)” has been 
added
x 
“More acid than normal in the blood” has been added 
x 
“Loss of appetite” has been added 
x 
“Increased blood level of potassium” has been added 
x 
“Decreased blood level of potassium” has been added 
x 
“Decreased blood level of magnesium” has been added 
x 
“Joint pain” has been added 
x 
“Bone pain” has been added 
x 
“Muscle weakness of the whole body” has been added 
x 
“Shrinking of muscles” has been added 
x 
“Muscle pain” has been added
x 
“Commonly known as “pins and needles”, where part of the body 
(typically a foot or hand) begins to tingle and becomes numb, or “falls 
asleep” ” has been added 
x 
“Weakness or paralysis (loss of muscle function) caused by damage to 
peripheral nerves (those nerves outside of brain and spinal cord)” has 
been added 
x 
“Inflammation (swelling and redness) or degeneration of the peripheral 
nerves (those nerves outside of brain and spinal cord) causing 
numbness, tingling, burning” has been added 
x 
“Anxiety, feelings of dread or danger” has been added 
x 
“Difficulty sleeping or falling asleep” has been added 
x 
“More protein in the urine than usual, often a sign of kidney disease” has 
been added 
x 
“Stuffy or runny nose, sneezing” has been added 
x 
“Sudden constriction of the muscles in the walls of the bronchioles 
(small airways of the lung)” has been added 
x 
“Cough” has been added 
x 
“Irritation or sores in the lining of the voice box” has been added 
x 
“Irritation or sores in the lining of the throat” has been added 
x 
“A collection of symptoms including fever, difficulty breathing, chest 
pain, fluid in the lungs (seen on chest X-ray), fluid around the lungs and 
heart, and lack of oxygen first seen in patients receiving the drug retinoic 
acid” has been added 
x 
“Sore throat” has been added 
x 
“Irritation or sores in the lining of the windpipe” has been added 
x 
“Hair loss” has been added 
x 
“Excess sweating” has been added 
x 
“Area of bleeding within the skin causing a reddish purple discoloration” 
has been added 
x 
“Inflammation (swelling and redness) of the skin” has been added 
x 
“Thickening of the skin” has been added 
x 
“Darkening of the skin” has been added 
x 
“Hives” has been added 
x 
“Increase in the number and size of the pores in the capillaries (small 
blood vessels) which causes leakage of fluid from the blood to the tissue 
spaces resulting in dangerously low blood pressure, swelling and 
multiple organ failure” has been added 
x 
“Sudden reddening of the face and/or neck” has been added 


 
S0535 
 
Revision #6 (contd.) 
 
Page 7 
 
 
 
 
x 
“High blood pressure” has been added 
x 
“Low blood pressure” has been added 
Pages 54b-54e have been added to prevent extensive repagination. 
Institutions must update their local consent forms to include the additions to the Model 
Consent Form. 
 
The Southwest Oncology Group considers that the Model Consent Form changes do not 
represent an alteration in risk-benefit ratio.  Therefore, local accrual does not need to be 
suspended pending implementation of these changes. 
 
Patients currently on treatment (and those who have already signed a consent form but 
have not yet started treatment) must be informed of these additions.  The manner by which 
this notification takes place is at the discretion of the local institution.  At a minimum, the 
patient must be notified at the next visit and this notification process must be documented 
in the patient chart. 
 
This amendment is being submitted in response to an RA from Dr. Naoko Takebe 
(takeben@mail.nih.gov; 301/496-1196). 
 
This memorandum serves to notify the NCI and Southwest Oncology Group Statistical 
Center. 
 
cc: 
PROTOCOL & INFORMATION OFFICE 
 
Kenneth J. Kopecky, Ph.D. 
 
Megan Othus, Ph.D. 
 
Holly Gundacker, M.S. 
 
Tracy Maher 
 
Camille White 
 
Jean Barce 
Michael Kelly - CALGB 
Ryan Palmer - ECOG 
Virginia Dixon-Lipscomb – Wyeth 
Karl Buer - Biologics 
 


 
 
 
 
 
May 15, 2010 
 
TO: 
ALL 
SOUTHWEST 
ONCOLOGY 
GROUP 
MEMBER, 
CCOP 
AND 
AFFILIATE MEDICAL ONCOLOGISTS AND PATHOLOGISTS; CTSU 
 
FROM: 
Sandi Jo McMillan, Protocol Coordinator 
 
RE: 
S0535, "A Phase II Study of ATRA, Arsenic Trioxide and Gemtuzumab 
Ozogamicin in Patients with Previously Untreated High-Risk Acute 
Promyelocytic Leukemia"  Study Coordinators:  Drs. J.E. Lancet, R. 
Komrokji, C.L. Willman, and M.L. Slovak. 
 
MEMORANDUM
 
Study Coordinator:  Jeffrey E. Lancet, M.D. 
Phone number:  813/745-6841 
E-mail:  lancetje@moffitt.usf.edu 
 
IRB Review Requirements 
 
 (   ) Full board review required.  Reason: 
 
(   ) 
Initial activation  
 
(   ) 
Increased risk to patient 
 
(   ) 
Complete study redesign 
 
(   ) 
Addition of tissue banking requirements 
 
(   ) 
Study closure due to new risk information 
 
( ¥ ) Expedited review allowed (for CALGB institutions) 
 
( ¥ ) No review required (for SWOG and ECOG institutions) 
 
 
MEMORANDUM
 
The purpose of this memorandum is to inform CALGB institutions of updated RT-PCR 
specimen submission requirements.  CALGB institutions must submit specimens to a 
CLIA-approved laboratory for RT-PCR testing.  Results of the RT-PCR testing will be 
reported by the CLIA-approved laboratory directly back to the site.   
 
Patients who are enrolled in CALGB-9862 must also continue to have specimens 
submitted for that correlative study as outlined in Section 15.4a.   
 
A protocol revision to update the information in the protocol document is forthcoming. 
 
Southwest Oncology Group and Eastern Oncology Group institutions will continue to 
submit specimens as outlined in the protocol. 
 
This memorandum serves to notify the NCI and Southwest Oncology Group Statistical 
Center. 
 
cc: 
PROTOCOL & INFORMATION OFFICE 
 
Kenneth J. Kopecky, Ph.D. 
 
Megan Othus, Ph.D. 
 
Holly Gundacker, M.S. 
 
Tracy Maher 
 
Camille White 
 
Jean Barce 
Michael Kelly - CALGB 
Ryan Palmer - ECOG 
Virginia Dixon-Lipscomb – Wyeth 
Karl Buer - Biologics 
 
 
Operations Office 
4201 Medical Drive (Suite 250) •San Antonio, TX 78229 • Telephone 210-614-8808 • FAX 210-614-0006 • http://swog.org 


 
 
 
 
 
April 15, 2010 
 
TO: 
ALL 
SOUTHWEST 
ONCOLOGY 
GROUP 
MEMBER, 
CCOP 
AND 
AFFILIATE MEDICAL ONCOLOGISTS AND PATHOLOGISTS; CTSU 
 
FROM: 
Sandi Jo McMillan, Protocol Coordinator 
 
RE: 
S0535, "A Phase II Study of ATRA, Arsenic Trioxide and Gemtuzumab 
Ozogamicin in Patients with Previously Untreated High-Risk Acute 
Promyelocytic Leukemia"  Study Coordinators:  Drs. J.E. Lancet, R. 
Komrokji, C.L. Willman, and M.L. Slovak. 
 
MEMORANDUM
 
Study Coordinator:  Jeffrey E. Lancet, M.D. 
Phone number:  813/745-6841 
E-mail:  lancetje@moffitt.usf.edu 
 
IRB Review Requirements 
 
 (   ) Full board review required.  Reason: 
 
(   ) 
Initial activation  
 
(   ) 
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 
 
 
MEMORANDUM
 
Due to the national shortage of daunorubicin, institutions without appropriate daunorubicin 
supply to treat patients according to the protocol schedule may substitute idarubicin for 
daunorubicin as follows: 
 
During Consolidation Cycles #3 and #4: 
 
Idarubicin 12 mg/m2 Days 1-2 
 
If Idarubicin is given, it must be documented on the S0535 Consolidation Cycles 3 and 4 
Treatment Summary Form in the "Other therapy" section as follows: (1) idarubicin must be 
written in "Specify agent(s)", and (2) the start and end treatment dates and the total 
idarubicin dose given for the reporting period must be recorded in the Comments section. 
 
The protocol and forms will be revised soon. Until that revision is made, the use of 
idarubicin should be documented as described above according to the schedules in 
protocol Section 14.8. 
 
This allowance is being made only for instances when daunorubicin is not available due to 
the national drug shortage. Any questions regarding this temporary allowance should be 
directed to the Study Coordinator. 
 
This memorandum serves to notify the NCI and Southwest Oncology Group Statistical 
Center. 
 
cc: 
PROTOCOL & INFORMATION OFFICE 
Jean Barce 
Kenneth J. Kopecky, Ph.D. 
Michael Kelly - CALGB 
Megan Othus, Ph.D. 
Ryan Palmer - ECOG 
Holly Gundacker, M.S. 
Virginia Dixon-Lipscomb – Wyeth 
Tracy Maher 
Karl Buer - Biologics 
Camille White 
 
 
Operations Office 
4201 Medical Drive (Suite 250) •San Antonio, TX 78229 • Telephone 210-614-8808 • FAX 210-614-0006 • http://swog.org 


 
 
 
 
 
Distribution Date: 
April 1, 2010 
CTEP Submission Date: March 25, 2010 
 
TO: 
ALL 
SOUTHWEST 
ONCOLOGY 
GROUP 
MEMBER, 
CCOP 
AND 
AFFILIATE MEDICAL ONCOLOGISTS AND PATHOLOGISTS; CTSU 
 
FROM: 
Sandi Jo McMillan, Protocol Coordinator 
 
RE: 
S0535, "A Phase II Study of ATRA, Arsenic Trioxide and Gemtuzumab 
Ozogamicin in Patients with Previously Untreated High-Risk Acute 
Promyelocytic Leukemia"  Study Coordinators:  Drs. J.E. Lancet, R. 
Komrokji, C.L. Willman, and M.L. Slovak. 
 
REVISION #5 
 
Study Coordinator:  Jeffrey E. Lancet, M.D. 
Phone number:  813/745-6841 
E-mail:  lancetje@moffitt.usf.edu 
 
IRB Review Requirements 
 
 (   ) Full board review required.  Reason: 
 
(   ) 
Initial activation  
 
(   ) 
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 #5
 
The primary purpose of this revision is to remove specimen submission requirements for 
SWOG-9007, “Cytogenetic Studies in Leukemia Patients” and S9910, “Leukemia 
Centralized Reference Laboratories and Tissue Repositories, Ancillary” from the above 
referenced study. For Southwest Oncology Group sites and other sites NOT affiliated with 
ECOG or CALGB, registration and submission of specimens to these ancillary studies will 
no longer be required. For these sites, RT-PCR testing according to the protocol schedule 
is still mandatory, but this testing may be done at any CLIA-approved laboratory.  Similarly, 
for these sites, cytogenetic studies should be performed according to the protocol 
schedule, but at the site’s preferred cytogenetics laboratory.  Results of these RT-PCR and 
cytogenetics studies will be submitted as part of the protocol data as described in protocol 
Section 14.0.  No changes are being implemented for CALGB or ECOG affiliated patients 
at this time. 
 
1.  
The Version Date has been updated. 
 
2.  
Page 14, Section 5.1b: This section has been revised to remove the mention of a 
central lab, since that no longer applies to SWOG sites and other sites NOT 
affiliated with ECOG or CALGB. Similar changes have been made in Sections 
7.8a, 7.8b, 7.8c and 7.8d (Page 22), 7.8e (Page 23), and 15.1 (Page 40). 
 
3.  
Page 14, Section 5.1f: This section has been updated to indicate that participation 
in SWOG cytogenetics study SWOG-9007 is no longer required for patients at 
SWOG sites or other sites NOT affiliated with ECOG or CALGB, but that 
submission of specimens to each site’s preferred cytogenetics laboratory is now 
required instead. Participation in cytogenetics studies remains mandatory for 
patients affiliated with CALGB or ECOG.  Similar changes have been made in 
Sections 5.2b (Page 16) and 19.4 (Page 98). 
 
Operations Office 
4201 Medical Drive (Suite 250) •San Antonio, TX 78229 • Telephone 210-614-8808 • FAX 210-614-0006 • http://swog.org 


 
S0535 
 
Revision #5 (contd.) 
 
Page 2 
 
 
 
 
 
 
 
 
4. 
Page 15, Section 5.1g: This section has been updated to indicate that participation 
in SWOG ancillary study S9910 is no longer required for patients at SWOG sites or 
other sites NOT affiliated with ECOG or CALGB, although pretreatment RT-PCR 
assay for PML-RARĮ is still required. The first sentence has been revised to 
emphasize that the pretreatment RT-PCR assay is still required for all patients. The 
third sentence has been updated to state that specimen submissions must be via 
the “mechanisms” indicated, since the mechanism for SWOG and other non-
ECOG/CAGLB patients does not involve an ancillary protocol. The last sentence 
has been updated to indicate that repository aspects of the ancillary protocols “for 
CALGB and ECOG” are optional. The first bullet regarding specimen submission 
for SWOG patients has been updated to remove the references to S9910 and the 
Southwest Oncology Group Leukemia Repository and to instead instruct that 
specimens must be submitted to a CLIA-approved laboratory. Similar changes 
have been made in Sections 5.2c (Page 16) and 5.3b (Page 17). 
 
5. 
Page 16, Section 5.2c: The reference to Section 15.3 has been updated to 15.2 in 
this section. This change has also been made in Section 5.3b (Page 17). 
 
6. 
Page 22, Sections 7.8a and 7.8b: The second sentence has been updated to 
indicate that specimens must be submitted for cytogenetics for patients affiliated 
with CALGB or ECOG and that specimens must be submitted for PCR for all 
patients. The fourth sentence has been revised to clarify that neither cytogenetic 
nor RT-PCR testing is required for repeat marrow aspiration and biopsy. Similar 
changes have been made in Sections 7.8e (Page 23) and 15.1 (Page 40).  The 
word “ONLY” has been removed from the last sentence for clarity. 
 
7. 
Page 10, Section 9.0:  The “Specimen Submission” row has been replaced by rows 
entitled “Cytogenetics” and “RT-PCR for PML-RARĮ”.  The “Ȉ” footnote has been 
included in both rows.  In the “Cytogenetics” row, Xs have been added to the Pre-
study and Induction columns.  In the “RT-PCR for PML-RARĮ” row, Xs have been 
added to the Pre-study, Induction and Consolidation #1 through 2 columns.  An 
“X¶” has been added to the Consolidation #3 through 4 (Prior) column, with 
associated “¶” footnote indicating that RT-PCR is required prior to Consolidation 
#3, but not #4.  An “X¿” has been added to each of the new rows in the “Follow-
Up” columns, with associated “¿” footnotes indicating that follow-up cytogenetics 
and RT-PCR are required at relapse only.  The “4" footnote has been updated to 
state that the marrow documenting CR may serve as the prior to Consolidation #1 
marrow, providing it was performed within 8 weeks prior to Consolidation 
registration.  A reference to Section 5.2 has also been included.  An “X” has been 
added to the “Maintenance” column of the “RT-PCR for PML-RARĮ” row, as this 
test is required prior to maintenance. 
 
8. 
Pages 38-39, Sections 14.4, 14.5, 14.7, 14.12, and 14.15:  Submission of RT-PCR 
reports for SWOG sites and sites NOT affiliated with ECOG or CALGB has been 
added to each of these sections.  The requirement for submission of the 
cytogenetics results has been added to Sections 14.4 and 14.15. 
 
9. 
Page 40, Section 15.1:  This section has been updated as follows to reflect the 
changes in specimen submission requirements for SWOG patients and other 
patients not affiliated with CALGB or ECOG: 
 
x 
The first sentence has been updated to remove the wording “regardless of 
Group affiliation”.   
x 
Information has been added indicating that RT-PCR and pretreatment 
cytogenetic requirements are applicable to all patients, regardless of group 
affiliation; associated times have been outlined.   
x 
The sentence referencing “additional details regarding specimen submission” 
has been updated to “additional details regarding mechanisms for obtaining 
these studies”.   


 
S0535 
 
Revision #5 (contd.) 
 
Page 3 
 
 
 
 
 
 
 
 
x 
The “b” footnote reference has been added to the “Cytogenetics” column of the 
“At the time of neutrophil recovery or on Day 42” row.  The associated “b” 
footnote has been added to state that these specimens are not required for 
SWOG sites and other sites not affiliated with ECOG or CALGB.   
x 
The “*” footnote has been updated to replace a reference to the “central” 
laboratory with references to the “testing” laboratory.  The sentence indicating 
that the lab “will” contact the site for collection and submission of an additional 
specimen if the analysis is indeterminate has been updated to state that the lab 
“may” contact the site.   
x 
The “a” footnote, previously stating that the RT-PCR result will be reported 
back to the submitting institution, has been updated to emphasize that the 
pretreatment RT-PCR determines whether the patient is eligible or should 
continue on protocol treatment, and that if the pretreatment RT-PCR result is 
indeterminate, additional specimens should be submitted for RT-PCR testing to 
avoid indeterminate pretreatment results whenever possible. 
 
10. 
Pages 40-41, Section 15.2a: This section, regarding patients at SWOG sites and 
other sites NOT affiliated with ECOG or CALGB, has been updated to replace 
specimen submission instructions for SWOG-9007 with instructions to perform 
required cytogenetic studies at each institution’s preferred cytogenetics laboratory.  
A similar change has been made in Section 19.4 (Pages 96 and 98).  The section 
heading has been revised accordingly. 
 
11. 
Page 41, Section 15.2b: This section, regarding patients at SWOG sites and other 
sites NOT affiliated with ECOG or CALGB, has been updated to remove specimen 
submission instructions for S9910. The section heading and Section 15.2b.1 have 
been revised accordingly.  Section 15.2b.2 has been deleted and subsequent 
sections have been renumbered accordingly.  The new Section 15.2b.2 (previously 
Section 15.2b.3) has been revised to clarify that RT-PCR testing must be 
performed at CLIA-approved laboratories.  A similar change has been made in 
Section 19.4 (Pages 96 and 98). 
 
12. 
Pages 42-42a, Sections 15.2c, 15.2d and 15.2e have been deleted, since they are 
no longer applicable.  Page 42 has intentionally been left blank. 
 
13. 
Page 50, Model Consent Form: In the “During the study…” section, the note to 
investigators after the last bullet on this page has been updated to indicate that this 
refers to the mandatory cytogenetic studies and RT-PCR testing (previously 
“submission of specimens to SWOG-9007 and S9910”). 
 
14. 
Page 61, Model Consent Form: A note to investigators has been added after 
question #2 (regarding banking of specimens for future research) indicating that 
this section is applicable only to CALGB and ECOG institutions. 
 
15. 
Page 63, Model Consent Form: The instruction “[For patients participating through 
SWOG or any other institution not affiliated with ECOG or CALGB, use the 
following]” and the text immediately following have both been deleted. 
 
16. 
Page 96, Section 19.4:  The last bullet under “Pre-study requirements for patient 
enrollment on S0535” has been revised to delete mention of SWOG-9007 and 
S9910.  The fourth bullet regarding CALGB sites has been updated to include 
requirement of registration to CALGB8461 and CALGB9862 prior to registration to 
S0535. 
 
17. 
Page 98, Section 19.4: The “Special materials or Substudies” section has been 
updated to delete mention of studies SWOG-9007 and S9910. All information 
regarding the SWOG Specimen Tracking System has also been deleted.  The 
information for CALGB sites has been updated to cite Section 15.4. 


 
S0535 
 
Revision #5 (contd.) 
 
Page 4 
 
 
 
 
 
 
 
 
Southwest Oncology Group institutions (and other institutions NOT affiliated with ECOG or 
CALGB) must update their local consent forms to include the changes to the Model 
Consent Form. 
 
The Southwest Oncology Group considers that the Model Consent Form changes do not 
represent an alteration in risk-benefit ratio.  Therefore, local accrual does not need to be 
suspended pending implementation of those changes. 
 
Patients currently on treatment need not be informed of these changes unless required by 
the local Institutional Review Board (IRB). 
 
ECOG and CALGB institutions need not update their local consents. 
 
This memorandum serves to notify the NCI and Southwest Oncology Group Statistical 
Center. 
 
cc: 
PROTOCOL & INFORMATION OFFICE 
 
Kenneth J. Kopecky, Ph.D. 
 
Megan Othus, Ph.D. 
 
Holly Gundacker, M.S. 
 
Tracy Maher 
 
Camille White 
 
Jean Barce 
Michael Kelly - CALGB 
Ryan Palmer - ECOG 
Virginia Dixon-Lipscomb – Wyeth 
Karl Buer - Biologics 
 
 
 


 
 
 
 
 
 
January 15, 2010 
 
TO: 
ALL 
SOUTHWEST 
ONCOLOGY 
GROUP 
MEMBER, 
CCOP 
AND 
AFFILIATE MEDICAL ONCOLOGISTS AND PATHOLOGISTS; CTSU 
 
FROM: 
Sandi Jo McMillan, Protocol Coordinator 
 
RE: 
S0535, "A Phase II Study of ATRA, Arsenic Trioxide and Gemtuzumab 
Ozogamicin in Patients with Previously Untreated High-Risk Acute 
Promyelocytic Leukemia"  Study Coordinators:  Drs. J.E. Lancet, R. 
Komrokji, C.L. Willman, and M.L. Slovak. 
 
MEMORANDUM
 
Study Coordinator:  Jeffrey E. Lancet, M.D. 
Phone number:  813/745-6841 
E-mail:  lancetje@moffitt.usf.edu 
 
IRB Review Requirements 
 
 (   ) Full board review required.  Reason: 
 
(   ) 
Initial activation  
 
(   ) 
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 
 
 
MEMORANDUM
 
The purpose of this memorandum is to provide further information about requirements for 
SWOG patients on study S0535, following the change in reimbursements for leukemia 
specimen submissions as explained in the Memorandum distributed 1/11/10.  A protocol 
revision that includes the following information, and that provides information about how to 
submit cytogenetics and PCR reports, is forthcoming. 
 
PCR studies.  SWOG institutions are no longer required to register patients on study 
SWOG-9910, “Leukemia Centralized Reference Laboratories and Tissue Repositories, 
Ancillary”, as stated in Sections 5.1g, 5.2c and 5.3b of protocol S0535.  However 
pretreatment PCR studies are still required to determine patient eligibility.  These studies 
must be done at CLIA-approved laboratories.  Patients must have a report documenting the 
PCR result as positive or indeterminate in order to be eligible; if PCR is negative or not 
done, the patient will be considered ineligible.   
 
Institutions should also attempt to complete the subsequent PCR studies according to the 
current protocol schedule (see Section 15.1 of protocol S0535).  Copies of all PCR reports 
should be obtained and kept in the patient’s medical record.   
 
The procedure for submitting PCR reports will be described in the forthcoming revision of 
protocol S0535. 
 
Operations Office 
4201 Medical Drive (Suite 250) •San Antonio, TX 78229 • Telephone 210-614-8808 • FAX 210-614-0006 • http://swog.org 


 
S0535 
 
Memorandum (contd.) 
 
Page 2 
 
 
 
 
 
 
 
 
Cytogenetic studies.  SWOG institutions are no longer required to register patients on 
study S9007 “Cytogenetic Studies in Leukemia Patients”, as stated in Sections 5.1f and 
5.2b of protocol S0535.  However it is requested that SWOG institutions perform local 
cytogenetic studies according to the protocol schedule (see Section 15.1 of protocol 
S0535), and that copies of the cytogenetics reports be obtained.  The procedure for 
submitting cytogenetics reports will be described in the forthcoming revision of protocol 
S0535. 
 
The Southwest Oncology Group considers this change to be administrative, and therefore 
does not require that this information be IRB approved prior to institutional implementation. 
 
This memorandum is applicable to SWOG sites and other sites not affiliated with CALGB 
or ECOG only.  CALGB and ECOG specimen submission requirements will remain 
unchanged. 
 
This memorandum serves to notify the NCI and Southwest Oncology Group Statistical 
Center. 
 
cc: 
PROTOCOL & INFORMATION OFFICE 
 
Kenneth J. Kopecky, Ph.D. 
 
Megan Othus, Ph.D. 
 
Holly Gundacker, M.S. 
 
Tracy Maher 
 
Camille White 
 
Jean Barce 
Michael Kelly - CALGB 
Ryan Palmer - ECOG 
Virginia Dixon-Lipscomb – Wyeth 
Karl Buer - Biologics 


 
 
 
 
 
 
Distribution Date: 
December 1, 2009 
CTEP Submission Date: October 29, 2009 
 
TO: 
ALL 
SOUTHWEST 
ONCOLOGY 
GROUP 
MEMBER, 
CCOP 
AND 
AFFILIATE MEDICAL ONCOLOGISTS AND PATHOLOGISTS; CTSU 
 
FROM: 
Sandi Jo McMillan, Protocol Coordinator 
 
RE: 
S0535, "A Phase II Study of ATRA, Arsenic Trioxide and Gemtuzumab 
Ozogamicin in Patients with Previously Untreated High-Risk Acute 
Promyelocytic Leukemia"  Study Coordinators:  Drs. J.E. Lancet, R. 
Komrokji, C.L. Willman, and M.L. Slovak. 
 
REVISION #4 
 
Study Coordinator:  Jeffrey E. Lancet, M.D. 
Phone number:  813/745-6841 
E-mail:  lancetje@moffitt.usf.edu 
 
IRB Review Requirements 
 
(   ) Full board review required.  Reason: 
 
(   ) 
Initial activation  
 
(   ) 
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 #4
 
1. 
Title page:  The version date has been updated.   
 
2. 
Pages 14-15, Sections 5.1f and 5.1g:  Information regarding specimen submission 
for cytogenetics and PCR testing for CALGB institutions has been added to 
Sections 5.1f and 5.1g, respectively. 
 
3. 
Page 16, Section 5.2b:  This criterion requiring MUGA/ECHO evaluation and 
ejection fraction  50% has been deleted as it is not necessary prior to 
consolidation Cycle #1.  Subsequent sections have been renumbered accordingly. 
 
4. 
Pages 16-17, Sections 5.2b, 5.2c and 5.3b:  In the CALGB bullet in each of these 
sections, the note advising that details will be inserted as they become available 
has been replaced by a reference to Section 15.4 for specimen submission 
requirements. 
 
5. 
Page 20, Sections 7.4d and 7.5c:  Section 7.4d has been added and Section 7.5c 
has been updated to advise that MUGA or echocardiogram must be performed 
prior to initiation of Consolidation Cycle 3, and that if it was performed at baseline 
or any time prior to Cycle 3, it does not need to be repeated immediately prior to 
Cycle 3.   
 
 
 
 
Operations Office 
14980 Omicron Drive•San Antonio, TX 78245-3217 • Telephone 210-450-8808 • FAX 210-677-0006 • http://swog.org 


 
S0535 
 
Revision #4 (contd.) 
 
Page 2 
 
 
 
 
 
 
 
 
6. 
Page 32, Section 9.0:  The "X" and corresponding "ȍ" footnote have been removed 
from the "Consolidation #1 through 2" column of the "MUGA/ECHO" row as the 
test is no longer required at this time point. 
 
7. 
Pages 42c-42d, Section 15.4:  This section has been updated to include specimen 
submission instructions for CALGB institutions for both PCR and cytogenetics 
testing. 
 
8. 
Master Forms Set:  The Induction Treatment Summary Form (Form #25817) has 
been updated to increase the number of spaces available for arsenic dose.  The 
form # has been updated from #25817 to #55067 in Sections 14.5 (Page 38) and 
18.2f (Page 46). 
 
9. 
Master Forms Set:  The S0535 Consolidation Eligibility Form (Form #46528) has 
been removed from the master forms set as it is no longer relevant.  As a result of 
this change, the requirement for submission of the Consolidation Eligibility Form 
has been deleted from above Section 5.2 (Page 16).  Section 14.6 on Page 38 
(previously requiring submission of the Consolidation Eligibility Form) has been 
deleted and subsequent sections on Pages 38-40 have been renumbered 
accordingly.  Section 18.2h on Page 46 (previously listing the Consolidation 
Eligibility Form) has been deleted and subsequent sections on that page have 
been renumbered accordingly. 
 
10. 
Master Forms Set:  The S0535 Consolidation Cycles 1 and 2 Treatment Summary 
Form has been updated to collect MUGA/ECHO results.  The form # has been 
updated from #9341 to #25052 in Sections 14.6 (Page 38) and 18.2h (Page 46). 
 
This memorandum serves to notify the NCI and Southwest Oncology Group Statistical 
Center. 
 
 
cc: 
PROTOCOL & INFORMATION OFFICE 
Kenneth J. Kopecky, Ph.D. 
Holly Gundacker, M.S. 
Tracy Maher 
Camille White 
Jean Barce 
Michael Kelly - CALGB 
Ryan Palmer - ECOG 
Virginia Dixon-Lipscomb – Wyeth 
Karl Buer - Biologics 
 


 
 
 
 
 
 
Distribution Date: 
December 1, 2009 
E-mailed Date: 
November 20, 2009 
 
 
TO: 
ALL 
SOUTHWEST 
ONCOLOGY 
GROUP 
MEMBER, 
CCOP 
AND 
AFFILIATE MEDICAL ONCOLOGISTS AND PATHOLOGISTS; CTSU 
 
FROM: 
Sandi Jo McMillan, Protocol Coordinator 
 
RE: 
S0535, "A Phase II Study of ATRA, Arsenic Trioxide and Gemtuzumab 
Ozogamicin in Patients with Previously Untreated High-Risk Acute 
Promyelocytic Leukemia"  Study Coordinators:  Drs. J.E. Lancet, R. 
Komrokji, C.L. Willman, and M.L. Slovak. 
 
MEMORANDUM
 
Study Coordinator:  Jeffrey E. Lancet, M.D. 
Phone number:  813/745-6841 
E-mail:  lancetje@moffitt.usf.edu 
 
IRB Review Requirements 
 
(   ) Full board review required.  Reason: 
 
(   ) 
Initial activation  
 
(   ) 
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 
 
 
MEMORANDUM
The purpose of this memorandum is to inform sites of the Thanksgiving holiday closure for 
Biologics Clinical Trial Services (BCTS), the distributor of gemtuzumab ozogamicin for this 
study.  BCTS will be closed on Thursday, November 26 and Friday, November 27, 2009.  
Regular business hours will be resumed on Monday, November 30, 2009.   
 
Please plan shipment needs for gemtuzumab ozogamicin accordingly. 
 
If you have questions or need to coordinate shipments in advance, please contact the 
S0535 Biologics Clinical Trial Project Manager, Karl Buer, at 800/693-4906 ext. 4991. 
 
This memorandum serves to notify the NCI and Southwest Oncology Group Statistical 
Center. 
 
cc: 
PROTOCOL & INFORMATION OFFICE 
Camille White 
Kenneth J. Kopecky, Ph.D. 
Jean Barce 
Megan Othus, Ph.D. 
Michael Kelly – CALGB 
Holly Gundacker, M.S. 
Ryan Palmer - ECOG 
Tracy Maher 
 
 
Operations Office 
14980 Omicron Drive•San Antonio, TX 78245-3217 • Telephone 210-450-8808 • FAX 210-677-0006 • http://swog.org 


 
 
 
 
 
 
Distribution Date: 
February 15, 2009 
CTEP Submission Date: January 28, 2009 
 
 
TO: 
ALL 
SOUTHWEST 
ONCOLOGY 
GROUP 
MEMBER, 
CCOP 
AND 
AFFILIATE MEDICAL ONCOLOGISTS AND PATHOLOGISTS; CTSU 
 
FROM: 
Sandi Jo McMillan, Protocol Coordinator 
 
RE: 
S0535, "A Phase II Study of ATRA, Arsenic Trioxide and Gemtuzumab 
Ozogamicin in Patients with Previously Untreated High-Risk Acute 
Promyelocytic Leukemia"  Study Coordinators:  Drs. J.E. Lancet, R. 
Komrokji, C.L. Willman, and M.L. Slovak. 
 
REVISION #3 
 
Study Coordinator:  Jeffrey E. Lancet, M.D. 
Phone number:  813/745-6841 
E-mail:  lancetje@moffitt.usf.edu 
 
IRB Review Requirements 
 
(   ) Full board review required.  Reason: 
 
(   ) 
Initial activation  
 
(   ) 
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 #3
 
1. 
Title page:  The version date has been updated.   
 
2. 
Pages 11-11a, Section 3.4c:  Wyeth, Corp. will now supply the drug gemtuzumab 
ozogamicin for this study.  The supplier information in Section 3.4c has been 
updated to indicate this, and drug ordering information has been added.  Page 11a 
has been added to prevent extensive repagination. 
 
3. 
Page 57, Model Consent Form: ATRA Syndrome has been moved from "Less 
Likely" to "Rare but Serious" in the risks and side effects related to maintenance 
therapy.  This side effect was incorrectly added to the "less likely" section during a 
previous revision.  
 
4. 
Page 59, Model Consent Form:  Wyeth Corp. has been added to the list of 
organizations that may access medical records of patients taking part in this study.  
Gemtuzumab ozogamicin has been removed from the list of commercially available 
drugs in the "what are the costs of taking part in this study?" section.  A sentence 
has been added indicating that the drug is commercially available but it will be 
provided free of charge by Wyeth, Corp. for this study. 
 
 
Operations Office 
14980 Omicron Drive•San Antonio, TX 78245-3217 • Telephone 210-450-8808 • FAX 210-677-0006 • http://swog.org 


 
S0535 
 
Revision #3 (contd.) 
 
Page 2 
 
 
 
 
 
 
 
 
Institutions must update their local consent forms to include this information for future 
registrations.  Patients currently being treated on this study should be informed in the 
manner determined by their local Institutional Review Board (IRB). 
 
The Southwest Oncology Group considers that the changes in the Model Consent Form 
that are associated with this Revision are solely administrative and editorial in nature, and 
do not impact the risk/benefit ratio for participants on this study.  Local accrual to the study 
does not have to be suspended pending implementation of these changes. 
 
This memorandum serves to notify the NCI and Southwest Oncology Group Statistical 
Center. 
 
 
 
 
 
cc: 
PROTOCOL & INFORMATION OFFICE 
Kenneth J. Kopecky, Ph.D. 
Holly Gundacker, M.S. 
Tracy Maher 
Camille White 
Jean Barce 
Michael Kelly – CALGB 
Ryan Palmer - ECOG 
 


 
 
 
 
 
 
December 1, 2008 
 
 
TO: 
ALL 
SOUTHWEST 
ONCOLOGY 
GROUP 
MEMBER, 
CCOP 
AND 
AFFILIATE MEDICAL ONCOLOGISTS AND PATHOLOGISTS; CTSU 
 
FROM: 
Sandi Jo McMillan, Protocol Coordinator 
 
RE: 
S0535, "A Phase II Study of ATRA, Arsenic Trioxide and Gemtuzumab 
Ozogamicin in Patients with Previously Untreated High-Risk Acute 
Promyelocytic Leukemia"  Study Coordinators:  Drs. J.E. Lancet, R. 
Komrokji, C.L. Willman, and M.L. Slovak. 
 
MEMORANDUM
 
Study Coordinator:  Jeffrey E. Lancet, M.D. 
Phone number:  813/745-6841 
E-mail:  lancetje@moffitt.usf.edu 
 
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 (for institution already participating) 
 
( ¥ ) No review required 
 
 
MEMORANDUM
 
Please note that Revision #2 contains the following error:  The cover memorandum states 
that "ATRA syndrome" has been added to the "Rare but Serious" side effects category for 
Maintenance therapy, but it was incorrectly added to the "Less Likely" category in the 
consent form.  ATRA syndrome is a "Rare but Serious" side effect, and the cover 
memorandum was correct in stating it should have been added to that category.  This 
correction will be made during the next revision/amendment, and institutions may make this 
correction to local consent forms in the meantime. 
 
This memorandum serves to notify the NCI and Southwest Oncology Group Statistical 
Center. 
 
cc: 
PROTOCOL & INFORMATION OFFICE 
Kenneth J. Kopecky, Ph.D. 
Holly Gundacker, M.S. 
Tracy Maher 
Michael Kelly – CALGB 
Ryan Palmer - ECOG 
 
 
 
 
Operations Office 
14980 Omicron Drive•San Antonio, TX 78245-3217 • Telephone 210-450-8808 • FAX 210-677-0006 • http://swog.org 


 
 
 
 
 
 
Distribution Date: 
November 15, 2008 
CTEP Submission Date: November 12, 2008 
 
 
TO: 
ALL 
SOUTHWEST 
ONCOLOGY 
GROUP 
MEMBER, 
CCOP 
AND 
AFFILIATE MEDICAL ONCOLOGISTS AND PATHOLOGISTS; CTSU 
 
FROM: 
Sandi Jo McMillan, Protocol Coordinator 
 
RE: 
S0535, "A Phase II Study of ATRA, Arsenic Trioxide and Gemtuzumab 
Ozogamicin in Patients with Previously Untreated High-Risk Acute 
Promyelocytic Leukemia"  Study Coordinators:  Drs. J.E. Lancet, R. 
Komrokji, C.L. Willman, and M.L. Slovak. 
 
REVISION #2 
 
Study Coordinator:  Jeffrey E. Lancet, M.D. 
Phone number:  813/745-6841 
E-mail:  lancetje@moffitt.usf.edu 
 
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 (for institution already participating) 
 
(   ) No review required 
 
 
REVISION #2
 
1. 
Title page:  The version date has been updated.   
 
2. 
Page 14, Section 5.1e:  This eligibility criterion has been revised to allow prior 
therapy with ATRA administered for up to 3 days prior to registration.  It is not felt 
that this ATRA exposure will affect the outcome of the trial, and is more feasible for 
enrollment as immediate start of ATRA is standard care for this disease.  The “ƒ” 
footnote has been added to the Study Calendar (Section 9.0, Page 32) explaining 
this as well.  Because of this change, Section 7.8a (Page 22) has been reworded 
to clarify that the marrow exam is performed on Day 42 after beginning protocol 
ATRA, and does not include any ATRA administration that may have occurred prior 
to starting protocol therapy.  This change has also been made in Section 15.2a.1b 
(Page 41). 
 
3. 
Pages 14-17, Sections 5.1f-5.1g, 5.2c-5.2d, and 5.3b:  These sections have been 
updated to indicate that SWOG patients and any patients not affiliated with ECOG 
or CALGB must submit specimens as outlined for each section (previously said 
any Southwest Oncology Group patients).  The reference to Section 15.2 in 
Section 5.3b has been changed to 15.3 for accuracy. 
 
 
Operations Office 
14980 Omicron Drive•San Antonio, TX 78245-3217 • Telephone 210-450-8808 • FAX 210-677-0006 • http://swog.org 


 
S0535 
 
Revision #2 (contd.) 
 
Page 2 
 
 
 
 
 
 
 
 
4. 
Page 18, Section 7.1e:  This section has been added to indicate that patients who 
become pregnant after registration must be removed from protocol therapy.  
Similar changes have been made in Section 7.11f (Page 26) and the Model 
Consent Form (Pages 51a and 58).  The sentence in Sections 3.1b (Page 5) 
stating that ATRA use in pregnant women is not prohibited on this protocol has 
been deleted. 
 
5. 
Page 18, Section 7.2c:  Serial coagulation studies outlined in this section have 
been changed from twice weekly during induction and then as clinically indicated 
thereafter to twice weekly during induction until normal and then as clinically 
indicated thereafter, as it is not necessary for this testing to be performed so often 
once numbers have stabilized.  The "'" footnote has been updated in the Study 
Calendar (Section 9.0, Page 32) indicating this as well. 
 
6. 
Page 32, Section 9.0:  The “¥” footnote has been updated to indicate that the 
marked tests are performed every 3 months until 3 years from initial registration 
(previously said for 3 years after off treatment). 
 
7. 
Page 55, Model Consent Form:  Increased blood level of a fat called triglyceride 
has been added to the risks/side effects (likely section) for Consolidation #3 and 4.  
This change was previously made to the Induction risks/side effects but the cover 
memorandum incorrectly stated that it had been changed in the Consolidation #3 
and 4 section instead of the Induction section.  The added risk is necessary for 
both sections, so will remain in the Induction section as well. 
 
8. 
Page 57, Model Consent Form:  ATRA syndrome has been added to the rare but 
serious risks/side effects for maintenance therapy, along with a brief explanation of 
related symptoms. 
 
9. 
Page 96, Section 19.4:  The italicized words “protocol number” have been replaced 
by the study number “S0535”. 
 
Institutions must update their local consent forms to include this information for future 
registrations.  Patients currently being treated on this study should be informed in the 
manner determined by their local Institutional Review Board (IRB). 
 
The Southwest Oncology Group considers that the changes in the Model Consent Form 
that are associated with this Revision are solely administrative and editorial in nature, and 
do not impact the risk/benefit ratio for participants on this study.  Local accrual to the study 
does not have to be suspended pending implementation of these changes. 
 
This memorandum serves to notify the NCI and Southwest Oncology Group Statistical 
Center. 
 
 
 
 
 
cc: 
PROTOCOL & INFORMATION OFFICE 
Kenneth J. Kopecky, Ph.D. 
Holly Gundacker, M.S. 
Tracy Maher 
Amy Edwards 
Michael Kelly – CALGB 
Ryan Palmer - ECOG 
 


 
 
 
 
 
 
Distribution Date: 
June 15, 2008 
CTEP Submission Date: May 30, 2008 
 
TO: 
ALL 
SOUTHWEST 
ONCOLOGY 
GROUP 
MEMBER, 
CCOP 
AND 
AFFILIATE MEDICAL ONCOLOGISTS AND PATHOLOGISTS; CTSU 
 
FROM: 
Sandi Jo Fredette, Protocol Coordinator 
 
RE: 
S0535, "A Phase II Study of ATRA, Arsenic Trioxide and Gemtuzumab 
Ozogamicin in Patients with Previously Untreated High-Risk Acute 
Promyelocytic Leukemia"  Study Coordinators:  Drs. J.E. Lancet, R. 
Komrokji, C.L. Willman, and M.L. Slovak. 
 
REVISION #1 
 
Study Coordinator:  Jeffrey E. Lancet, M.D. 
Phone number:  813/745-6841 
E-mail:  lancetje@moffitt.usf.edu 
 
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 (for institution already participating) 
 
(   ) No review required 
 
 
REVISION #1
 
1. 
Title page:  The version date has been updated.  The page number for Section 
16.0 has been updated.  The spelling of the drug Tretinoin has been corrected 
(previously written as Trentinoin).  This change has also been made in Section 3.1 
(Page 4).  CTSU has been added to the participants list. 
 
2. 
Pages 2-2a:  The Study Coordinator information for the cooperative groups ECOG 
and CALGB have been added.  CTSU participation information and CTSU address 
and contact information text boxes have been added.  Page 2a has been added to 
prevent extensive repagination. 
 
3. 
Pages 14-15, Sections 5.1f-5.1g:  These sections have been updated to include 
specimen submission requirements for the cooperative group ECOG as part of the  
eligibility criteria.  These sections have also been structured to allow for the 
addition of CALGB requirements which are still pending.  Similar changes have 
been made in Sections 5.2c and 5.2d (Page 16) and 5.3b (Page 17). 
 
4. 
Page 20, Section 7.5c:  The phrase "if performed" has been added to the 
requirement to use the same test (MUGA or echocardiogram) that was used during 
Consolidation Cycle 1 for clarity. 
 
 
Operations Office 
14980 Omicron Drive•San Antonio, TX 78245-3217 • Telephone 210-450-8808 • FAX 210-677-0006 • http://swog.org 


 
S0535 
 
Revision #1 (contd.) 
 
Page 2 
 
 
 
 
 
 
 
 
5. 
Page 32, Section 9.0:  A "" footnote has been added to the "MUGA/ECHO" row in 
the prior to Consolidation #1 through 2 column.  This footnote states that this test is 
only to be performed for patients who experienced signs or symptoms of clinically 
significant cardiac toxicity during or after Induction therapy, and references Section 
5.2b.  A "" footnote has been added to the "MUGA/ECHO" row in the prior to 
Consolidation #3 through 4 column.  This footnote states that if MUGA/ECHO was 
performed prior to Consolidation #1, the same test should be used prior to 
Consolidation #3, and references Section 7.5c.  A "†" footnote has been added to 
the "Height, Weight and BSA" row in the during Consolidation #1 through 2, # 3 
through 4 and #5 through 6 columns.  This footnote states that these are required 
prior to each cycle of consolidation. 
 
6. 
Page 36, Section 13.0:  A note has been added directing non-SWOG participants 
to Appendix 19.4 for CTSU participation procedures. 
 
7. 
Pages 40-42d, Sections 15.1-15.4:  Sections 15.1-15.4 have been restructured to 
allow for the addition of ECOG and CALGB participation information.  Section 15.1 
now contains the specimen submission summary for all groups, Section 15.2 
contains information for SWOG (and other institutions not associated with ECOG 
or CALGB), and Section 15.3 contains information for ECOG. Section 15.4 has 
been kept as a placeholder for the CALGB specimen submission information which 
is still pending.  Pages 42a-42d were added to prevent extensive repagination. 
 
8. 
Page 44, Section 16.1:  Footnote "b" in Table 16.1 has been updated to reflect 
changes in Southwest Oncology Group Policy No. 23.  It now states that following 
an AdEERS report, supporting data does not need to be submitted unless 
specifically requested by SWOG. In addition, the requirement to submit evidence of 
IRB notification to SWOG has been rescinded (although the requirement to notify 
IRBs of all SAEs has not). 
 
9. 
Pages 50-51a, Model Consent Form:  Treatment tables have been added for each 
of the treatment cycles in order to provide a treatment summary for patients as 
requested by several local IRBs.  Page 51a has been added to prevent extensive 
repagination. 
 
10. 
Page 53-55, Model Consent Form:  Several items have been moved in the risks 
and side effects sections in order to more closely coincide with the associated 
probability of each risk as listed in the drug information sections of the protocol.  In 
the Induction Therapy section, "Nosebleed" has been moved from "Less Likely" to 
"Likely" and "Severe injury to liver (veno-occlusive disease)" has been moved from 
"Rare, but Serious" to "Less Likely".  In the Consolidation #3 and #4 section, "Eye 
problems, visual disturbances" has been moved from "Less Likely" to "Likely".  
"Increased blood level of a form of fat called triglyceride" had been added to the 
"Likely" section to coincide with the drug toxicology in Section 3.1b. 
 
11. 
Pages 57-58, Model Consent Form:  The section for Risks and side effects related 
to Maintenance Therapy with gemtuzumab ozogamicin has been removed.  
Gemtuzumab ozogamicin is not used during Maintenance therapy, and therefore 
this section is not pertinent to this protocol.  
 
12. 
Page 59, Model Consent Form:  CTSU has been added to the list of organizations 
that might have access to patient information under the "will my medical 
information be kept private" section. 
 
13. 
Pages 63, Model Consent Form and 65, Specimen Consent Supplemental Sheets:  
The existing specimen and repository information and address have been updated 
to indicate that they are relevant for patients participating through SWOG or other 
institutions not affiliated with ECOG or CALGB.  Information for the ECOG 
specimen repository has been added to each page as well. 
 
 


 
S0535 
 
Revision #1 (contd.) 
 
Page 3 
 
 
 
 
 
 
 
 
 
 
14. 
Page 91, Section 19.0:  "19.4 Cancer Trials Support Unit (CTSU) Participation 
Procedures" was added to the Appendix list. 
 
15. 
Pages 96-100, Appendix 19.4:  "Cancer Trials Support Unit (CTSU) Participation 
Procedures" was added as Appendix 19.4.  Pages 96-100 were added to the 
protocol. 
 
Institutions must update their local consent forms to include this information for future 
registrations.  Patients currently being treated on this study should be informed in the 
manner determined by their local Institutional Review Board (IRB). 
 
The Southwest Oncology Group considers that the changes in the Model Consent Form 
that are associated with this Revision are solely administrative and editorial in nature, and 
do not impact the risk/benefit ratio for participants on this study.  Local accrual to the study 
does not have to be suspended pending implementation of these changes. 
 
This memorandum serves to notify the NCI and Southwest Oncology Group Statistical 
Center. 
 
 
 
 
 
cc: 
PROTOCOL & INFORMATION OFFICE 
Kenneth J. Kopecky, Ph.D. 
Holly Gundacker, M.S. 
Tracy Maher 
Amy Edwards 
Michael Kelly – CALGB 
Ryan Palmer - ECOG 
 


 
 
 
 
 
 
November 15, 2007 
 
 
 
TO: 
ALL 
SOUTHWEST 
ONCOLOGY 
GROUP 
MEMBER, 
CCOP 
AND 
AFFILIATE MEDICAL ONCOLOGISTS AND PATHOLOGISTS; CTSU 
 
FROM: 
Southwest Oncology Group Operations Office 
 
RE: 
S0535, “A Phase II Study of ATRA, Arsenic Trioxide and Gemtuzumab 
Ozogamicin in Patients with Previously Untreated High-Risk Acute 
Promyelocytic Leukemia”  Study Coordinators:  Drs. J.E. Lancet, R. 
Komrokji, C.L. Willman, and M.L. Slovak. 
 
STATUS NOTICE 
 
Study Coordinator:  Jeffrey E. Lancet, M.D. 
Phone number:  813/745-6841 
E-mail:  lancetje@moffitt.usf.edu 
 
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 
 
 
ACTIVATION
 
The study referenced above is now open for participation.  The entire protocol is attached 
for your use. 
 
This memorandum serves to notify the NCI and Southwest Oncology Group Statistical 
Center. 
 
 
 
 
 
cc: 
PROTOCOL & INFORMATION OFFICE 
Kenneth J. Kopecky, Ph.D. 
Holly Gundacker, M.S. 
Tracy Maher 
Amy Edwards 
Michael Kelly – CALGB 
Ryan Palmer - ECOG 
 
 
 
Operations Office 
14980 Omicron Drive•San Antonio, TX 78245-3217 • Telephone 210-450-8808 • FAX 210-677-0006 • http://swog.org 


SOUTHWEST ONCOLOGY GROUP 
PROTOCOL FAST FACT SHEET
THIS FORM HAS BEEN DESIGNED AS A RESOURCE ONLY AND IS NOT INTENDED FOR USE IN THE 
FULFILLMENT OF PATIENT REGISTRATION AND TREATMENT REQUIREMENTS  
S0535
A Phase II Study of ATRA, Arsenic Trioxide and Gemtuzumab Ozogamicin in Patients with 
Previously Untreated High-Risk Acute Promyelocytic Leukemia  
 Drugs provided:  Gemtuzumab Ozogamicin
 Induction  
ATRA 45mg/m2/day(in 2 doses, 22.5 mg/m2 every 12 hours PO, Day 1 to CR 
Gemtuzumab Ozogamicin 9 mg/m2 IV infusion over 2h, Day 1 only 
Arsenic Trioxide 0.15 mg/kg/d IV infusion over 2 hours 5 days/wk beginning on Day 10 and continuing until CR
Consolidation Cycles 1 and 2 
Arsenic Trioxide 0.15 mg/kg/day IV over 2 hours 5 days/week x 5 weeks, repeat after 2 weeks rest
Consolidation Cycles 3 and 4  
ATRA 45mg/m2/day(in 2 doses, 22.5 mg/m2 every 12 hours PO, Days 1-7 
Daunomycin 50 mg/m2/day IV bolus or 1 hour infusion Days 1-3 
Consolidation Cycles 5 and 6 
Gemtuzumab Ozogamicin 9 mg/m2 IV infusion over 2 hours Day 1 only
Maintenance Chemotherapy
ATRA 45/m2/day(in 2 doses, 22.5 mg/m2 every 12 hours PO, Days 1-7 every 14 days 
6MP 60mg/m2/day PO daily for 1 year 
Methotrexate 20mg/m2 PO once per week for 1 year
Eligibility 
Ineligibility 
Morphologically confirmed diagnosis of high risk acute promyelocytic 
leukemia (APL).  Based on bone marrow examination performed 
within 14 days before registration.  The WBC confirming high risk 
must be obtained within 14 days prior to registration. 
Known PML-RARĮ-negative by the RT-PCR 
assay.   
Patient must have reached their 18th birthday 
Prior systemic therapy for acute leukemia 
(except ATRA for up to 3 days prior to 
registration).  Administration of hydroxyurea, 
corticosteroids, and leukapheresis to control high 
cell counts prior to registration is permitted.  
Participation in cytogenetic studies is mandatory.  Collection of 
pretreatment specimens must be completed within 14 days prior to 
registration. 
Patients must not be pregnant or nursing 
because ATRA as well as other drugs used in 
this protocol may cause fetal harm and because 
of the potential for serious adverse reactions in 
nursing infants from the drug.  Women of child 
bearing potential must have a negative 
pregnancy test performed within 14 days prior to 
registration.  Women/men of reproductive 
potential must have agreed to use an effective 
contraceptive method. 
Pretreatment specimens for baseline RT-PCR assays for PML-
RARĮ must be collected and submitted within 14 days prior to 
registration 
No other prior malignancy is allowed except for 
the following:  adequately treated basal cell or 
squamous cell skin cancer, in situ cervical 
cancer, adequately treated Stage I or II cancer 
from which the patient is currently in complete 
remission, or any other cancer from which the 
patient has been disease-free for 5 years. 
Patient must not have prolonged QTc > 0.47 seconds 
 
 *This form has been developed with the support of the SWOG Nurse Oncologists’ Committee. 


Revised 5/30/08
Revised 12/26/14
S0535
Revised 11/1/11
Page 1 
Revised 4/16/14
Version Date 12/26/14
PRIVILEGED COMMUNICATION
Activated November 15, 2007
FOR INVESTIGATIONAL USE ONLY 
 
SWOG
A PHASE II STUDY OF ATRA, ARSENIC TRIOXIDE AND GEMTUZUMAB OZOGAMICIN IN PATIENTS 
WITH PREVIOUSLY UNTREATED HIGH-RISK ACUTE PROMYELOCYTIC LEUKEMIA
STUDY CHAIRS: 
AGENTS: 
Principal Coordinator:
All Trans Retinoic Acid (Tretinoin) (NSC-122758)
Jeffrey E. Lancet, M.D. (Medical Oncology)
Arsenic Trioxide (Trisenox®) (NSC-706363)
H. Lee Moffitt CC 
 
Daunomycin (Cerubidine) 
12902 Magnolia Drive
(daunorubicin hydrochloride) (NSC-82151)
SRB-4 
Gemtuzumab Ozogamicin (Mylotarg) 
Tampa, FL 33612 
 
(NSC-720568)
Phone:  813/745-6841  
6-Mercaptopurine (NSC-755)
FAX:  813/979-3071 
 
Methotrexate (NSC-740)
E-mail: lancetje@moffitt.org
Rami Komrokji, M.D. (Medical Oncology)
BIOSTATISTICIANS: 
H. Lee Moffitt CC
12902 Magnolia Drive
Shannon McDonough, M.S. (Biostatistics)
SRB-4 
Megan Othus, Ph.D. (Biostatistics)
Tampa, FL 33612
Southwest Oncology Group Statistical Center
Phone:  813/745-4291
at Fred Hutchinson Cancer Research Center
FAX:  813/745-5617
1100 Fairview Avenue North, M3-C102
E-mail:  rami.komrokji@moffitt.org
P.O. Box 19024 
 
Seattle, WA  98109-1024
Jerald P. Radich, M.D. (Surface Marker Studies)
Phone:  206/667-4623
Fred Hutchinson Cancer Research Ctr
FAX:  206/667-4408
1100 Fairview Ave N
E-mail:  smcdonou@fhcrc.org
D4-100
E-mail:  mothus@fhcrc.org
Seattle, WA 98109
Phone: 206/667-4118
ECOG STUDY CHAIRS:
FAX:  206/667-2917
E-mail: jradich@fhcrc.org
ECOG Co-Chair:
Martin Tallman, M.D.
Min Fang, M.D, Ph.D. (Cytogenetics/FISH)
Northwestern University
Fred Hutchinson Cancer Research Ctr
Email:  m-tallman@northwestern.edu
825 Eastlake Ave E
M/S G7-500
Elisabeth Paietta, Ph.D. (Immunophenotyping)
Seattle, WA 98109
Our Lady of Mercy Cancer Center
Phone: 206/288-1385
FAX:  206/288-7567
Robert Gallagher, M.D. (Molecular Studies)
E-mail: mfang@fhcrc.org
Montefiore Medical Center
Email:  rgallagh@aecom.yu.edu
Diane Roulston, Ph.D. (Cytogenetics/FISH) 
 
University of Michigan Medical School
Rhett Ketterling, M.D. (Cytogenetics/FISH)
Pathology - Cytogenetics Lab
Mayo Clinic Cytogenetics Laboratory
2900 Huron Pkwy
Ann Arbor, , MI 48105
CALGB STUDY CHAIRS: 
Phone: 734/763-5804
FAX:  734/998-5804
CALGB Co-Chair:  
E-mail: droulstn@umich.edu
Daniel DeAngelo, M.D.
Dana Farber Cancer Institute
E-mail:  ddeangelo@partners.org
 
 
 
 


S0535
Page 2
Version Date 12/26/14
Revised 12/26/14
PARTICIPANTS
ALLIANCE/Alliance for Clinical Trials in Oncology
ECOG-ACRIN/ECOG-ACRIN Cancer Research Group
SWOG/SWOG
 
 
 
 


Revised 5/30/08
S0535
Revised 4/16/14
Page 3
Version Date 12/26/14
TABLE OF CONTENTS
Page
CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION........ 5
1.0
OBJECTIVES................................................................................................................... 6
1.1
Primary Objective............................................................................................................. 6
1.2
Secondary Objective ........................................................................................................ 6
1.3
Translational Medicine Objective ..................................................................................... 6
2.0
BACKGROUND............................................................................................................... 6
3.0
DRUG INFORMATION .................................................................................................... 7
3.1
All Trans Retinoic Acid (Tretinoin) (NSC-122758) ........................................................... 7
3.2
Arsenic Trioxide (Trisenox®) (NSC-706363) .................................................................... 8
3.3
Daunomycin (Cerubidine) (daunorubicin hydrochloride) (NSC-82151)............................ 13
3.4
Gemtuzumab ozogamicin (Mylotarg®) (NSC-720568) (IND-66,366) ............................... 14
3.5
6-Mercaptopurine (NSC-755)........................................................................................... 17
3.6
Methotrexate (NSC-740) .................................................................................................. 18
4.0
DIAGNOSTIC AND STAGING CRITERIA....................................................................... 19
4.1
Diagnostic Criteria............................................................................................................ 19
4.2
Risk Categories................................................................................................................ 19
4.3
Staging Criteria................................................................................................................. 19
5.0
ELIGIBILITY CRITERIA .................................................................................................. 20
5.1
Initial Registration............................................................................................................. 20
5.2
Consolidation Therapy Registration ................................................................................. 22
5.3
Maintenance Therapy Registration .................................................................................. 23
6.0
STRATIFICATION FACTORS......................................................................................... 24
7.0
TREATMENT PLAN ........................................................................................................ 24
7.1
Good Medical Practice ..................................................................................................... 24
7.2
General Considerations.................................................................................................... 24
7.3
Induction Chemotherapy .................................................................................................. 25
7.4
Consolidation Cycles 1 and 2........................................................................................... 26
7.5
Consolidation Cycles 3 and 4........................................................................................... 26
7.6
Consolidation Cycles 5 and 6........................................................................................... 27
7.7
Maintenance Therapy....................................................................................................... 27
7.8
Assessment of Response ................................................................................................ 28
7.9
Supportive Care Guidelines ............................................................................................. 29
7.10
Intake Calendar................................................................................................................ 31
7.11
Criteria for Removal from Protocol Treatment ................................................................. 31
7.12
Discontinuation of Treatment ........................................................................................... 32
7.13
Follow-Up Period.............................................................................................................. 32
8.0
TOXICITIES TO BE MONITORED AND DOSAGE MODIFICATIONS........................... 32
8.1
NCI Common Terminology Criteria for Adverse Events (CTCAE)................................... 32
8.3
Induction Therapy............................................................................................................. 33
8.4
Consolidation Therapy ..................................................................................................... 35
8.5
Maintenance Therapy....................................................................................................... 37
8.6 
Dose Modifications for Obese Patients............................................................................ 38
8.7
Dose Modification Contacts ............................................................................................. 38
8.8
Adverse Event Reporting ................................................................................................. 38
9.0
STUDY CALENDARS...................................................................................................... 39
10.0 
CRITERIA FOR EVALUATION AND ENDPOINT DEFINITIONS ................................... 41
10.1
Disease Status Criteria:.................................................................................................... 41
10.2
Complete Remission (CR) ............................................................................................... 41
10.3
Molecular Remission (MCR) ............................................................................................ 41
10.4
Partial Remission (PR)..................................................................................................... 41
10.5
Treatment Failures........................................................................................................... 41
10.6
Relapse from CR.............................................................................................................. 42
10.7
Event-free survival (EFS) at 3 years ................................................................................ 42
10.8
Toxicity Criteria................................................................................................................. 42
10.9
Performance Status.......................................................................................................... 42
10.10
Time to Death................................................................................................................... 42
 
 
 
 


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11.0
STATISTICAL CONSIDERATIONS ................................................................................ 43
11.1
Primary Objective............................................................................................................. 43
11.2  
Molecular Response and Toxicity .................................................................................... 44
11.3  
Accrual ............................................................................................................................. 45
11.4
Data Safety Monitoring..................................................................................................... 45
12.0
DISCIPLINE REVIEW...................................................................................................... 45
13.0
REGISTRATION GUIDELINES ....................................................................................... 45
13.1 
Registration Timing .......................................................................................................... 45
13.2 
Registration Requirements............................................................................................... 45
13.3 
Registration Procedures................................................................................................... 45
13.4 
For either method of registration, exceptions to Southwest Oncology Group registration ...
policies will not be permitted. ........................................................................................... 46
14.0
DATA SUBMISSION SCHEDULE................................................................................... 46
14.1
Data Submission Requirements....................................................................................... 46
14.2
Master Forms................................................................................................................... 46
14.3
Data Submission Procedures........................................................................................... 47
14.4
Data Submission Overview and Timepoints .................................................................... 47
15.0
SPECIAL INSTRUCTIONS.............................................................................................. 49
15.1
Summary of all specimen submission.............................................................................. 49
15.2
Southwest Oncology Group institutions and other institutions NOT affiliated with ECOG
-or CALGB........................................................................................................................ 50
15.3
ECOG Institutions............................................................................................................. 51
15.4
CALGB institutions ........................................................................................................... 53
16.0
ETHICAL AND REGULATORY CONSIDERATIONS ..................................................... 55
16.1
Adverse Event Reporting Requirements.......................................................................... 56
17.0
BIBLIOGRAPHY.............................................................................................................. 61
18.0
APPENDIX ....................................................................................................................... 62
18.1
Determination of Expedited Adverse Event Reporting Requirements ............................. 63
18.2
Writing Committee ........................................................................................................... 65
18.3
Intake Calendar................................................................................................................ 66
18.4
Cancer Trials Support Unit (CTSU) Participation Procedures ......................................... 67
 
 
 
 


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CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION
This study is supported by the NCI Cancer Trials Support Unit (CTSU).
Institutions not aligned with SWOG will participate through the CTSU mechanism as outlined below and 
detailed in the CTSU logistical appendix.
x
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://members.ctsu.org
x
Send completed site registration documents to the CTSU Regulatory Office. Refer to the CTSU 
logistical appendix for specific instructions and documents to be submitted. 
x
Patient enrollments will be conducted by the CTSU. Refer to the CTSU logistical appendix for 
specific instructions and forms to be submitted.
x
Data management will be performed by the Southwest Oncology Group. Case report forms (with the 
exception of patient enrollment forms), clinical reports, and transmittals must be sent to SWOG 
unless otherwise directed by the protocol. Do not send study data or case report forms to the CTSU 
Data Operations. 
x
Data query and delinquency reports will be sent directly to the enrolling site by the Southwest 
Oncology Group. Please send query responses and delinquent data to the Southwest Oncology 
Group Data Operations Center and do not copy the CTSU Data Operations.
x
Each site should have a designated CTSU Administrator and Data Administrator and must keep their 
CTEP AMS account contact information current. This will ensure timely communication between the 
clinical site and the SWOG data center.
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
CTSU Patient Registration
Voice Mail – 1-888-462-3009
Fax – 1-888-691-8039
Hours: 9:00 AM – 5:30 PM Eastern Time, 
Monday – Friday (excluding holidays)
[Registrations received after 5:00 PM ET 
will be handled the next business day. 
For CTSU patient enrollments that must 
be completed within approximately one 
hour, or other extenuating 
circumstances, call 301-704-2376
between 9:00 am and 5:30 pm.]
Preferred method:
Fax: 800/892-4007
Mailing address:
Southwest Oncology Group 
Data Operations Center
Cancer Research and 
Biostatistics
1730 Minor Ave, STE 1900
Seattle, WA 98101-1468
Do not submit study data or 
forms to CTSU Data 
Operations. Do not copy the
CTSU on data submissions.  
For patient eligibility or treatment-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. 
The CTSU Public Web site is located at: www.ctsu.org 
The CTSU Registered Member Web site is located at https://members.ctsu.org
CTSU logistical information is located in Appendix 18.4
 
 
 
 


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1.0
OBJECTIVES
1.1
Primary Objective
To assess the event-free survival and death during the first six weeks in patients with 
previously untreated high-risk acute promyelocytic leukemia treated with a combined 
regimen of all trans retinoic acid (ATRA), arsenic trioxide, and gemtuzumab ozogamicin.
1.2
Secondary Objective
To estimate the frequency and severity of toxicities of this regimen in this group of 
patients.
1.3
Translational Medicine Objective
To investigate the molecular response rate utilizing this regimen in high-risk patients.
2.0
BACKGROUND
The outlook for patients with APL has improved markedly over the past decade, mostly because 
of the development of all trans retinoic acid and an increased appreciation for the importance of 
anthracycline dose in therapy. Nonetheless, at least 20% of patients presenting with APL still die 
of the disease or a complication of its treatment.  The Spanish (PETHEMA) and Italian (GIMEMA) 
cooperative groups have identified risk factors for treatment failure based on presenting white 
blood cell (WBC) and platelet counts. (1)  Low risk patients are those presenting with a WBC 
10,000 and a platelet count > 40,000, intermediate risk patients also have a WBC 10,000 but 
have a platelet count 40,000, while high risk patients have a presenting WBC > 10,000. Other 
groups, including the British (MRC) and French, have reported similar findings. (2,3) Using 
modern therapies, both low and intermediate risk patients can be expected to enter complete 
remission in at least 95% of cases, and have a risk of relapse during the first year of therapy of 
less than 5%. (4) These outstanding results raise the question of whether these patients may be 
receiving more therapy than necessary, a question that will be addressed in the North American 
Leukemia Intergroup study for low- and intermediate-risk APL, study S0521.  For patients with 
high-risk disease, as defined by the PETHEMA and GIMEMA groups, the outcomes of treatment 
have been less favorable, with early death seen in at least 20% of patients, most often due to 
hemorrhage, usually of the CNS or lungs, and/or infection, and a substantial risk for relapse, 
estimated to be at least 25%.  For example, in the MRC trial, among patients presenting with a 
WBC of over 10,000, the risk of early death in patients treated with ATRA until CR was 24% and 
the risk of relapse was 47%.  In the recently reported PETHEMA LPA99 trial, although outstanding
results were reported in the low- and intermediate-risk groups, early deaths were seen in at least 
20% of high-risk patients, and the recurrence rate was 24% for this group. (5) Thus, for patients 
with high-risk disease, improved therapies are needed.
The last North American Intergroup study, CALGB 9710, included induction therapy with ATRA, 
an anthracycline and cytarabine, and consolidation with an anthracycline and ATRA.  In addition, 
the study asked two questions, both in a randomized fashion. First, the study asked whether 
additional consolidation with arsenic trioxide impacted outcome.  And second, the study asked 
whether the addition of methotrexate and 6-mercaptopurine to ATRA maintenance improved 
disease-free and overall survival.  The study has completed its accrual goal of 500 patients, but 
additional follow-up will be needed to determine the answers to the randomized questions. While 
data from the study according to specific treatment arm are not available, the Data and Safety 
Monitoring Board has released sufficient information to at least confirm the general conclusions of 
the PETHEMA and GIMEMA groups.  These data both confirm the PETHEMA/GIMEMA risk 
stratification, and emphasize the need to find better therapy for high-risk patients.
There have been various attempts to improve therapy in this high-risk group. One approach has 
been to add additional supportive care measures. For example, the PETHEMA group has 
reported on the use of prophylactic prednisone and prophylactic tranexamic acid, and concluded 
that neither was effective in reducing the incidence of early deaths in newly diagnosed APL. (6)
 


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Encouraging results have been reported with the combination of ATRA plus arsenic trioxide, but 
these studies have not been confined to high-risk patients. (7,8) Gemtuzumab ozogamicin (G.O.) 
is composed of a humanized anti-CD33 monoclonal antibody conjugated to calicheamicin, a 
potent antitumor antibiotic.  Because CD33 is brightly expressed by APL blasts in virtually all 
cases of APL, the conjugate has been studied as therapy for patients with recurrent disease. 
Initial results appeared promising and led Estey et al. to combine gemtuzumab with ATRA as 
initial therapy for APL. (9,10) This regimen was found to have a high rate of CR, including a 43% 
rate of PCR negativity at the conclusion of induction therapy.  (11)
Most recently, Estey et al.
have conducted a pilot study of the combination of ATRA, arsenic trioxide and gemtuzumab 
ozogamicin as initial therapy for 18 patients with high-risk APL, i.e. those with a WBC > 10,000.  
(12)
They report a CR rate of 86% in this high-risk group, a figure superior to what they have 
achieved with any other regimen they have tested.  In addition, all evaluable patients became 
PCR negative at 3 and 6 months from the date of initial CR.  
Given the clinical problem posed by the patients with high-risk APL and the encouraging results so
far utilizing the combinations described above, the Southwest Oncology Group has proposed the 
Phase II study described herein, utilizing a novel treatment regimen including induction therapy 
with ATRA, arsenic and gemtuzumab ozogamicin, in order to explore both its impact on disease-
free survival and toxicity. 
Inclusion of Women and Minorities
This study was designed to include women and minorities, but was not designed to measure 
differences of intervention effects.
3.0
DRUG INFORMATION
3.1
All Trans Retinoic Acid (Tretinoin) (NSC-122758) 
a.
DESCRIPTION:
Chemistry:  All trans retinoic acid (tRA) is a natural retinol metabolite formed from 
the intestinal oxidation of B-carotene and from tissue anabolism of retinaldehyde.  
Both retinol and tRA circulate in the blood in tight association with serum proteins, 
retinol binding protein for retinol and albumin for tRA.  tRA is a major endogenous 
metabolite of Vitamin A (retinol).  tRA induces differentiation and/or growth-
inhibition in many tumorigenic cell lines and demonstrates therapeutic efficacy in 
the treatment of certain leukemias particularly promyelocytic leukemia.  It also 
acts to stimulate clonal proliferation of hematopoietic cells and augments, either 
directly or indirectly, a variety of immune functions.
b.
TOXICOLOGY:
Human Toxicology:  The toxicities of tRA closely resemble those of 
hypervitaminosis A.  Cheilitis (80% of patients) and headache (77%) are the most 
common toxicities of tRA usage.  Other toxicities include visual disturbances, 
dryness of mucous membranes, pruritis, dry skin, peeling, fatigue and epistaxis in 
10 - 50% of patients.  10% or less of patients develop musculoskeletal pain, 
conjunctivitis and psychological changes.  The CNS toxicity appears dose-
related, occurring in 4% or less when tRA is administered at 30 mg/day, but 
occurring in 50% when tRA is administered at 70 - 100 mg/day.  Increases in 
SGOT/SGPT/bilirubin, triglycerides, cholesterol and fibrinogen have also been 
seen.  All trans retinoic acid has been associated with cases of pseudotumor 
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Skeletal changes have been reported in adults receiving prolonged treatment with 
cis retinoic acid (cRA).  Whether these effects accompany tRA administration of 
long term is not well defined.  In APL patients treated with tRA, 55% developed 
hypertriglyceridemia and 40% manifested increased liver transaminases.  
Patients with APL have also experienced hyperleukocytosis and a cardio-
pulmonary syndrome.
Like cRA, tRA must be considered a teratogen, and may potentially cause 
craniofacial abnormalities, CNS abnormalities, thymic aplasia and cardiac 
abnormalities.  It is considered a class C FDA pregnancy risk since animal 
studies have shown adverse effects and toxicities on the fetus.  No adequate or 
well-controlled studies have been done on pregnant women.
It is strongly recommended that women of childbearing potential have a 
pregnancy test performed within two weeks prior to all trans retinoic acid 
therapy.  Females should be fully counseled regarding the risk to the fetus 
of using ATRA.  
Females should be fully counseled on the serious risk to the fetus should 
they become pregnant while undergoing treatment.  An effective form of 
contraception should be used for at least one month before and also 
throughout all trans retinoic acid therapy, and two months after.  If 
pregnancy does occur during treatment, the physician and patient should 
discuss the desirability of continuing the pregnancy.
c.
PHARMACOLOGY
Pharmacokinetics:  Unlike cRA, little published data exists regarding the 
pharmacokinetics of tRA.  However, the pharmacologic transformations of tRA 
may resemble cRA. Under ambient light, cRA in solution equilibrates with tRA in 
2 hours in a ratio of 3:1, cis:trans.  In vivo conversion occurs to a variable extent, 
tRA representing 0 - 30% of cRA plasma concentration in patients taking oral 
cRA.  cRA is conjugated to glucoronic acid and is excreted via the biliary tract into 
the enterohepatic circulation.  cRA achieves peak plasma concentration after oral 
dosing in 1.5 - 3.0 hours.  An 80 mg dosage of cRA produces peak plasma levels 
approaching 1 μM; doses of 4 mg/kg produce peak plasma concentrations of 4 
μM.  cRA shows a biphasic elimination profile with a t1/2ß of 2 - 4 hours and t1/2ȕ
of 10 - 77 hours.  cRA oxidizes to 13-cis-4-ketoretinoic acid, the major serum 
metabolite which accumulates with chronic cRA oral therapy to produce an AUC 
5-fold greater than the parent compound.
Formulation:  10 mg capsules of the active ingredient formulated with butylated 
hydroxyanisole, disodium edate, refined soybean oil, BHA, and a wax mixture 
consisting of purified beeswax, hydrogenated soybean oil flakes and 
hydrogenated vegetable oil.  The capsules should be stored at room temperature 
protected from light.
Administration:  PO.
Supplier:  All Trans Retinoic Acid 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 product's package insert for full prescribing and toxicity 
information.
3.2
Arsenic Trioxide (Trisenox®) (NSC-706363) 
a.
Description
Arsenic trioxide is a trivalent inorganic arsenical.  The molecular formula is As2O3.
 


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b.
Toxicology
Comprehensive Adverse Events and Potential Risks list (CAEPR) for Arsenic 
trioxide (Trisenox, NSC 706363)
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 Agent Specific Adverse Event List (ASAEL), 
appears in a separate column and is identified with bold and italicized text. This 
subset of AEs (ASAEL) contains events that are considered 'expected' for 
expedited reporting purposes only. Refer to the 'CTEP, NCI Guidelines: Adverse 
Event Reporting Requirements' 
http://ctep.info.nih.gov/protocolDevelopment/electronic_applications/docs/aeguideline
s.pdf further clarification. Frequency is provided based on 680 patients. Below is 
the CAEPR for Arsenic trioxide (Trisenox).
Version 2.0, March 26, 20101
Adverse Events with Possible 
Relationship to Arsenic trioxide (Trisenox)
(CTCAE 4.0 Term)
[n= 680]
EXPECTED AEs FOR 
CTEP-AERS
REPORTING
Agent Specific 
Adverse Event List
(ASAEL)
Likely (> 20%)
Less Likely (<=20%)
Rare but 
Serious (<3%)
Expected
BLOOD AND LYMPHATIC SYSTEM DISORDERS
Anemia
Anemia
Febrile neutropenia
Febrile neutropenia
Blood and lymphatic 
system disorders -
Other (pancytopenia)
CARDIAC DISORDERS
Conduction disorder
Conduction disorder
Palpitations
Palpitations
Sinus tachycardia
Sinus tachycardia
Ventricular 
arrhythmia
Ventricular arrhythmia
EAR AND LABYRINTH DISORDERS
Tinnitus
Tinnitus
GASTROINTESTINAL DISORDERS
Abdominal 
distension
Abdominal distension
Abdominal pain
Abdominal pain
Anal mucositis
Anal mucositis
Constipation
Constipation
Diarrhea
Diarrhea
Dry mouth
Dry mouth
Dyspepsia
Dyspepsia
Mucositis oral
Mucositis oral
Nausea
Nausea
Pancreatitis
Pancreatitis
Rectal mucositis
Rectal mucositis
Small intestinal 
mucositis
Small intestinal 
mucositis
Toothache
Toothache
Vomiting
Vomiting
 


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GENERAL DISORDERS AND ADMINISTRATION SITE 
CONDITIONS 
Chills
Chills
Edema face
Edema face
Edema limbs
Edema limbs
Fatigue
Fatigue
Fever
Fever
Injection site reaction
Injection site reaction
Non-cardiac chest 
pain
Pain
Pain
INFECTIONS AND INFESTATIONS
Infection2
Infection²
Infections and 
Infestations - Other 
(opportunistic 
infection associated 
with >=Grade 2 
lymphopenia)
INJURY, POISONING AND PROCEDURAL 
COMPLICATIONS 
Bruising
Bruising
INVESTIGATIONS 
Alanine 
aminotransferase 
increased
Alanine 
aminotransferase 
increased
Aspartate 
aminotransferase 
increased
Aspartate 
aminotransferase 
increased
Blood bilirubin 
increased
Blood bilirubin 
increased
Creatinine increased
Creatinine increased
Electrocardiogram 
QT corrected interval 
prolonged
Electrocardiogram QT 
corrected interval 
prolonged
GGT increased
GGT increased
Lipase increased
Lipase increased
Neutrophil count 
decreased
Neutrophil count 
decreased
Platelet count 
decreased
Platelet count 
decreased
Serum amylase 
increased
Serum amylase 
increased
Weight gain
Weight gain
Weight loss
Weight loss
White blood cell 
decreased
White blood cell 
decreased
METABOLISM AND NUTRITION DISORDERS
Acidosis
Acidosis
Anorexia
Anorexia
Hyperglycemia
Hyperglycemia
Hyperkalemia
Hypokalemia
Hypokalemia
Hypomagnesemia
Hypomagnesemia
 


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MUSCULOSKELETAL AND CONNECTIVE TISSUE 
DISORDERS
Arthralgia
Arthralgia
Bone pain
Bone pain
Generalized muscle 
weakness
Generalized muscle 
weakness
Musculoskeletal and 
connective tissue 
disorder - Other 
(muscle atrophy)
Musculoskeletal and 
connective tissue 
disorder - Other 
(muscle atrophy)
Myalgia
Myalgia
NERVOUS SYSTEM DISORDERS
Dizziness
Dizziness
Headache
Headache
Paresthesia
Peripheral motor 
neuropathy
Peripheral motor 
neuropathy
Peripheral sensory 
neuropathy
Peripheral sensory 
neuropathy
PSYCHIATRIC DISORDERS
Anxiety
Insomnia
Insomnia
RENAL AND URINARY DISORDERS
Acute kidney injury
Acute kidney injury
Proteinuria
Proteinuria
RESPIRATORY, THRORACIC AND MEDIASTINAL 
DISORDERS
Allergic rhinitis
Allergic rhinitis
Bronchospasm
Bronchospasm
Cough
Cough
Dyspnea
Dyspnea
Epistaxis
Laryngeal mucositis
Laryngeal mucositis
Pharyngeal 
mucositis
Pharyngeal mucositis
Pleural effusion
Pleural effusion
Retinoic acid 
syndrome
Retinoic acid syndrome
Sore throat
Tracheal mucositis
Tracheal mucositis
SKIN AND SUBCUTANEOUS TISSUE DISORDERS
Alopecia
Alopecia
Dry skin
Dry skin
Hyperhidrosis
Hyperhidrosis
Pruritus
Pruritus
Purpura
Purpura
Rash maculo-
papular
Rash maculo-papular
Skin and 
subcutaneous tissue 
disorders - Other 
(dermatitis)
Skin and 
subcutaneous tissue 
disorders - Other 
(hyperkeratosis)
Skin and subcutaneous 
tissue disorders - Other 
(hyperkeratosis)
 


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SKIN AND SUBCUTANEOUS TISSUE DISORDERS (contd.)
Skin 
hyperpigmentation
Skin hyperpigmentation
Urticaria
Urticaria
VASCULAR DISORDERS
Capillary leak 
syndrome
Capillary leak syndrome
Flushing
Flushing
Hypertension
Hypertension
Hypotension
Hypotension
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 Gastrointestinal hemorrhage includes Anal hemorrhage, Cecal hemorrhage, 
Colonic hemorrhage, Duodenal hemorrhage, Esophageal hemorrhage, 
Esophageal 
varices 
hemorrhage, 
Gastric 
hemorrhage, 
Hemorrhoidal 
hemorrhage, 
Ileal 
hemorrhage, 
Intra-abdominal 
hemorrhage, 
Jejunal 
hemorrhage, Lower gastrointestinal hemorrhage, Oral hemorrhage, Pancreatic 
hemorrhage, Rectal hemorrhage, Retroperitoneal hemorrhage, and Upper 
gastrointestinal hemorrhage under the GASTROINTESTINAL DISORDERS 
SOC.
Also reported on Arsenic trioxide (Trisenox) trials but with the relationship 
to Arsenic trioxide (Trisenox) still undetermined:
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system 
disorders - Other (lymphadenopathy); Disseminated intravascular coagulation; 
Leukocytosis
CARDIAC DISORDERS - Heart failure; Ventricular tachycardia
EAR AND LABYRINTH DISORDERS - External ear pain; Vertigo
EYE DISORDERS - Blurred vision; Conjunctivitis; Dry eye; Eye pain; Watering 
eyes
GASTROINTESTINAL 
DISORDERS
-
Dysphagia; 
Fecal 
incontinence; 
Flatulence; Gastrointestinal hemorrhage³; Ileus 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Gait 
disturbance; Malaise
HEPATOBILIARY DISORDERS - Hepatobiliary disorders - Other (cytolytic 
hepatitis)
IMMUNE SYSTEM DISORDERS - Allergic reaction
INVESTIGATIONS
-
Alkaline 
phosphatase 
increased; 
INR 
increased; 
Investigations - Other (blood lactate dehydrogenase); Investigations - Other 
(electrocardiogram T wave abnormal); Investigations - Other (inverted T wave)
METABOLISM 
AND 
NUTRITION 
DISORDERS
-
Dehydration; 
Hypermagnesemia; 
Hypoalbuminemia; 
Hypocalcemia; 
Hypoglycemia; 
Hyponatremia
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Back pain; 
Musculoskeletal and connective tissue disorder -
Other (joint swelling); 
Musculoskeletal and connective tissue disorder -  Other (muscle cramps); Neck 
pain; Pain in extremity
NERVOUS SYSTEM DISORDERS
-
Depressed level of consciousness; 
Dysgeusia; Lethargy; Nervous system disorders - Other (hypoesthesia); Nervous 
system disorders - Other (restless leg syndrome); Neuralgia; Seizure; Tremor
 


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PSYCHIATRIC DISORDERS - Agitation; Confusion; Depression
RENAL AND URINARY DISORDERS - Renal and urinary disorders - Other 
(renal insufficiency); Urinary incontinence; Urinary tract pain
REPRODUCTIVE SYSTEM AND BREAST DISORDERS- Vaginal hemorrhage
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS
-
Adult 
respiratory distress syndrome; Bronchopulmonary hemorrhage; Hypoxia; Nasal 
congestion; 
Pharyngolaryngeal 
pain; 
Pneumonitis; 
Pulmonary 
edema; 
Respiratory, thoracic and mediastinal disorders - Other (bronchitis); Respiratory, 
thoracic and mediastinal disorders - Other (crepitations); Respiratory, thoracic 
and mediastinal disorders - Other (rales); Wheezing
SKIN 
AND 
SUBCUTANEOUS 
TISSUE 
DISORDERS
-
Palmar-plantar 
erythrodysesthesia syndrome; Periorbital edema; Skin and subcutaneous tissue 
disorders - Other (folliculitis); Skin hypopigmentation
VASCULAR DISORDERS - Thromboembolic event; Vasculitis
Note: Arsenic trioxide (Trisenox) 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.
c.
Pharmacology
Formulation:  Each ampule contains 10 mg of arsenic trioxide (1 mg/mL) in a 
sterile, nonpyrogenic, preservative-free clear solution in water for injection using 
NaOH and HCI to adjust to pH 7-9.  The drug should be diluted in 100 mL to 500 
mL of 5% Dextrose in Water Injection, USP or 0.9% Sodium Chloride Injection, 
USP prior to infusion.
Storage and Stability:  Intact ampules should be stored at room temperature.  The 
solution as diluted above is chemically and physically stable at room temperature 
for 24 hours.
Administration:  The route of administration is intravenous.
Supplier:  Arsenic trioxide 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 product's package insert for full prescribing and toxicity 
information.
3.3
Daunomycin (Cerubidine) (daunorubicin hydrochloride) (NSC-82151) 
a.
DESCRIPTION
Daunomycin (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.
TOXICITY
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 
 


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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 eliminated 
by the kidney and 40% by biliary excretion.
Formulation: The drug is supplied in vials containing 20 mg of daunomycin as a 
reddish lyophilized powder.  The daunomycin 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 daunomycin activity for intravenous administration only.
Supplier:  Daunomycin 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 product's package insert for full prescribing and toxicity 
information.
3.4
Gemtuzumab ozogamicin (Mylotarg®) (NSC-720568) (IND-66,366)
a.
DESCRIPTION
Antineoplastic Agent, Monoclonal Antibody.
Mechanism of Action: Antibody to CD33 antigen, which is expressed on leukemic 
blasts in 80% of patients with acute myeloid leukemia (AML), as well as normal 
myeloid cells. Binding results in internalization of the antibody-antigen complex. 
Following internalization, the calicheamicin derivative is released inside the 
myeloid cell. The calicheamicin derivative binds to DNA resulting in double strand 
breaks and cell death. Pluripotent stem cells and nonhematopoietic cells are not 
affected.  
b.
TOXICOLOGY
Human Toxicology: The following toxicities occurred in adults > 60 years of age.  It is 
anticipated that these same toxicities are likely to occur (less frequently or to a 
lesser degree) in younger patients.  Percentages estimated in adults > 60 years of 
age. > 10%: Cardiovascular:  Peripheral edema (21%), hypertension (20%), 
hypotension (16%). Central nervous system: Chills (66%), fever (80%), headache 
(26%), pain (25%), dizziness (11%), insomnia (18%).  Dermatologic: Rash (23%), 
petechiae (21%), ecchymosis (15%).  Endocrine and metabolic: Hypokalemia (30%), 
hypokalemia.  Gastrointestinal:  Nausea (64%), vomiting (55%), diarrhea (38%), 
anorexia (31%), abdominal pain (29%), constipation (28%), stomatitis/mucositis 
(25%), abdominal distention (11%), dyspepsia (11%).  Hematologic: Neutropenia 
(98%; 
median 
recovery 
40.5 
days), 
thrombocytopenia
(99%; 
median
 


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recovery 39 days); anemia (47%), bleeding (15%), lymphopenia.  Hepatic:  
Hyperbilirubinemia (23%) increased LDH (18%), increased transaminases (9% to 
17%).  Local:  Local reaction (25%).  Neuromuscular & skeletal: Weakness 
(45%), back pain (18%).  Respiratory:  Dyspnea (36%), epistaxis (29%; severe 
3%), cough (19%), pharyngitis (14%).  Miscellaneous:  Infection (28%), sepsis 
(24%), neutropenic fever (20%).
Percentages estimated in adults > 60 years of age.  1% to 10%:  Cardiovascular: 
Tachycardia (10%).  Central nervous system:  Depression (10%), cerebral 
hemorrhage (2%), intracranial hemorrhage (2%).  Endocrine and metabolic: 
Hypomagnesemia (4%), hyperglycemia (2%).  Genitourinary:  Hematuria (10%; 
severe 1%), vaginal hemorrhage (7%) 
Hematologic:
Hemorrhage 
(8%), 
disseminated intravascular coagulation (DIC) (2%).  Hepatic: Elevated PT.  
Respiratory: Rhinitis (10%), hypoxia (6%), pneumonia (10%), rhinitis (10%).  
Neuromuscular & skeletal: Arthralgia (10%).
Percentages estimated in adults > 60 years of age.  < 1% (limited to significant 
and/or life threatening): Hepatic failure, jaundice, hepatosplenomegaly, veno-
occlusive disease.
Hypersensitivity:  Gemtuzumab ozogamicin administration can result in severe 
hypersensitivity reactions (including anaphylaxis), and other infusion-related 
reactions 
which 
may 
include 
severe 
pulmonary 
events. 
Infrequently, 
hypersensitivity reactions and pulmonary events have been fatal. In most cases, 
infusion-related symptoms occurred during the infusion or within 24 hours of 
administration 
of 
gemtuzumab 
ozogamicin 
and 
resolved. Gemtuzumab 
ozogamicin infusion should be interrupted for patients experiencing dyspnea or 
clinically significant hypotension.  Patients should be monitored until signs and 
symptoms completely resolve.  Discontinuation of gemtuzumab ozogamicin 
treatment should be strongly considered for patients who develop anaphylaxis, 
pulmonary edema, or acute respiratory distress syndrome.  Physicians should 
consider leukoreduction with hydroxyurea or leukapheresis to reduce the 
peripheral white count below 30,000 prior to administration of gemtuzumab 
ozogamicin. 
Overdosage/Toxicology:  Symptoms are unknown. General supportive measures 
should be instituted. Gemtuzumab ozogamicin is not dialyzable.
Drug Interactions:  No formal drug interaction studies have been conducted.
Pregnancy/Breast-Feeding 
Implications: 
May 
cause 
fetal 
harm 
when 
administered to a pregnant woman. Women of childbearing potential should avoid
becoming pregnant while receiving treatment. If used in pregnancy, or if patient 
becomes pregnant during treatment, the patients should be apprised of potential 
hazard to the fetus. Excretion in breast milk unknown, breast feeding is not 
recommended.
c.
PHARMACOLOGY
Kinetics: Half-life: Total calicheamicin:  45 hours (initial dose); 60 hours on repeat 
dosing. Unconjugated calicheamicin:  100 hours (no change noted in repeat 
dosing).
Formulation: Powder for injection:  5 mg.
Storage and Stability:  Light sensitive; protect from light. Store vials under 
refrigeration 2° to 8°C or 36° to 46°F. Reconstituted vials may be stored under 
refrigeration for up to 8 hours.
 


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Reconstitution: Prepare in biologic safety hood with the fluorescent light turned 
off. Allow to warm to room temperature prior to reconstitution. Reconstitute vial 
with 5 mL sterile water for injection, USP. Final concentration in vial is 1 mg/mL. 
Dilute desired dose in 100 mL of 0.9% sodium chloride injection. The resulting 
I.V. bag should be placed in a UV protectant bag and infused immediately.
If not used immediately, the reconstituted admixture may be placed in the 
refrigerator (at 2° to 8°C) until 30 minutes before time of use. Before 
administration, take the IV bag from the refrigerator and warm it to room 
temperature in the UV light protectant bag.  The infusion must be completed 
within 18 hours of initial infusion of the drug.
Compatibility: No information (infuse via separate line)
Administration: Administer as infusion only, over at least 2 hours. Do not 
administer I.V. push (bolus). Infuse through a separate line equipped with a low 
protein-binding 0.2-1.2 micronPES (polyether sulfone), 0.8-1.2 micron cellulose 
acetate/cellulose nitrate (mixed ester), or 1.2 micron acrylic copolymer terminal 
filter.  May be infused peripherally or through a central line. Pre-medication with 
acetaminophen 
and 
diphenhydramine 
and/or 
corticosteroids 
should 
be 
administered prior to each infusion.
Supplier: Gemtuzumab ozogamicin is considered investigational for this study 
and will be supplied free of charge by Pfizer, Inc. to each site for distribution by 
Biologics', Inc. to patients on this study.  Participating institutions are instructed to 
order as outlined below.
Drug Ordering: Orders need to be submitted by faxing the Clinical Drug Request 
Form to Biologics' Clinical Trial Division at 919/256-0794.  The form can be found 
on the protocol abstract page of the Southwest Oncology Group website 
(www.swog.org) or on the protocol abstract page of the CTSU website 
(www.ctsu.org).
Patient initials, SWOG patient ID, dose, and signature of the 
investigator or an authorized designate will all be required at the time of drug 
order.  Biologics will ship drug on the same day for orders received before 4:00 
p.m. E.S.T. Monday through Thursday.  Orders received after 4:00 p.m. E.S.T. 
Monday through Thursday or any time on Friday will be processed and shipped 
the next business morning.  Drug will be ordered and shipped in 1 cycle 
increments.  To avoid treatment delays, drug may be pre-ordered for patients 
who are planned to be enrolled.  The SWOG patient ID will not be required for 
pre-orders.  Subsequent drug requests can be directly faxed to 919/256-0794. 
Unused drug should be destroyed according to local policies and procedures.  
Drug Returns:  Unused drug supplies should NOT be returned.  Unused drug 
should be disposed of per local institutional guidelines.
Drug Accountability:  The investigator, or a responsible party designated by the 
investigator, must maintain a careful record of the receipt, disposition and 
disposal of all drugs received by the supplier using the NCI Drug Accountability 
Record Form (DARF) available at http://ctep.cancer.gov.
Questions regarding drug ordering/shipping should be directed to the Biologics 
Clinical Trial Department at 800/850-4306.
Please refer to the product’s package insert for full prescribing and toxicity 
information.
 


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3.5
6-Mercaptopurine (NSC-755)
a.
DESCRIPTION
6-Mecaptopurine (6MP) is an antimetabolite chemically known as 1,7-dihydro-6H-
purine-6-thione monohydrate, an analogue of the purine bases, adenine and 
hypoxanthine.  6MP competes with hypoxanthine and guanine for the enzyme, 
HGPRTase.  The conversion to TIMP inhibits IMP conversion to xanthylic A and 
adenylic acid.  TIMP also inhibits glutamine-5-phosphoribosylpyrophosphate 
amidotransferase, the first enzyme unique to the de novo pathway for purine 
ribonucleotide synthesis.
b.
TOXICOLOGY
The dose limiting toxicity is myelosuppression.  Hyperuricemia may occur as a 
result of rapid cell lysis.  Tumor lysis syndrome with hyperuricemia can be 
minimized with increased hydration, urine alkalinization and xanthine oxidase 
inhibitors.  Since xanthine oxidase catabolizes 6MP, the simultaneous 
administration of allopurinol (a xanthine oxidase inhibitor) should alert the 
investigator to reduce the dose of 6MP by 25 - 30% of the usual dose.  In 
addition, enhanced marrow suppression has occurred in patients receiving 
trimethoprim-sulfamethoxizole.  Other reactions include mucositis; skin rash; 
intestinal, rectal and genital ulcerations; nausea and vomiting; anorexia, and 
diarrhea.  Progressive liver damage, increases in LFTs, jaundice with intrahepatic 
cholestasis and parenchymal cell necrosis occur and may progress to 
encephalopathy.  Drug fever, pulmonary infiltrates, electrolyte imbalances, 
alopecia and fatigue have been reported.  Oligospermia has been observed with 
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c.
PHARMACOLOGY
Kinetics:  Absorption of the oral dose of 6MP is incomplete and variable, 
averaging 50% of administered dose.  After intravenous administration, half life is 
21 minutes in children and 47 minutes in adults.  46% of an oral dose is excreted 
in the urine in 24 hours.  The blood-brain transport is negligible.  Monitoring 
plasma levels of 6MP is of questionable value.
Formulation:  The drug is available in 50 mg tablets in bottles of 25 and 250.  
Storage and Stability:  The tablets should be stored at 15° - 25°C (59-77°F) in a 
dry place.
Administration:  PO.
Supplier:  6-Mercaptopurine 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 product’s package insert for full prescribing and toxicity 
information.
3.6
Methotrexate (NSC-740)
a.
DESCRIPTION
Methotrexate is an antimetabolite and has as its principle mechanism of action 
the competitive inhibition of dihydrofolate reductase.
b.
TOXICOLOGY
Human Toxicology:  Adverse reactions include mucositis (gingivitis, pharyngitis, 
stomatitis, enteritis, hematemesis, melena and ulceration), nausea, vomiting, 
diarrhea, 
anorexia, 
myelosuppression, 
skin 
rashes, 
itching, 
hives, 
photosensitivity, 
pigmentation 
changes, 
alopecia, 
ecchymosis, 
acne, 
telangiectasia, furunculosis, malaise, fatigue, chills, fever, dizziness, headache, 
blurred vision, decreased resistance to infection, impaired renal function 
(including cystitis, azotemia, hematuria and acute renal failure), hepatotoxicity 
(including elevated transaminase, fibrosis and cirrhosis), and pulmonary toxicity 
(including death from interstitial pneumonitis and chronic interstitial obstructive 
pulmonary disease).  Pulmonary symptoms (especially a dry, nonproductive 
cough) may require interruption of treatment and special investigation.  Central 
nervous system toxicities have included headache, drowsiness, blurred vision, 
aphasia, hemiparesis, paresis, convulsions, transient subtle cognitive dysfunction, 
mood alteration and unusual cranial sensations.  Leukoencephalopathy may 
occur in patients who have had cranial irradiation.  Toxicity is directly related to 
duration of blood levels.  Because the drug is excreted in the urine, impaired renal 
function is usually a contraindication to its use.  Calcium leucovorin must be 
administered after high-dose methotrexate to prevent life threatening toxicity.  
Other potential toxicities include reproductive dysfunctions (defective oogenesis 
or spermatogenesis, transient oligospermia, menstrual dysfunction, vaginal 
discharge, infertility), opportunistic infection, loss of libido, myalgia, arthralgia, 
diabetes, osteoporosis, tinnitus, eye discomfort, epistaxis, sweating and sudden 
death.  A few cases of anaphylactoid reactions have been reported.  Patients with 
a known hypersensitivity to methotrexate should not receive the drug.  Fetal death 
and/or congenital anomalies have been reported.  Women of childbearing 
potential should be cautioned.  Unexpectedly severe (sometimes fatal) marrow 
suppression and gastrointestinal toxicity have been reported with concomitant 
administration of methotrexate (usually in high doses) along with some non-
steroidal anti-inflammatory drugs.  METHOTREXATE FORMULATIONS AND 
DILUENTS CONTAINING PRESERVATIVES MUST NOT BE USED FOR 
INTRATHECAL OR HIGH-DOSE METHOTREXATE THERAPY.
 


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c.
PHARMACOLOGY
Kinetics:  Oral absorption appears to be dose dependent.  The absorption of 
doses greater than 80 mg/m2 is significantly less than lower doses.  Methotrexate 
in serum is approximately fifty percent protein-bound.  It does not penetrate the 
blood-brain barrier.  Terminal half-life is 3 - 10 hours for doses less than 30 
mg/m2 and 8 - 15 hours with higher doses.  With intravenous administration, 80 -
90% of unchanged methotrexate is excreted in the urine within 24 hours.  Ten 
percent or less is excreted in the bile.
Formulation:  Methotrexate is available as tablets for oral administration.
Storage and Stability:  The tablets should be stored at 15° - 25°C (59 - 77°F) in a 
dry place.
Administration:  PO.
Supplier:
Methotrexate 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 product’s package insert for full prescribing and toxicity 
information.
4.0
DIAGNOSTIC AND STAGING CRITERIA
4.1
Diagnostic Criteria
a.
Definitions:
1.
Bone marrow cellularity:  The volume of hematopoietic nucleated cells, 
expressed as a percentage of marrow volume less volume of fibrosis.
2.
Blasts:  Neoplastic promyelocytes defined as promyelocytes with heavy 
granulation and irregular nuclei and/or primitive promyelocytes with very 
large, numerous Auer rods.
3.
Bone Marrow Blast Percentage is calculated as the percent of blasts 
among all nucleated marrow cells.
b.
Acute Promyelocytic Leukemia (APL, FAB M3, ICD-O code 9866/3) is defined by 
 20% neoplastic promyelocytes, and the presence of t(15;17), PML-5$5Į Rr
5$5Į-PML.
The variant form of APL (FAB M3V) is defined morphologically by the presence of 
cells with reniform, bi- or multilobed, or convoluted nuclei, and either sparse fine 
granules or agranular cytoplasm.
4.2
Risk Categories
Risk categories are defined for APL on the basis of pretreatment WBC and platelet count 
as follows within 14 days of registration: (1)
a.
Low risk:  WBC PFO (10 X 109/L) and platelets > 40,000/mcl (40 x 109/L) 
b.
Intermediate risk:  WBC mcl (10 X 109/L) and SODWHOHWVmcl (40 
x 109/L) 
c.
High risk:  WBC > 10,000/mcl (10 X 109/L) 
4.3
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 S0535 Prestudy Form and submit to the Data 
Operations Center in Seattle (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 four weeks later would be considered Day 28.  
This allows for efficient patient scheduling without exceeding the guidelines.  If Day 7, 14 or 28 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)
5.1
Initial Registration
a.
Patients must have a morphologically confirmed diagnosis of high risk (see 
Section 4.2c) acute promyelocytic leukemia (APL), based on bone marrow 
examination performed within 14 days before registration.  The WBC confirming 
high risk must be obtained within 14 days prior to registration.
b.
Patients who are known to be PML- 5$5Įnegative by the RT-PCR assay required 
in Section 5.1g below are not eligible. (NOTE:  If the RT-PCR result is 
indeterminate, additional blood specimens should be submitted for RT-PCR 
testing to avoid indeterminate pretreatment results whenever possible; if the RT-
PCR result remains indeterminate after the initial and any additional specimens 
are assayed, the patient will be eligible provided all other eligibility criteria are met.  
Patients may be registered before the RT-PCR assay result is known, but if the 
result is negative they must be removed from protocol treatment and treated at the 
physician’s discretion; see Section 7.3d.)
c.
Patients must have reached their 18th birthday.
d.
Patients must not have prolonged QTc > 0.47 seconds.
e.
Patients must not have received prior systemic chemotherapy for acute leukemia,
with the exception of the ATRA, which may be administered for up to 5 days prior 
to registration.  Administration of hydroxyurea, corticosteroids, or leukapheresis to 
control high cell counts prior to registration is permitted.  
f.
Pretreatment cytogenetics must be performed on all patients.  Participation in 
cytogenetic studies is mandatory for patients affiliated with CALGB or ECOG.
Collection of pretreatment specimens must be completed within 14 days prior to 
registration to S0535.  Note that there are also additional time points at which 
specimens are required to be submitted for cytogenetics (see Section 15.2).  
Collection and submission of required materials must be by one of the following 
mechanisms:
x
SWOG Sites and Other Sites not Affiliated with ECOG or CALGB:
Specimens must be submitted to each institution’s preferred cytogenetics 
laboratory (see Section 15.2).
x
ECOG Sites:  Baseline karyotypes must be submitted via E3903.  Register 
patient to E3903 PRIOR to registration to S0535.  The ECOG patient number 
will be required at the time of S0535 registration (see Section 15.3).
x
CALGB Sites: CALGB patients must be registered on CALGB 8461 PRIOR 
to registration to S0535. The CALGB patient number will be required by 
CTSU at the time of S0535 registration (see Section 15.4).
 


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Revised 6/15/10
SWOG Patient No.
Patient's Initials (L, F, M)
g.
For all patients, pretreatment specimens for baseline RT-PCR assays for PML-
5$5Į PXVW EH FROOHFWHG DQG VXEPLWWHG ZLWKLQ  GD\V SULRU WR UHJLVWUDWLRQ WR
S0535.  Note that there are also additional time points at which specimens are 
required to be submitted for RT-PCR assays (see Section 15.0).  Specimen 
submissions must be via the mechanisms indicated below.  Repository aspects of 
the ancillary protocols for CALGB and ECOG are optional as outlined in the 
informed consent documents.
x
SWOG and CALGB Sites and other sites not affiliated with ECOG:
Specimens must be submitted to a CLIA-approved laboratory.  See Sections
15.2 and 15.4.
x
ECOG Sites:
Pretreatment specimens of marrow and/or peripheral blood 
must be submitted to the Leukemia Translational Studies Laboratory (LTSL) 
at Our Lady of Mercy Cancer Center, New York via E3903, "Ancillary 
laboratory protocol for collecting diagnostic material on patients considered 
for ECOG treatment trials for Leukemia or related hematologic disorders".  
Register patient to E3903 PRIOR to registration to S0535.  The ECOG 
patient number will re required at the time of S0535 registration.  See Section 
15.3.
x
CALGB Sites: CALGB patients must be offered participation on CALGB 
9862.  Consenting patients must be registered to CALGB 9862 PRIOR to 
registration to S0535 (see Section 15.4).
h.
Patients must not be pregnant or nursing because ATRA as well as other drugs 
used in this protocol may cause fetal harm and because of the potential for 
serious adverse reactions in nursing infants from the drug.  Women of 
childbearing potential must have a negative pregnancy test performed within 14 
days prior to registration.  Women/men of reproductive potential must have 
agreed to use an effective contraceptive method.
i.
No other prior malignancy is allowed except for the following: adequately treated 
basal cell or squamous cell skin cancer, in situ cervical cancer, adequately 
treated Stage I or II cancer from which the patient is currently in complete 
remission, or any other cancer from which the patient has been disease-free for 5 
years.
j.
All patients must be informed of the investigational nature of this study and must 
sign and give written informed consent in accordance with institutional and federal 
guidelines.
k.
At the time of patient registration, the treating institution's name and ID number 
must be provided to the Data Operations Center in Seattle in order to ensure that 
the current (within 365 days) date of institutional review board approval for this 
study has been entered into the data base.
 


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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.  Any potential eligibility issues 
should be addressed to the Data Operations Center in Seattle at 206/652-2267 prior to registration.
SWOG Patient No.
Patient's Initials (L, F, M)
5.2
Consolidation Therapy Registration 
After completing induction therapy, patients will be registered for consolidation treatment 
provided that they were eligible for the initial registration and satisfy the following 
additional criteria.
a.
Patients must have achieved A1 marrow status, B1 peripheral blood status and 
C1 extramedullary disease status (see Section 10.1).  Patients must have 
maintained a B1 peripheral blood status for at least 7 days prior to registration for 
this protocol step.
b.
For patients affiliated with CALGB or ECOG, collection of cytogenetic specimens 
must be completed within 8 weeks (preferably within 4 weeks) prior to this 
registration.  Collection and submission of required materials must be by one of 
the following mechanisms: 
x
ECOG Sites: See Section 15.3.
x
CALGB Sites: See Section 15.4
c.
For all patients, specimens for RT-PCR assays for PML-5$5ĮPXVWEHFROOHFWHG
and submitted within 8 weeks (preferably within 4 weeks) prior to this registration.  
Note that submission of specimens for RT-PCR assays is also required prior to 
Consolidation Cycle 3.  Specimen submissions must be via the mechanisms
indicated below.  
x
SWOG Sites and other sites not affiliated with ECOG or CALGB: Specimens 
must be submitted to a CLIA-approved laboratory.  See Section 15.2.
x
ECOG Sites: See Section 15.3.
x
CALGB Sites: See Section 15.4.
 


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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 APL Disease Assessment Form and submit to the 
Data Operations Center in Seattle (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.
SWOG Patient No.
Patient's Initials (L, F, M)
5.3
Maintenance Therapy Registration
After completing consolidation therapy, patients will be registered for maintenance 
treatment provided that they were eligible for the consolidation registration and satisfy the 
following additional criterion:
a.
Patients must remain in A1 marrow status, B1 peripheral blood status and C1 
extramedullary disease status (see Section 10.1).  Patients must have maintained 
a B1 peripheral blood status for at least 7 days prior to registration for this 
protocol step.
b.
For all patients, specimens for RT-PCR assays for PML-5$5ĮPXVWEHFROOHFWHG
and submitted within 8 weeks (preferably within 4 weeks) prior to this registration.  
Specimen submissions must be via the mechanisms indicated below.  
x
SWOG Sites and other sites not affiliated with ECOG or CALGB: Specimens 
must be submitted to a CLIA-approved laboratory.  See Section 15.2.
x
ECOG Sites: See Section 15.3.
x
CALGB Sites:  See Section 15.4
 


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6.0
STRATIFICATION FACTORS
There are no stratification factors in this study.
7.0
TREATMENT PLAN
For treatment or dose modification questions, please contact the Study Chair, Dr. Lancet at 
813/745-6841, or if Dr. Lancet is not available, Dr. Komrokji at 513/584-6915.
For dosing 
principles or questions, please consult the Southwest Oncology Group 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
Good Medical Practice
This clinical trial can fulfill its objectives only if patients appropriate for the trial are 
enrolled.  All relevant medical and other considerations should be taken into account 
when deciding whether this protocol is appropriate for a particular patient.  To maximize 
patient safety, patients should be treated on this protocol only at centers having ready 
access to blood product support and adequate staff to care for the severely neutropenic 
patient with multiple-therapy induced toxicities.  Physicians should consider the risks and 
benefits of any therapy, and, therefore, only enroll patients for whom the agents 
administered are appropriate.  Although they will not be considered as formal eligibility 
criteria, as part of this decision-making process, physicians should recognize that the 
following problems may increase the risk to the patient entering this protocol.  These are 
guidelines, not strict eligibility criteria.  See Section 5.0 for strict eligibility criteria.  These 
guidelines apply to all registration steps (Initial Registration, Consolidation Therapy 
Registration, and Maintenance Therapy Registration).
a.
Patient should not have other serious illnesses that would limit survival to < 2 
years.
b.
Patient should not have psychiatric conditions that would prevent compliance with 
treatment or informed consent.
c.
Patient should not have uncontrolled or severe cardiovascular or pulmonary 
disease.  This would include history of a recent acute myocardial infarction, 
congestive heart failure, or active angina.
d.
Abnormalities in measured parameters of hepatic and renal function must be 
considered as potentially serious obstacles for safe tolerance of the therapy 
prescribed in this protocol.  The degree to which such perturbations are 
attributable to comorbid disease or are leukemia-related should be considered in 
the decision to enroll a patient on this protocol.
e.
Patients who become pregnant after registration must be removed from protocol 
therapy.
7.2
General Considerations
a.  
Immediate measures to diagnose and begin treatment of infections should be
instituted prior to induction therapy.
b.  
A lumbar puncture is recommended following completion of induction, but not 
required.  Prophylactic intrathecal chemotherapy may be given at the treating 
physician's discretion.
c.
All patients should be carefully followed serially with coagulation studies (PTT, 
PT, fibrinogen, FDP, and D-dimer).  These tests should be done pretreatment, 
twice weekly during induction until normal and as clinically indicated thereafter.  
Optimal management of coagulopathy is controversial. Heparin usage is 
discouraged since all patients will be receiving ATRA; however, patients with 
either biochemical or clinical evidence of coagulopathy may be treated at the 
investigator’s discretion.
 


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d.
Additional electrolyte studies for calcium, magnesium, cholesterol and 
triglycerides should be obtained.
e.
Hydroxyurea therapy is permitted up to 24 hours before initiation of gemtuzumab
ozogamicin (G.O.).
f.
All patients will be started on allopurinol 300 mg/day orally.  For patients allergic 
to allopurinol, rasburicase may be substituted.  Reversible abnormalities of 
metabolic function should be treated aggressively and corrected prior to institution 
of therapy.
g.
Investigators may contact the SWOG Study Chairs or Leukemia Committee Chair 
for assistance with the management of patients with high WBC count prior to 
confirmation of molecular diagnosis.
7.3
Induction Chemotherapy
AGENT
DOSE
ROUTE
Time
NOTES
ATRA ¿
45 mg/m2/day
PO
every 12 hrs,
With food.  See
(in 2 doses,
Day 1 to CR *
Section 7.3a
22.5 mg/m2
below.
every 12 hours)
Gemtuzumab 
9 mg/m2
IV infusion
Day 1 only S
Ozogamicin ¨
over 2 hours
Arsenic
0.15 mg/kg/d
IV infusion
5 days/wk
Trioxide
over 2 hours
beginning on
Day 10 and 
continuing until
CR ȥ
*
For maximum of 90 days, unless prohibited by either unacceptable toxicity or 
progressive disease.
S
G.O. may be delayed until Day 6 pending confirmation of APL diagnosis by 
FISH/cytogenetics, or RT-PCR.  Hydroxyurea may be utilized during this time, up to 24 
hours prior to initiation of gemtuzumab ozogamicin.
ȥ
For a maximum of 60 days, unless prohibited by either unacceptable toxicity or 
progressive disease.
¨
Recommended premedications prior to gemtuzumab:  acetaminophen 1 gm orally, 
diphenhydramine 50 mg IV, and methylprednisolone 125 mg IV.
¿
Day 1 of treatment will be the first day the patient is treated with ATRA, regardless of 
patient’s registration status.
a.  
ATRA will be “rounded” up to the nearest 10 mg, divided into 2 daily doses, given 
orally every 12 hours with food.  
b.
ATRA syndrome:  A spectrum of clinical manifestations of a cardiorespiratory 
distress syndrome has been described, including respiratory distress, hypoxemia, 
fever, erythematous rash, pulmonary infiltrates, pleural or pericardial effusions, 
congestive heart failure with impaired myocardial contractility and episodic 
hypotension.  Patients with this syndrome may develop rapidly progressive 
cardiopulmonary failure.
If this syndrome is suspected, ATRA should be held and dexamethasone 10 mg 
IV or PO BID will be given for 3 days.  ATRA will be resumed once the 
signs/symptoms of the syndrome have resolved.  Patients with persistent 
signs/symptoms of the ATRA syndrome after 3 days of dexamethasone or who 
have recurrence of the ATRA syndrome after restarting ATRA should be 
discussed with the Study Chair.
 


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c.
Prolonged QTC:  Prolongation of the QTc has been reported with the use of 
arsenic trioxide in association with electrolyte abnormalities.  Therefore, any 
identified electrolyte abnormalities of potassium, calcium, or magnesium should 
be promptly corrected to within normal limits prior to and during treatment with 
arsenic trioxide.  EKG must be obtained twice weekly during induction therapy 
and as clinically indicated.
d.
Patients may be registered on this study and begin induction chemotherapy 
before the result of the required pretreatment RT-PCR assay for PML-RARD is 
available (see Section 5.1b).  If the patient is found to be PML-RARD-negative,
then the patient is removed from protocol treatment and should receive 
appropriate chemotherapy for non-APL acute myeloid leukemia.
7.4
Consolidation Cycles 1 and 2
a.
Patients who achieve A1 bone marrow, B1 peripheral blood, and C1 
extramedullary disease status (see Section 10.1) may be eligible for registration 
to consolidation therapy (see Section 5.2).  Consolidation Cycle 1 therapy should 
be started within 4 weeks and no later than 8 weeks following documentation of 
CR.
b.
Consolidation Cycles 1 and 2 Treatment Plan 
AGENT
DOSE
ROUTE
Time
NOTES
Arsenic
0.15 mg/kg/day
IV over
5 days/
Repeat after 2 
Trioxide
2 hours
week x
weeks rest*
5 weeks
* Consolidation Cycle 2 may be given after 2 weeks of rest following Cycle 1.
c.
Prolonged QTC:  Prolongation of the QTc has been reported with the use of 
arsenic trioxide in association with electrolyte abnormalities.  Therefore, any 
identified electrolyte abnormalities of potassium, calcium, or magnesium should 
be promptly corrected to within normal limits prior to and during treatment with 
arsenic trioxide.
d.
MUGA or echocardiogram must be performed prior to initiation of Consolidation 
Cycle 3 (see Section 7.5c). If the test has been performed at baseline or any time 
prior to Consolidation Cycle 3, it does not need to be repeated immediately before 
Cycle 3.
7.5
Consolidation Cycles 3 and 4
a.
Patients who remain in A1 bone marrow, B1 peripheral blood, and C1 
extramedullary disease status (see Section 10.1) may continue consolidation 
therapy.  Consolidation Cycle 3 should be started within 4 weeks following
completion of Consolidation Cycle 2 if possible.
b.
Consolidation Cycle 4 should be started no earlier than 2 weeks, and no later 
than 8 weeks from recovery to B1 peripheral blood status.  
c.
MUGA or echocardiogram must be performed prior to initiation of Consolidation 
Cycle 3.  If the test has been performed at baseline or any time prior to 
Consolidation Cycle 3, it does not need to be repeated immediately before Cycle 
3. EKG should be obtained as clinically indicated thereafter.
d.
Patients who cannot receive daunomycin because of cardiac or other toxicity, or 
are unable to initiate Consolidation Cycle 4 within 8 weeks of recovering 
peripheral blood counts to B1 status, must be discussed with the Study Chair; if in 
CR, these patients will proceed to Consolidation Cycle 5.
 


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e.
Consolidation Cycles 3 and 4 Treatment Plan 
AGENT
DOSE
ROUTE
Time
NOTES
ATRA
45 mg/m2/day
PO
every 12 hours,
With food.
(in 2 doses,
Days 1-7
See Section
22.5 mg/m2
7.5e below.
every 12 hours)
Daunomycin*
50 mg/m2/day
IV bolus
Days 1-3
or 1 hour
infusion
*
Idarubicin, 12mg/m²/day, on Days 1-3, may be used in place of daunomycin 
only if daunomycin is unavailable due to the national shortage. This must be 
documented on the S0535 Consolidation Cycles 3 and 4 Treatment Summary 
Form.
f.
ATRA will be “rounded” up to the nearest 10 mg, divided into 2 daily doses, given 
orally every 12 hours with food.
g.
Prior ATRA syndrome:  Patients who experienced the ATRA syndrome during 
induction may receive ATRA during Consolidation Cycles 3 and 4, since the 
ATRA syndrome is not expected to occur during remission.
7.6
Consolidation Cycles 5 and 6
a.
Patients who remain in B1 peripheral blood, and C1 extramedullary disease 
status (see Section 10.1) may continue consolidation therapy.  Consolidation 
Cycle 5 should be started no earlier than 2 weeks and no later than 8 weeks after 
recovery of peripheral blood counts to B1 status (see Section 10.1).
b.
Consolidation Cycle 6 should be started no earlier than 2 weeks, and no later 
than 8 weeks after recovery to B1 peripheral blood status.
c.
Patients who cannot receive gemtuzumab ozogamicin because of previous 
toxicity or who are unable to initiate Consolidation Cycle 6 within 8 weeks after 
recovering peripheral blood counts to B1 status must be discussed with the Study 
Chair; if in CR, these patients will proceed to Maintenance Therapy.
d.
Consolidation Cycles 5 and 6 Treatment Plan
AGENT
DOSE
ROUTE
Time
NOTES
Gemtuzumab 
9 mg/m2
IV infusion
Day 1    
Ozogamicin ¨
over 2 hours
¨ Recommended premedications prior to gemtuzumab:  acetaminophen 1 gm
orally, diphenhydramine 50 mg IV, and methylprednisolone 125 mg IV.
7.7
Maintenance Therapy
a.
Patients who remain in A1 bone marrow, B1 peripheral blood, and C1 
extramedullary disease status (see Section 10.1), may be eligible for registration 
to maintenance therapy (see Section 5.3).  Maintenance should be started no 
earlier than 2 weeks and no later than 8 weeks after recovery of ANC > 1,000/mcl
(1.0 x 109/L) and platelets > 100,000/mcl (100 x 109/L).
 


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b.
Maintenance Treatment Plan 
AGENT
DOSE
ROUTE
Time
NOTES
ATRA
45 mg/m2/day
PO
With food.
(in 2 doses,
Days 1-7
See Section
22.5 mg/m2
every 14
7.7c below.
every 12 hours)
days
6-MP
60 mg/m2/d
PO
Daily
For 1 year
Methotrexate
20 mg/m2
PO
Once per week 
for 1 year.
c.
ATRA will be “rounded” up to the nearest 10 mg, divided into 2 daily doses, given 
orally every 12 hours with food.
d.
Prior ATRA syndrome:  Patients who experienced the ATRA syndrome during 
induction may receive ATRA during Maintenance, since the ATRA syndrome is 
not expected to occur during remission.
7.8
Assessment of Response
a.
Induction
A bone marrow aspirate and biopsy will be obtained at the time of neutrophil 
recovery ( 1,000/mcl) or on Day 42 after beginning protocol ATRA (i.e. not 
counting any days of ATRA given prior to the patients registration to this study), 
whichever comes first.  Specimens of marrow aspirate (or peripheral blood if dry 
tap) must be submitted for cytogenetics (for patients affiliated with CALGB or 
ECOG) and PCR (for all patients) as described in Section 15.0.  Subsequently, 
the bone marrow aspirate and biopsy will be repeated every 2 weeks until criteria 
for CR are met.  These subsequent samples will NOT be submitted centrally for 
cytogenetic or RT-PCR testing, but the tests will still be performed locally.  Testing 
for clinical/hematological CR should be performed locally for all of these 
subsequent specimens.  Patients will continue ATRA and arsenic trioxide until CR 
is achieved, up to a maximum of 90 days.  Patients with a CR will proceed to 
consolidation therapy as outlined above in Section 7.4.
b.
Consolidation
A bone marrow aspirate and biopsy will be obtained within 8 weeks (preferably 
within 4 weeks) preceding Consolidation Cycle 1.  This should be performed at 
the time when peripheral blood counts have recovered to baseline or as clinically 
indicated.  A bone marrow aspirate and biopsy are also required prior to 
Consolidation Cycle 3.
The pre-Consolidation Cycle 3 specimens of marrow 
aspirate (or peripheral blood if dry tap) must be submitted for PCR as described 
in Section 15.0.
c.
Maintenance
A bone marrow aspirate and biopsy will be obtained within 8 weeks (preferably 
within 4 weeks) prior to beginning maintenance therapy.  Specimens of marrow 
aspirate (or peripheral blood if dry tap) must be submitted for PCR testing as 
described in Section 15.0.
d.
A bone marrow aspirate and biopsy will be obtained every 3 months during 
Maintenance therapy.  Specimens from these samples should NOT be submitted 
for RT-PCR testing or cytogenetics.  Testing for clinical/hematological CR for 
these samples should be performed locally.
 


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Revised 3/25/10
e.
A bone marrow aspirate will be obtained every 3 months for the first year following 
completion of maintenance therapy, every 6 months for the second year following 
completion of maintenance therapy and at the end of the third year following 
completion of maintenance therapy.  At the time of relapse cytogenetic studies 
and RT-PCR testing must be performed as described in Section 15.0.
7.9
Supportive Care Guidelines
a.
Infection Prophylaxis
1.
Extremely careful hand washing by all members of health care team is 
required.
2.
Diet should exclude raw fruits, vegetables and unprocessed foods.
3.
Antibiotic prophylaxis with oral antimicrobial agents is strongly 
recommended for all patients as indicated in the following table.
AGENT
DOSE
ROUTE
COMMENTS
Fluconazole
200 mg/d
PO
If empiric ampho-
or
or
tericin preparations 
100 mg q 12 hr
IV
are used, hold 
fluconazole or
voriconazole for 
the duration of 
amphotericin-
based therapy.  
Ciprofloxacin
500 mg q 12 hr
PO
Discontinue when 
broad-spectrum IV
antibiotics are 
started.  Note that 
bioavailability of 
cipro is reduced 
if co-administered 
with agents 
containing magne-
sium, aluminum 
or calcium (e.g., 
antacids, sucral-
fate).
Acyclovir
800 mg q 12 hr
PO
Use only in patients 
or
or
who are seropo-
250 mg/m2 q 12 hr
IV
sitive for herpes 
simplex virus or 
have a history of 
HSV infection.
Antimicrobial prophylaxis should be given to all patients during the 
induction therapy.  Treatment with all agents (except for fluconazole and 
acyclovir) will start at the initiation of induction chemotherapy, if not 
started previously, and stop when the absolute granulocyte count is > 
 


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500/mcl.  During each cycle of consolidation it is recommended that the 
same treatment be resumed on Day 7 and stopped when the absolute 
granulocyte count is > 500/mcl.  If the absolute granulocyte count does 
not drop below 500/mcl following chemotherapy, then the antimicrobial 
prophylaxis should be stopped on Day 21 of each cycle.
b.
Management of Infection and Use of Antibiotics
1.
Any neutropenic patient (absolute granulocyte count < 500/mcl) with an 
oral temperature exceeding 38°C on more than one occasion within a 
single (24 hour) day or a single temperature greater than 38.5°C should
have broad-spectrum intravenous empiric antibiotics started expeditiously 
at the discretion of the treating physician.  Prior to antibiotic 
administration urine culture, urinalysis and 2 sets of blood cultures should 
be obtained.  Careful physical exam and chest radiograph should also be 
performed.  Oral ciprofloxacin prophylaxis should be stopped when 
empiric intravenous antibiotics are started.
2.
There are many appropriate choices of broad-spectrum empiric 
antibiotics for use in the febrile neutropenic patient.  The regimen should 
be chosen based on the susceptibility pattern of the predominant 
pathogens at the treating hospital.  Possible regimens to use are listed 
below.
i.
Monotherapy with imipenem
ii.
Combination 
therapy
with an anti-pseudomonal penicillin 
(piperacillin) and a third generation cephalosporin (ceftazidime or 
cefoperazone).
iii.
Combination 
therapy with an anti-pseudomonal penicillin 
(piperacillin) 
and 
an 
anti-pseudomonal 
aminoglycoside 
(amikacin).
iv.
Combination therapy with a third generation cephalosporin 
(ceftazidime 
or 
cefoperazone) 
and 
an 
anti-pseudomonal 
aminoglycoside (amikacin).
3.
If the patient is persistently febrile after 72 hours, additional antibiotic 
and/or antifungal coverage should be considered.  If culture data indicate 
a more favorable antibiotic regimen, then the appropriate antibiotics will 
be substituted.  An infectious disease consultant should be considered 
for patients with persistent fever at 72 hours while receiving adequate 
antibiotic coverage.  Although vancomycin is not recommended for 
empiric use, it should be noted that the use of ciprofloxacin may increase 
the emergence of streptococci and coagulate-negative staphylococci.
4.
Patients placed on aminoglycosides should be carefully followed for renal 
insufficiency and for appropriate serum drug levels.  Any patient placed 
on amphotericin B should be carefully monitored for renal insufficiency, 
hypokalemia and hypomagnesemia.
5.
The patient will be continued on broad-spectrum antibiotics until the 
absolute granulocyte count is > 500/mcl and the patient is afebrile.
 


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c.
Blood Product Support
1.
The hemoglobin should be maintained at a safe level, especially in 
severely thrombocytopenic patients (e.g., hemoglobin > 8 - 10 grams/dl).
2.
The platelet count should be maintained greater than 10,000/mcl in non-
bleeding patients.  In the presence of fever or hypertension, platelet 
transfusion to 20,000/mcl is recommended.  In the presence of active 
hemorrhage or suspected gastrointestinal bleeding, platelet transfusion to 
a minimum count of 50,000/mcl is recommended.  Maintenance of 
platelet count of 30,000-50,000/mcl, particularly at or near the time of 
diagnosis and initiation of therapy, is recommended, particularly in the 
setting of active DIC.
3.
Patients who are refractory to random donor platelets (single donor or 
pooled) should receive HLA-matched platelet transfusions if possible.  An 
unsatisfactory one-hour platelet count increment is less than 20% of 
expected rise (expected rise is 5,000 per unit platelets transfused).
4.
Cryoprecipitate should be administered to maintain the fribrinogen at a 
level of 100-150 mg/dl.
d.
Mucosal and Nutritional Considerations
1.
Mucositis may be severe.  Although prophylactic use of fluconazole and 
acyclovir is expected to reduce infectious causes, mucosal lesions should 
be cultured for fungal, viral and bacterial organisms.
2.
Malnutrition may be severe and prolonged in elderly patients undergoing 
intensive chemotherapy.  Early institution of hyperalimentation is 
recommended when oral intake becomes inadequate.
e.
Growth Factors
1.
Growth factors (e.g., GM-CSF, G-CSF, or erythropoietin) may be used at 
the discretion of the treating physician in cases of serious or life-
threatening infection.  It should be pointed out that the benefit of growth 
factors in this setting is unclear.
7.10
Intake Calendar
ATRA, 6-MP, and methotrexate drug compliance will be recorded by patients on the 
Intake Calendar (see Appendix 18.3).  Institutional CRAs will review and ascertain patient 
adherence with protocol treatment.  Do not submit the Intake Calendar to the Data 
Operations Center.
7.11
Criteria for Removal from Protocol Treatment
a.
Patients whose pretreatment RT-PCR assays are found to be PML-RARĮ-
negative will be removed from protocol treatment and receive no further treatment
under this protocol (see Section 7.3d).
b.
Delay of more than 5 days prior to initiation of gemtuzumab ozogamicin during 
induction.
c.
Patients who fail to achieve A1 marrow, B1 blood, and C1 extramedullary disease 
status (see Section 10.1) within 90 days of initiation of induction therapy will not 
be eligible for consolidation therapy and will receive no further treatment under 
this protocol.
 


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d.
Unacceptable toxicity as defined in Section 8.0.
e.
Patients who do not maintain CR
or
relapse before or while receiving 
consolidation or maintenance therapy.
f.
Patients who become pregnant.
g.
Successful completion of all stages of therapy.
h.
The patient may withdraw from the study at any time for any reason.
7.12
Discontinuation of Treatment
All reasons for discontinuation of treatment must be documented on the Off Treatment 
Notice.
7.13
Follow-Up Period
All patients will be followed until death or a maximum of 3 years from time of initial 
registration.
8.0
TOXICITIES TO BE MONITORED AND DOSAGE MODIFICATIONS
 
8.1
NCI Common Terminology Criteria for Adverse Events (CTCAE)
 
Two different versions of the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) will be used on this study.
 
a.
Serious Adverse Event (SAE) reporting
The CTCAE (NCI Common Terminology Criteria for Adverse Events) Version 4.0 will
be utilized for SAE reporting only.  The CTCAE Version 4.0 is identified and located 
at the CTEP website at
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  All 
appropriate treatment areas should have access to a copy of the CTCAE Version 
4.0.
b.
Routine toxicity reporting
 
This study will utilize the CTCAE Version 3.0 for routine toxicity reporting.  A copy of 
the CTCAE Version 3.0 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 3.0. 
 
8.2
Toxicities to be Monitored
The toxicities of the agents included in this regimen are well established, and are outlined 
above in Section 3.0. Dose modifications of study medications will be made based upon 
attribution of toxicity to drug therapy rather than disease.
 


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8.3
Induction Therapy
a.
Dose Modifications for ATRA During Induction
x
Commonly observed toxicities with ATRA include hepatotoxicity (increased 
AST and ALT), neurologic changes (headache or pseudotumor cerebri), 
mucocutaneous changes (dry skin, peeling of palms and soles) and others 
including cheilitis, epistaxis, fatigue, musculoskeletal pain, and conjunctivitis. 
If a patient experiences a Grade 3 toxicity, ATRA will be held until the toxicity 
has resolved to  Grade 1.  At that time, restart ATRA at 75% dose.  
Recurrent episodes of t Grade 3 toxicity will result in discontinuation of ATRA 
until the toxicity resolves to d Grade 1; ATRA will then be resumed with an 
additional 25% dose reduction.  Patients requiring dose reductions that would 
reduce the dose to less than 25% of the starting dose should be removed 
from ATRA (continue other therapy) for the remainder of the cycle.  ATRA 
may be used again in subsequent cycles if toxicity has resolved to  Grade 1.
x
The ATRA syndrome should be treated as outlined in Section 7.3b.
x
If ATRA related Grade t 3 toxicity (excluding ATRA syndrome) does not 
resolve to d Grade 1 within 14 days of occurrence, ATRA will be permanently 
discontinued.
 


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b.
Dose Modification for Arsenic Trioxide During Induction
Missed doses due to holidays or dose modifications will not be made up.  
Modification of the arsenic dose in these cycles should be made as follows:
x
Renal Toxicity
Creatinine
Adjust Dose:
t 1.5 x baseline but < 3.0 mg/dL
Hold treatment until creatinine < 1.5 x
baseline, then resume treatment at full 
dose.
t 3.0 mg/dL or oliguric renal failure
Hold treatment until creatinine < 1.5 x 
baseline, then resume treatment with a 
50% dose reduction (0.075 mg/kg/day)*
* If toxicity persists for more than 14 days or recurrent renal toxicity occurs 
despite a dose reduction, then discontinue arsenic trioxide.
Hepatotoxicity:  Give the following dose, based on lab values obtained within 2 
days prior to therapy
AST (SGOT)
Bilirubin
Adjust dose:
2-3 fold 
increase over 
upper limit of 
normal (ULN)
Hold 
treatment 
until bilirubin < 2x 
ULN, 
then 
resume 
at 
full 
dose
> 5-fold increase 
over ULN
and/or
> 3-fold 
increase over 
ULN
Hold 
treatment 
until AST < 3x 
ULN or bilirubin < 
2x 
ULN, 
then 
resume treatment 
with a 50% dose 
reduction (0.075 
mg/kg/day)*
* If toxicity persists for more than 14 days or recurrent hepatotoxicity occurs 
despite a dose reduction, then discontinue arsenic trioxide.
Hematologic Acute Hemolysis:  In the case of acute hemolysis (CTCAE 3.0 
Grade  3), hold treatment until complete resolution, then resume treatment with 
a 50% dose reduction (0.075 mg/kg/day).  No dose adjustment is necessary for 
pancytopenia of any grade.  If toxicity persists for more than 14 days after holding 
treatment or recurrent acute hemolysis occurs despite dose reduction, then 
discontinue arsenic trioxide.
Dermatologic Toxicity:  In the case of rash (CTCAE 3.0 Grade  3), hold 
treatment until clear clinical evidence of improvement to d Grade 1, then resume 
treatment with a 50% dose reduction (0.075 mg/kg/day).  If toxicity persists for 
more than 14 days after holding treatment or recurrent dermatologic toxicity 
occurs despite dose reduction, then discontinue As2O3.
Nausea/Vomiting:  Nausea/vomiting of any grade should be handled with 
symptomatic treatment with anti-emetics.  If CTCAE 3.0 Grade  3 vomiting 
occurs despite adequate trial of anti-emetics, then hold treatment until clinical 
improvement and then resume treatment at full dose.  If treatment-refractory
 


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nausea/vomiting recurs, then hold treatment until improvement is d Grade 1 
and then resume treatment with a 50% dose reduction (0.075 mg/kg/day).  If 
toxicity persists for more than 14 days after holding treatment or recurrent 
nausea and vomiting occur despite dose reduction and anti-emetics, then 
discontinue As2O3 .
x
Neurologic Toxicity:  In the case of moderate-severe objective sensory loss 
or paresthesias; motor weakness; clinically evident hearing loss; locomotor 
ataxia or dysmetria; agitation, confusion, or hallucination then hold treatment 
until clear clinical evidence of resolution to d Grade 1 and then resume 
treatment with a 50% dose reduction (0.075 mg/kg/day).  If toxicity persists 
for more than 14 days after holding treatment or recurrent moderate-severe 
neurologic toxicity occurs despite dose reduction, then discontinue As2O3.
x
Cardiac Toxicity:  Guidelines for the management of prolonged QTc interval 
are as follows:
x
EKG must be obtained twice weekly during induction therapy and as 
clinically indicated.
-
Measure the QT interval (from the start of the Q wave to the end of 
the T wave) and the preceding RR interval.  The QTc interval will be 
calculated as the QT interval (msec) divided by the square root of the 
RR interval (msec).
-
QTc interval  500 msec: No specific therapy needed.  Continue 
As2O3.  Serum K+ and Mg++ should be monitored and repeated only 
if low.
-
QTc interval 500-600 msec:  Hold As2O3 temporarily and replete 
serum K+ and Mg++ with IV and/or oral K+ and Mg++ to minimum 
target levels of 4.0 and 2.0 mg/dL, respectively.  Resume As2O3 on 
same day if target levels are achieved and re-check prior to next 
dose.
-
QTc interval ! 600 msec:  Hold As2O3.  Aggressive IV K+ and Mg++ 
repletion (for adults MgSO4 can be given as 2 g IV, followed by up to 
12 g in 6 hours).  If the QTc interval falls below 600 msec, the patient 
can be sent home with additional oral supplements and should return 
the following day for re-checking prior to further As2O3 treatment.  If 
the QTc interval does not fall below 600 msec with this level of 
repletion, the patient should undergo EKG monitoring by telemetry, 
preferably in the hospital, along with continued IV K+ and Mg++.
x
Other Arsenic Trioxide-Related Toxicity ,I *UDGH   WKHQ KROG
treatment until clear clinical evidence of resolution to Grade 1 and then 
resume treatment with a 50% dose reduction (0.075 mg/kg/day). If 
toxicity persists for more than 14 days after holding treatment or recurrent 
toxicity occurs despite dose reduction, then discontinue As2O3.
8.4
Consolidation Therapy
a.
Dose Modifications for ATRA Toxicity during Consolidation Therapy
x
Follow dose modifications outlined in Section 8.3a.
x
The ATRA syndrome (see Section 7.3b) is not expected in patients in CR or 
PR; however, if the syndrome is suspected, discontinue ATRA, start
dexamethasone at 10 mg IV or PO BID, and contact the Study Chair.
x
Patients who experienced severe or recurrent ATRA-related toxicity during 
induction that necessitated permanent discontinuation should be discussed 
with the Study Chair before reinstituting ATRA during consolidation.  Such 
patients can remain on protocol treatment without continuation of ATRA.
 


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b.
Dose Modifications for Gemtuzumab Ozogamicin (G.O.) during Consolidation
x
Hepatotoxicity
If CTCAE 3.0 Grade 2-3 AST, ALT, or bilirubin elevation occurred during 
induction therapy (thought to be drug-related, and not disease related), G.O. 
dose will be reduced to 6 mg/m2 during Consolidation Cycle 5.  If Grade 2-3
AST, ALT, or bilirubin elevation recurs following Day 1 of G.O. during 
Consolidation Cycle 5, the dose of G.O. during Consolidation Cycle 6 will be 
decreased to 3 mg/m2.
For patients in whom Grade 2-3 AST, ALT, or bilirubin elevation did NOT 
occur during induction, but occurs following Day 1 of Consolidation Cycle 5,
the dose of G.O. during Consolidation Cycle 6 will be decreased to 6 mg/m2.
For patients that experience Grade 4 AST, ALT, or bilirubin elevation 
following G.O. during any course, further G.O. will NOT be administered.  In 
these instances, a hepatic doppler ultrasound is required to evaluate for 
hepatic sinusoidal obstructive syndrome.
In any case where there is Grade 3 bilirubin elevation, a hepatic doppler 
ultrasound is recommended to evaluate for hepatic sinusoidal obstructive 
syndrome.
x
Hematologic Toxicity
Following the initiation of Consolidation Cycle 5, delayed recovery of 
peripheral blood to B1 status (see Section 10.1) beyond 8 weeks will require 
discontinuation of further G.O. therapy, and patients will proceed to 
Maintenance Therapy.
x
Anaphylactic reaction
For patients experiencing anaphylactic reaction with this agent during 
induction, gemtuzumab ozogamicin will be permanently discontinued.
c.
Dose Modification for Daunomycin during Consolidation
x
Hepatotoxicity (for patients with evidence of hepatic dysfunction, 
reassess regularly during daunorubicin treatment).  
Bilirubin
% Dose to Give
> 3.0 mg/dL
75%
x
Cardiotoxicity:  Adequate LV function will be required as described 
previously.  Patients judged not to have adequate LV function should be 
discussed with the Study Chair.
d.
Dose Modifications for Arsenic Trioxide during Consolidation
x
See Section 8.3.b above.  For patients requiring dose reduction of arsenic 
trioxide during induction due to toxicity, the starting dose for consolidation 
should be reduced to the acceptable dose determined during induction.  For 
patients in whom arsenic trioxide was permanently discontinued during 
induction therapy, arsenic trioxide will be omitted from Consolidation Cycles 1
and 2, and patients will proceed to Consolidation Cycle 3.  For patients 
experiencing toxicity from arsenic trioxide during consolidation (in the 
absence of previous toxicity during induction), dose adjustment guidelines as 
stated in Section 8.3b should be followed.
 


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8.5
Maintenance Therapy
x
Dose Modifications for 6-MP and MTX during Maintenance Therapy
x
Because patients begin maintenance therapy in CR, the non-leukemia NCI 
CTCAE scale should be used during maintenance therapy.
Grade
ANC/mcl
and/or
Hgb (g/dl)
and/or
Platelets /mcl
6-MP & MTX
1
< LLN - 1,500
 LLN – 10
 LLN - 75,000
100%
2
 1,500 - 1,000
8 - 10
 75,000 - 50,000
50%
3
 1,000 - 500
6.5 -  8
 50,000 - 25,000
0*
4
 500
 6.5
 25,000
0*
*
Discontinue 6-MP and methotrexate.  Treatment may resumed at 50% doses when 
toxicity has resolved to d Grade 1.  Both drugs may then be escalated individually to 
tolerance.
If more than one of the dose modifications apply, use the most 
stringent (i.e., the greatest dose reduction).  The intent of this treatment 
is to give the highest tolerable daily dosages of 6-MP and oral 
methotrexate (up to 100%).  If hematologic toxicity does not resolve, a 
bone marrow exam should be performed to evaluate for relapse.
x
Hyperbilirubinemia
Give the following percentages of full dose:
Bilirubin (md/dL)
6-MP & MTX
 3.0
100%
t 3.0 but  5.0
75%
t 5.0
0*
* Hold treatment for up to four weeks.  Contact the Study Chair if toxicity 
does not resolve.
x
Elevated ALT/AST
Grade
ALT/AST
6-MP & MTX
1
! ULN – 2.5 X ULN
100%
2
! 2.5 – 5.0 X ULN
100%
3
! 5.0 – 20.0 X ULN
0*
4
! 20.0 X ULN
0*
*
Discontinue 6-MP and methotrexate.  When toxicity has resolved to d
Grade 1, treatment with both drugs may resume with a 50% dose 
reduction.  Both drugs then may be escalated individually to tolerance.  If 
toxicity recurs, discontinue both drugs.  Treatment may resume again 
after another 50% dose reduction (i.e., 25% of original dose) when 
toxicity resolves to d Grade 1.  If toxicity reoccurs after a second dose 
reduction then discontinue drugs and contact the Study Chair.  Persistent 
hepatic transaminase elevation may require liver biopsy for diagnosis.
 


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Revised 4/16/14
The intent of this treatment is to give the highest tolerable daily 
dosages of 6-MP and weekly methotrexate that produce  Grade 3 
toxicity.
x
Mucositis
For t Grade 2 oral ulceration, hold oral methotrexate until mucositis clears, 
then reinstate at 75% of previous dose.  Observe for hematologic toxicity if 
mucositis is noted.
x
Other 6-MP or MTX-5HODWHG 7R[LFLWLHV ,I *UDGH   WKHQ KROG WUHDWPHQW
Treatment may resume after a 50% dose reduction when toxicity resolves to 
 Grade 1.  If toxicity reoccurs after a first dose reduction, treatment may 
resume again after another 50% dose reduction (i.e., 25% of original dose) 
when toxicity resolves to Grade 1.  If toxicity reoccurs after a second dose 
reduction then discontinue drug(s).
x
Dose Modification for ATRA during Maintenance Therapy
x
See Section 8.4.a above
8.6 
Dose Modifications for Obese Patients
There is no clearly documented adverse impact of treatment of obese patients when 
dosing is performed according to actual body weight.  Therefore, all dosing is to be 
determined by the patient’s actual weight.  Failure to use actual body weight in the 
calculation of drug dosages will be considered a major protocol deviation.  Physicians who 
are uncomfortable with administering chemotherapy dose based on actual body weight 
should not enroll obese patients on this protocol.
8.7
Dose Modification Contacts
For treatment or dose modification questions, please contact the Study Chair, Dr. Lancet 
at 813-745-6841 or if Dr. Lancet is not available, Dr. Komrokji at 513/584-6915.
8.8
Adverse Event Reporting
Toxicities (including suspected reactions) that meet the expedited reporting criteria as 
outlined in Section 16.0 of the protocol must be reported to the Operations Office, Study 
Chair and NCI via AdEERS, and to the IRB per local IRB requirements.
 


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9.0
STUDY CALENDARS
REQUIRED STUDIES
CONSOLIDATION 
CONSOLIDATION 
CONSOLIDATION
MAINTENANCE
PRE-
STUDY
INDUDCTION
#1 through 2
#3 through 4
#5 through 6
Follow 
Up
PHYSICAL
Prior
During
Prior
During
Prior
During
Prior
During
History & Physical Exam
X
2X/week
X
X&
X
X Į
X
X&
X
X&
X¥
Height, Weight and BSA
X
X
X†
X
X†
X
X†
X
X&
X¥
Performance Status (Zubrod)
X
X&
X
X Į
X
X&
X
X&
X¥
Toxicity Notation 
2X/week
X
X
X
X
X&
X¥
LABORATORY STUDIES
CBC, Diff, Plts
X
2X/week
X
weekly
X
weekly
X
weekly
X
X&
X¥
Pregnancy test
X
Electrolytes (incl. Ca+ and Mg++), 
creatinine  *
X
2X/week
X
weekly
X
weekly
X
weekly
X
X&
Bilirubin, AST, ALT, Alkaline 
phosphatase   *
X
2X/week
X
weekly
X
weekly
X
weekly
X
X&
Cholesterol, triglycerides  * 
X
X
X
X
X&
PTT, PT, fibrinogen, FDP, D-dimer   ǻ *
X
2X/week 
BM Aspirate/Biopsy Ĭ
X
X ȥ
X
X
X
X Ȇ
X
Cytogenetics    
X
;ԇ
X¿
RT-PCR for PML-5$5Į
X
X
X¶
X
X¿
Lumbar Puncture   (see Section 7.2b)
X
X-RAYS AND SCANS
Chest X-Ray   %
X
MUGA/ECHO  
;
EKG   $
X
2X/week
X
TREATMENT (See Section 7.0)
Allopurinol/rasburicase
X
ATRA
X  ƒ
X
X
Daunomycin
X
Arsenic trioxide
X
X
6-mercaptopurine
X
Methotrexate
X
Gemtuzumab ozogamicin
X
X
NOTE: Forms are found in Section 18.0. Forms submission guidelines are found in Section 14.0.
Click here to view footnotes.
 


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Revised 4/16/14
Footnotes:
*
Results of these tests do not determine eligibility but should be done prior to registration in accordance with good medical practice.  
&
Monthly.
¥ After the patient is off treatment, the remaining of Months 3, 6, 9, 12, 18, 24 and 36 from the time of initial registration.
ǻ These tests should be done at pretreatment, twice weekly during induction until normal, and as clinically indicated thereafter.
Ĭ Pretreatment, during induction (on Day 42, then q 2 wks until CR is met), prior to Consolidation #1, prior to Consolidation #3, prior to Maintenance, 
then every 3 months during maintenance.  Once maintenance is complete, every 3 months for the 1st year, then every 6 months for the 2nd year, 
then at the end of the 3rd year from registration.  Following completion of maintenance, only aspirate is required.  Note that the marrow 
documenting CR may serve as the prior to Consolidation #1 marrow, providing it was performed within 8 weeks prior to Consolidation registration 
(see Section 5.2).
 See Section 15.0.
%  Chest X-Ray should be done pretreatment and as clinically indicated.
$
Obtain within 72 hours prior to the day of treatment.  To be performed twice per week for the first 2 weeks of induction, prior to consolidation Cycle 
3, and thereafter as clinically indicated.
ȥ On Day 42, then every 2 weeks until criteria for CR are met.
Ȇ Every 3 months during maintenance.
Į Every 2 weeks.
See Section 7.5c.
†
To be performed prior to each cycle of consolidation.
ƒ
ATRA administration is permitted for up to 5 days prior to registration.
¶
RT-PCR required prior to Consolidation #3, but not #4.
¿    Follow-up cytogenetics and RT-PCR required at relapse only.
ԇ2QO\VXEPLWWHGFHQWUDOO\IRUSDWLHQWVDIILOLDWHGZLWK&$/*%RU(&2*VHH6HFWLRQ7.8a).
 


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10.0 
CRITERIA FOR EVALUATION AND ENDPOINT DEFINITIONS
10.1
Disease Status Criteria:
NOTE that the kinds of cells considered equivalent to blasts and included in the 
calculation of blast percentages depend on the FAB classification (see Section 4.1a.2)
a.
Bone Marrow:
A1.
Maturation of all cell lines; and < 5% blasts; and no Auer rods.
A2.
Same aV$H[FHSWEODVWVDQG
A3.
Failure to meet the criteria for A1 or A2.
b.
Peripheral Blood:
B1.
Neutrophils > 1,000/mcl; and platelets > 100,000/mcl; and no leukemia 
blasts in the peripheral blood.
B2.
Failure to meet the criteria for B1.
c.
Extramedullary Disease:
C1.
None
C2.
Any
10.2
Complete Remission (CR) 
Attainment of A1 marrow status and B1 peripheral blood status and C1 extramedullary 
disease status.
10.3
Molecular Remission (MCR)  
Attainment of CR with no evidence of the PML-RAR alpha transcript as measured by 
PCR.
10.4
Partial Remission (PR)
Attainment of A2 marrow status and B1 peripheral and C1 extramedullary disease status.
10.5
Treatment Failures  
Patients who fail to achieve CR or PR following induction will be classified according to 
the type of failure:
a.
Resistant Disease:
patient survives > 30 days following completion of initial 
treatment course and has persistent leukemia in the most recent peripheral blood 
smear or bone marrow after completion of therapy.
b.
Not Assessable:  patient survives > 30 days following completion of initial 
treatment course then dies with no persistent leukemia in the peripheral smear 
but no post-induction bone marrow examination.
 


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c.
Treatment Failure Due to Death:
1.
patient survives < 30 days after completion of initial treatment course with 
evidence of persistent leukemia in the peripheral smear and post 
induction bone marrow examination.
2.
patient survives < 30 days following completion of initial treatment course 
then dies without determination of response. 
10.6
Relapse from CR  
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 or reappearance of PML-RAR alpha (in patients who had achieved MCR) via 
cytogenetics, FISH, or PCR in the blood or bone marrow, confirmed at least once 4 - 8
weeks later.  If there are no circulating blasts and no extramedullary disease and the bone 
PDUURZEODVWSHUFHQWDJHLV!EXWWKHQDUHSHDWERQHPDUURZSHUIRUPHGDW
least 7 days after the first marrow examination and documenting bone marrow blast 
percentage is > 5% is necessary to establish relapse.
10.7
Event-free survival (EFS) at 3 years
For this study, EFS at 3 years is defined as a binary variable as follows:  Yes if the patient 
achieves CR (Section 10.2) and remains in continuous CR until at least 3 years after 
entering the study; otherwise No.
10.8
Toxicity Criteria
The NCI Common Terminology Criteria for Adverse Events Version 3.0 will be used to 
determine severity of toxicity.  
10.9
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.
10.10
Time to Death
From date of registration until date of death from any cause.
 


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11.0
STATISTICAL CONSIDERATIONS
11.1
Primary Objective
The primary objective of this study is to test whether the regimen incorporating ATRA, 
arsenic trioxide, and gemtuzumab ozogamicin is sufficiently safe and effective among 
patients with previously untreated high-risk acute promyelocytic leukemia to warrant 
Phase III study.  This objective will be met by analyzing the probabilities of continuous 
complete remission (CCR) at 3 years and of death from any cause within the first 6 weeks 
of protocol treatment.  If the 3-year CCR rate is sufficiently high AND the 6-week mortality 
rate is sufficiently low, then Phase III study might be warranted; otherwise further study 
would not be recommended.  To define a test criterion based on both outcomes, it is 
necessary to define null and alternative hypotheses in terms of the joint distribution of 
efficacy and toxicity.
The regimen would not warrant Phase III study if its true 3-year CCR rate is 50% or less 
OR its 6-week mortality rate is 30% or more.  Therefore, the joint distribution of the null 
hypothesis with marginal probabilities is the following:
 


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Null Hypothesis Joint Distribution:
Death within
Died or relapsed
Alive in CR
first 6 weeks
within 3 years, or no CR               at 3 years
Yes
30%
0%
No
20%
50%
The regimen would warrant Phase III study if its true 3-year CCR rate is 70% or higher 
AND its true fatal toxicity rate is 15% or less.  Therefore, the joint distribution of the 
alternative hypothesis with marginal probabilities is the following:
Alternative Hypothesis Joint Distribution:
Death within
Died or relapsed
Alive in CR
first 6 weeks 
within 3 years, or no CR
at 3 years
Yes
15%
0%
No
15%
70%
Because there is only limited Group-wide experience with this regimen, accrual will be 
conducted in two steps.  In the first step, 32 eligible patients will be accrued.  If more than 
seven of these patients die within the first 6 weeks, then the study will be terminated early 
with the conclusion that the study does not warrant Phase III study.  Otherwise an 
additional 38 eligible patients will be accrued.  Patients enrolled before RT-PCR results 
are known and who are subsequently found to be negative for PML-RARD and RARD-
PML will not be counted towards these accrual goals.
If, among the total of 70 eligible patients, at least 41 are alive and in continuous CR at 3 
years and fewer than 17 die in the first 6 weeks, then Phase III study will be warranted.  
For the null hypothesis joint distribution above, the probability of early stopping is 0.79,
and the critical level (the probability of erroneously concluding that the regimen warrants 
Phase III study) of the study is 0.033.  For the joint distribution of the alternative 
hypothesis, the probability of early stopping is 0.096, and the power (the probability of 
correctly concluding that Phase III study is warranted) is 0.89.  The statistical 
characteristics are summarized in the following table:
Hypothesis
Null
Alternative 
Probability of 8+ deaths
0.79
0.096
within 6 weeks in first 32 patients
Probability of 41+ CCR at 3 yrs and 
0.033
0.89
< 17 deaths within 6 weeks in 70 patients
11.2  
Molecular Response and Toxicity
With 70 eligible patients, the probabilities of molecular response and of any particular 
toxicity can be estimated to within at most ± 12% (95% confidence interval).  Any toxicity 
occurring with at least 5% probability is very likely to be observed in at least one patient 
SUREDELOLW\
 


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11.3  
Accrual
The recent intergroup APL study C9710, accrued about 25 eligible high-risk patients per 
year.  Therefore accrual of 70 eligible patients to this study is expected to require 
approximately 34 months assuming there is not a lengthy delay between the two stages of 
accrual.
11.4
Data Safety Monitoring 
There is no formal data and safety monitoring committee for Phase II studies.  Toxicity 
and accrual monitoring are done routinely by the Study Chair, study Statistician and the 
Disease Committee Chair.  Response 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, and Executive Officer monitor toxicities on an ongoing basis.
12.0
DISCIPLINE REVIEW
Discipline review is not necessary for this study.
13.0
REGISTRATION GUIDELINES
NOTE:  For non-SWOG member procedures (CTSU participation) see Appendix 18.4.
13.1 
Registration Timing
Patients must be registered prior to initiation of Induction (Step 1—Initial Registration), 
Consolidation (Step 2—Consolidation Therapy Registration), or Maintenance (Step 3—
Maintenance Therapy Registration) treatment no more than one working day prior to 
planned start of treatment.
13.2 
Registration Requirements
For either phone or web registration, the individual registering the patient must have 
completed the appropriate Southwest Oncology Group Registration Form. The completed 
form must be referred to during the registration but should not be submitted as part of the 
patient data.
The individual registering the patient must also be prepared to provide the treating 
institution's name and ID number in order to ensure that the current (within 365 days) date 
of institutional review board approval for this study has been entered into the data base.  
Patients will not be registered if the IRB approval date has not been provided or is > 365 
days prior to the date of registration.
13.3 
Registration Procedures
a.
You may register patients from Member, CCOP and approved Affiliate institutions 
to a therapeutics study using the SWOG Registration program. To access the 
Registration program go to the SWOG Web site (http://swog.org) and click on the 
Logon 
link 
to 
go 
to 
the 
SWOG 
Members 
Area 
logon 
page 
(https://swog.org/visitors/logon.asp).  This Web program is available at any time 
except for periods listed under Down Times.  Log on as an Individual User using 
your SWOG Roster ID Number and individual web user password.  Help for the 
logon process may be found at https://swog.org/visitors/logonhelp.asp. After you 
have logged on, click on the Clinical Trials link and then the Patient Reg link to go
 


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to the Entry Page for the Patient Registration program. If you are a Registrar at 
an institution with Internet access you are encouraged to register this way. For 
new users, the link to a "Starter Kit" of help files may be found by clicking on 
Starter Kit link at the logon page.
To register a patient the following must be done (in order):
1.
You are entered into the Southwest Oncology Group Roster and issued a 
SWOG Roster ID Number, 
2.
You are associated as an investigator or CRA/RN to the institution where 
a registration is occurring, and 
3.
You are granted permission to use the Patient Registration program at 
that institution. 
For assistance with points 1 and 2 call the SWOG Operations Office at 210/614-
8808. For point 3 you must contact your Web User Administrator.  Each SWOG 
institution has one or more Web User Administrators who may set up Web Users 
at their institution and assign permissions and passwords to these users. For 
other password problems or problems with the Patient Registration program, 
please e-mail webreghelp@crab.org. Include your name, Roster ID Number, and 
telephone number, when the problem occurred, and exactly what you were doing.
b.  
If the Web Reg program is not used, the registration must be done by phone.
Member, Affiliate and CCOP Institutions
Registration by phone of patients from member, affiliate and CCOP institutions 
must be done through the Southwest Oncology Group Data Operations Center in 
Seattle by telephoning 206/652-2267, 6:30 a.m. to 4:00 p.m. Pacific Time, 
Monday through Friday, excluding holidays.
13.4 
For either method of registration, exceptions to Southwest Oncology Group 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 Requirements
Data must be submitted according to the protocol requirements for ALL patients 
registered, 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.
14.2
Master Forms
Master forms are included in Section 18.0 and (with the exception of the sample consent 
form and the Registration Form) must be submitted to the Data Operations Center in 
Seattle.  Data from approved SWOG institutions must be submitted on-line via the Web; 
see Section 14.3a for details.  Exceptions to online data submission are patient-
completed (e.g. Quality of Life) forms and source documents (e.g. pathology/operative/lab 
reports).
 


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14.3
Data Submission Procedures
a.
Southwest Oncology Group institutions must submit data electronically via the Web 
by using the SWOG CRA Workbench.  To access the CRA Workbench, go to the 
SWOG Web site (http://swog.org) and logon to the Members Area.  After you have 
logged on, click on the CRA Workbench link to access the home page for CRA 
Workbench website.  Next, click on the Data Submission link and follow the
instructions.  For new users, the link to a "Starter Kit" of help files may be found by 
clicking on the Starter Kit link at the Members’ logon page.
To submit data via the web the following must be done (in order):
1. 
You are entered into the Southwest Oncology Group 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, and
3. 
Your Web User Administrator has added you as a web user and has 
given you the appropriate system permissions to submit data for that 
institution.
For assistance with points 1 and 2 call the Operations Office at 210/450-8808.  
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).  For 
other 
difficulties 
with 
the 
CRA 
Workbench, 
please 
email 
technicalquestion@crab.org.
b.
If you need to submit data that are not available for online data submission, the 
only alternative is via facsimile.  Should the need for this occur, institutions may 
submit data via facsimile to 800/892-4007 or 206/342-1680 locally.  Please do not 
use cover sheet for faxed data.
14.4
Data Submission Overview and Timepoints
a.
WITHIN 14 DAYS AFTER INITIAL REGISTRATION (STEP 1):
Submit the following:
S0535 Prestudy Form 
Pathology Report
Pretreatment Cytogenetics Report (only required for patients from SWOG sites 
and other sites NOT affiliated with ECOG or CALGB)
Pretreatment RT-PCR Report (only required for patients from SWOG sites,
CALGB sites and other sites NOT affiliated with ECOG)
See Section 15.0 for sample submission requirements.
b.
WITHIN 14 DAYS AFTER COMPLETING INDUCTION TREATMENT:
Submit the following:
S0535 Induction Treatment Summary Form 
S0535 Adverse Event Summary Form 
 


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APL Disease Assessment Form 
Off Treatment Notice (Please enter Step "1" on form.)
RT-PCR Report (only required for patients from SWOG sites, CALGB sites and
other sites NOT affiliated with ECOG)
c.
WITHIN 14 DAYS AFTER COMPLETING EACH OF CONSOLIDATION CYCLES 
1 AND 2 TREATMENT:
Submit the following:
S0535 Consolidation Cycles 1 and 2 Treatment Summary Form 
S0535 Adverse Event Summary Form 
d.
WITHIN 14 DAYS AFTER COMPLETING CONSOLIDATION CYCLE 2:
Submit the following:
APL Disease Assessment Form 
RT-PCR Report (only required for patients from SWOG sites, CALGB sites and
other sites NOT affiliated with ECOG)
e.
WITHIN 14 DAYS AFTER COMPLETING EACH OF CONSOLIDATION CYCLES
3 AND 4 TREATMENT:
Submit the following:
S0535 Consolidation Cycles 3 and 4 Treatment Summary Form
S0535 Adverse Event Summary Form 
f.
WITHIN 14 DAYS AFTER COMPLETING EACH OF CONSOLIDATION CYCLES 
5 AND 6 TREATMENT:
Submit the following:
S0535 Consolidation Cycles 5 and 6 Treatment Summary Form 
S0535 Adverse Event Summary Form 
g.
WITHIN 14 DAYS AFTER COMPLETING CONSOLIDATION CYCLE 6:
Submit the following:
APL Disease Assessment Form 
h.
WITHIN 14 DAYS AFTER GOING OFF CONSOLIDATION TREATMENT:
Submit the following:
Off Treatment Notice (Please enter Step "2" on form.)
i.
WITHIN 14 DAYS AFTER REGISTRATION FOR MAINTENANCE THERAPY 
(Step 3):
Submit the following:
APL Disease Assessment Form 
RT-PCR Report (only required for patients from SWOG sites, CALGB sites and
other sites NOT affiliated with ECOG)
 


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j.
EVERY 3 MONTHS WHILE ON MAINTENANCE THERAPY:
Submit the following:
S0535 Maintenance Treatment Summary Form 
S0535 Adverse Event Summary Form 
APL Disease Assessment Form 
k.
WITHIN 14 DAYS AFTER GOING OFF MAINTENANCE TREATMENT:
Submit the following:
Off Treatment Notice (Please enter Step "3" on form.)
l.
WITHIN 14 DAYS AFTER KNOWLEDGE OF A RELAPSE FROM COMPLETE 
REMISSION:
Submit the following:
A copy of the APL Disease Assessment Form documenting the date of and 
evidence for complete remission or relapse.  
Submit Cytogenetics Report (only required for patients from SWOG sites and 
other sites NOT affiliated with ECOG or CALGB)
RT-PCR Report (only required from SWOG sites, CALGB sites and other sites 
not affiliated with ECOG)
m.
AFTER OFF TREATMENT:  THE REMAINING OF MONTHS 3, 6, 9, 12, 18, 24 
AND 36 FROM THE TIME OF INITIAL REGISTRATION:
Submit the following:
Follow Up Form.
n.
WITHIN 4 WEEKS AFTER KNOWLEDGE OF DEATH:
If death occurs while patient is on protocol treatment submit a copy of the Notice 
of Death, the S0535 Adverse Event Summary Form and the Treatment Summary 
Form that corresponds with the Step and Cycle of treatment the patient was 
receiving at the time of death.
If the death occurs after off treatment submit a final Southwest Oncology Group 
Follow Up Form. Also submit a copy of the Notice of Death.
15.0
SPECIAL INSTRUCTIONS
15.1
Summary of all specimen submission
The table below outlines the required RT-PCR tests and cytogenetic studies for all 
patients.  RT-PCR at each time listed below and cytogenetic studies at pretreatment and 
relapse are required for all patients, regardless of group affiliation.  Additional details 
regarding mechanisms for obtaining these studies are Group specific.  See Section 15.2 
for SWOG (and other sites not affiliated with ECOG or CALGB), Section 15.3 for ECOG 
and Section 15.4 for CALGB.
 


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Specimen collection time
RT-PCR*
Cytogenetics
Pretreatment (Prior to Induction)
BM, PBa
BM
At the time of neutrophil recovery or on Day 42 
BM, PB
BMb
(see Section 7.8a)
Prior to Consolidation #3 (see Section 7.8b)
BM, PB
Prior to Maintenance (see Section 7.8c)
BM, PB
At relapse
BM, PB
BM
* SWOG institutions may only submit peripheral blood if bone marrow aspirate is “dry 
tap”.
RT-PCR analyses of specimens collected at pretreatment are time-sensitive and RT-
PCR results will be reported by the testing laboratory to the institution within 10 days 
after the specimens are received.  RT-PCR assays of the remaining specimens are not 
time sensitive, and results will not be reported to the institution.
If the RT-PCR result of the time-sensitive analysis is indeterminate (e.g. specimen 
damaged in shipment or extracted RNA yield or quality is inadequate), the testing
laboratory may contact the institution to request collection and submission of an 
additional specimen in an attempt to obtain a positive or negative result before reporting 
the molecular status.
a The pretreatment RT-PCR determines whether the patient is eligible for the study or, if 
already registered, should continue on protocol treatment; see Section 5.1b.
If the 
pretreatment RT-PCR result is indeterminate (e.g. specimens damaged in shipment or 
extracted RNA yield or quality is inadequate), additional blood specimens should be 
submitted for RT-PCR testing to avoid indeterminate pretreatment results whenever 
possible.  
b Not required for SWOG sites and other sites not affiliated with ECOG or CALGB.
15.2
Southwest Oncology Group institutions and other institutions NOT affiliated with ECOG or 
CALGB
NOTE:  No specimens will be banked for SWOG and other sites not affiliated with ECOG 
or CALGB.
a.
Cytogenetic studies
Effective with Revision #5, submission of specimens for cytogenetic studies 
through protocol SWOG-9007 is no longer required.  Cytogenetic studies must 
still be performed at each institution’s preferred cytogenetics laboratory, 
according to the schedule in Section 15.1, and reports of the results must be 
submitted as described in Section 14.0.
b.
PCR testing
1.
Effective with Revision #5, submission of specimens for RT-PCR testing 
through protocol S9910 is no longer required.  However, RT-PCR testing 
must still be performed at the following times:
 


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a.
Pretreatment (prior to Induction)
b.
At the time of neutrophil recovery ( 1,000/mcl) or on Day 42 
after beginning ATRA (whichever comes first).  (See Section 
7.8a.)
c.
Prior to Consolidation #3 (within 8 weeks [preferably within 4 
weeks] before starting Consolidation #3 treatment; see Section 
7.8b)
d.
Prior to Maintenance
e.
At Relapse
2.
Specimens for PCR testing may be submitted to any CLIA-approved 
laboratory; reports of the results must be submitted as described in 
Section 14.0. CLIA certificates will be verified at the time of an audit.
15.3
ECOG Institutions
The sample submission schedule is indicated in Section 15.1.
It is required that 
pretreatment specimens and karyotypes must be submitted via E3903 “Ancillary 
laboratory protocol for collecting diagnostic material on patients considered for ECOG 
treatment trials for leukemia or related hematologic disorders”.
It is required that ALL biological sample submissions be logged into the ECOG Sample 
Tracking System (ECOG-STS) and a shipping manifest generated by this system is to 
accompany all submissions. See Section 15.3c.
If the ECOG-STS is unavailable at the time of shipping, submit a completed E3903 
Material Submission Form and indicate the collection “TIME POINT” in the comment 
section of the form. The form MUST contain the treatment protocol number S0535 and
the patient’s S0535 case number. Once STS is available, retroactively log the shipment 
into STS, using the actual collection and shipping dates. 
NOTE: The E3903 Material Submission Form may be obtained from the ECOG website.  
a.
Specimens for PCR testing
1.
Submissions
Baseline samples are to be submitted via E3903.
Copies of the patient’s signed E3903 and S0535 consents and signed 
authorizations must be submitted to the Leukemia Translational Studies 
Laboratory (LTSL) prior to or with the first sample submissions on these 
studies. 
 


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An ECOG-STS shipping manifest must be submitted with each shipment.  
The following samples must be submitted at each RT-PCR time point 
listed in Section 15.1:
a.
Heparinized (10 units heparin/ml) bone marrow aspirate, 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.
b.
Heparinized peripheral blood (green top tubes) (30-40 cc) 
c.
One air dried smear must be submitted.
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:
x 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.
x Ship by overnight courier (preferably Federal Express) to arrive 
within 24 hours to:
Elisabeth Paietta, Ph.D.
Our Lady of Mercy Cancer Center
600 East 233rd Street
6th Floor, Immunology Laboratory
Bronx, NY 10466-2697
Phone: 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 718/20-9992.   
2.
Notification of PCR test
The LTSL will process and forward the appropriate materials to Dr. Robert 
Gallagher for determination of molecular PML-5$5Į status (positive or 
negative).  The results for the time sensitive tests will be FAXed to the site 
within 10 days of receipt of the sample.
Copies of the reports will also be submitted to SWOG.
 


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b.
Cytogenetic Review
At each cytogenetic time point listed in Section 15.1, submit two original 
karyotypes and institution’s cytogenetics laboratory report from the bone marrow
cytogenetic studies performed by the institution’s cytogenetic laboratory.  
NOTE:  Karyotypes from peripheral blood cytogenetic studies will NOT be
accepted as a substitute for the bone marrow cytogenetic analysis.
Submit the karyotypes, reports and a completed ECOG Leukemia Cytogenetics 
Form (#365R) to the ECOG Cytogenetics Committee:
Gary Hicks
Mayo Clinic Cytogenetics Laboratory
970 Hilton
200 First Street, S.W.
Rochester, MN 55905
Phone: 507/284-2950
Fax: 507/284-0043
Failure to submit these materials will render the case unevaluable.
The cytogenetic reviews will be performed by the ECOG Cytogenetics Laboratory 
at Mayo Clinic. Original karyotypes will be returned when the review and analysis 
are complete. Copies of the karyotypes will be scanned and stored electronically 
for future reference.
c.
ECOG Sample Tracking System (ECOG-STS)
It is required (barring special circumstances) that all samples be entered and tracked
using the ECOG Sample Tracking System (ECOG-STS). As of June 2007, the 
software will allow the use of either 1) an ECOG user-name and password 
previously assigned (for those already using 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:  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/ecoginst/trans/. Please take a moment to familiarize yourself 
with the software prior to using the system.
A shipping manifest must be generated and shipped with all sample submissions.
Please direct your questions or comments pertaining to the ECOG-STS to 
ecog.tst@jimmy.harvard.edu.
15.4
CALGB institutions
Information for specimen submissions for CALGB institutions.
a.
Specimens for PCR Testing and CALGB-9862
 


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1. 
Specimens for PCR Testing
Effective with Revision #7, submission of specimens for RT-PCR testing 
through protocol CALGB-9862 is no longer required. However, RT-PCR 
testing must still be performed at the time points listed in Section 15.4a.3.
Specimens for PCR testing may be submitted to any CLIA-approved 
laboratory; reports of the results must be submitted as described in 
Section 14.0. CLIA certificates will be verified at the time of an audit.
2.
Specimens for CALGB-9862
For consenting patients, specimens for banking must be submitted to the 
CALGB Leukemia Tissue Repository at the time points listed in Section 
15.4a.3.
3.
PCR and Banking Specimen Submission Time Points
a. 
Pretreatment (prior to Induction)
b.
$W WKH WLPH RI QHXWURSKLO UHFRYHU\  PFO RU RQ 'D\ 
after beginning ATRA (whichever comes first). (See Section 
7.8a.)
c. 
Prior to Consolidation #3 (within 8 weeks [preferably within 4
weeks] before starting Consolidation #3 treatment; see Section 
7.8b)
d. 
Prior to Maintenance
e. 
At Relapse
b.
Specimens for Cytogenetics
Enrollment on CALGB 8461 will be required for patients participating through 
CALGB institutions. Submission of samples to your local, CALGB-approved 
cytogeneticist is mandatory. The cytogenetic sample must be obtained 
prior to the initiation of therapy. Specimens must also be submitted at time 
of achievement of CR and at relapse.
With the specimen sent to the local approved cytogeneticist, enclose a completed 
CALGB Cytogenetic Referral Form (C-030) with CALGB patient number. Send a 
copy of the form to the CALGB Statistical Center, Data Operations. As soon as it 
is available, a copy of the cytogenetic report must be faxed to the CALGB 
Cytogenetics Office (614-293-3575) and to the CALGB Statistical Center, Data 
Operations (919-668-9348). Questions concerning sample submission may be 
directed to the CALGB Cytogenetics Office at The Ohio State University (614-
293-2542).
Cytogenetic Sample Procurement: Consult with the institutional CALGB 
cytogeneticist regarding how the sample(s) should be collected. An adequate 
NONDILUTE specimen of marrow is usually required to obtain metaphases. Two 
to 3 mLs of the initial aspiration (in a sterile heparinized syringe) from a 
repositioned needle is ideal. Success is often dependent on the prompt delivery 
of the specimen to the cytogeneticist.
 


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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. 
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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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.
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 prescribe 
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. A CTEP-AERS report must be submitted 
to the Southwest Oncology Group Operations Office electronically via the CTEP-
AERS Web-based application located at 
http://ctep.cancer.gov/protocolDevelopmnet/electronic_applications/adverse_even
ts.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 Internet connectivity is disrupted, a 24-hour notification is to be 
made to SWOG by telephone at 210-614-8808.  Once Internet connectivity is 
restored, a 24-hour notification that was phoned in must be entered electronically 
into CTEP-AERS by the original submitter at the site.
When the adverse event requires expedited reporting, submit the report within the 
number of calendar days of learning of the event specified in Table 16.1 or 16.2,
as applicable. 
d.
Other recipients of adverse event reports
The 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 also be reported according to local 
policies and procedures.
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(s) used in Induction and Consolidation 
Cycles 5 and 6 of this study is gemtuzumab ozogamicin.  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 Non-CTEP IND within 30 Days of the Last Administration of 
the Investigational Agent/Intervention1  Gemtuzumab Ozogamicin
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 
IRUKRXUV
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 
KUV
10 Calendar Days
24-Hour 5 
Calendar 
Days
Not resulting in
Hospitalization 
KUV
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:
x
All Grade 4, and Grade 5 AEs
Expedited 10 calendar day reports for:
x
Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization 
x
Grade 3 adverse events
May 5, 2011
 


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f.
Additional Instructions or Exceptions to CTEP-AERS Expedited Reporting 
Requirements for Phase 2 and 3 Trials Utilizing an Agent under a non-
CTEP-IND:
1)
Group-specific instructions.
Within 10 calendar days (5 calendar days if 24-hour reporting was 
required), submit the following to the Operations Office  by fax to 
210-614-0006 or mail to the address below:
x
Printed copy of the first page of the CTEP-AERS report
x
Copies of clinical source documentation of the event
x
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.
The Operations Office will notify drug companies as required.
2)
For this study, the adverse events listed below do not require 
expedited reporting via CTEP-AERS:
x
Grade 4 myelosuppression
g.
Expedited reporting for commercial agents
Commercial reporting requirements are provided in Table 16.2. The commercial 
agent(s) used in this study are all trans retinoic acid (ATRA), arsenic trioxide, 
daunomycin, 6-mercaptopurine and methotrexate. 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.
Table 
16.2. 
Expedited 
reporting 
requirements 
for adverse events 
experienced by patients on this study who have received the commercial 
drug(s) listed in 16.1f above.
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 by fax to 
210-614-0006. 
 


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h.
Reporting Secondary Malignancy, 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.
SWOG requires all secondary malignancies that occur following 
treatment with an agent under a Non-NCI IND to be reported via CTEP-
AERS.  Three options are available to describe the event.
x
Leukemia secondary to oncology chemotherapy (e.g., Acute 
Myelocytic Leukemia [AML])
x
Myelodysplastic syndrome (MDS)
x
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.
Second Malignancy: A second malignancy is one unrelated to the 
treatment of a prior malignancy (and is NOT a metastasis from the initial 
malignancy). Second malignancies require ONLY routine reporting via 
CDUS unless otherwise specified.
For more information see:
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/
aeguidelines.pdf 
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 by fax to 210-614-
0006 or mail to the address below:
x
a copy of the pathology report confirming the AML/ALL /MDS 
diagnosis
x
(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.
i. 
Reporting Pregnancy, Fetal Death, and Death Neonatal
1.
Pregnancy Study participants who become pregnant while on study; that 
pregnancy should be reported in an expedited manner via CTEP-AERS as 
Grade 3 “Pregnancy, puerperium and perinatal conditions – Other 
(pregnancy)”
under 
the 
Pregnancy, 
puerperium 
and 
perinatal 
conditions SOC.  
 


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Additionally, the pregnancy outcome for patients on study should be 
reported via CTEP-AERS at the time the outcome becomes known, 
accompanied by the same Pregnancy Report Form used for the initial 
report.
2.
Fetal Death Fetal Death defined in CTCAE as “A disorder characterized by 
death in utero; failure of the product of conception to show evidence of 
respiration, heartbeat, or definite movement of a voluntary muscle after 
expulsion from the uterus, without possibility of resuscitation” should be 
reported expeditiously as Grade 4 “pregnancy, puerperium and perinatal 
conditions 
–
Other 
(pregnancy 
loss)” 
under 
the 
Pregnancy, 
puerperium and perinatal conditions SOC.  
3.
Death Neonatal  Neonatal death, defined in CTCAE as “A disorder 
characterized by cessation of life occurring during the first 28 days of life” 
that is felt by the investigator to be at least possibly due to the investigational 
agent/intervention should be reported expeditiously.  
A neonatal death should be reported expeditiously as Grade 4 “General 
disorders and administration – Other (neonatal loss)” under the
General disorders and administration SOC.
Fetal death and neonatal death should NOT be reported as a Grade 5 event.  If 
reported as such, the CTEP-AERS interprets this as a death of the patient being 
treated.
NOTE:  When submitting CTEP-AERS reports for “Pregnancy, “Pregnancy loss”, or 
“Neonatal loss”, the Pregnancy Information Form should also be completed and 
faxed with any additional medical information to 301-230-0159.  The potential risk of 
exposure of the fetus to the investigational agent(s) or chemotherapy agent(s) 
should be documented in the “Description of Event” section of the CTEP-AERS 
report.
The Pregnancy Information Form is available at: 
http://ctep.cancer.gov/protocolDevelopment/adverse_effects.htm 
 
 


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17.0
BIBLIOGRAPHY
1. 
Sanz MA, Lo Coco F, Martin G, Avvisati G, Rayon C, Barbui T, Diaz-Mediavilla J, Fioritoni G, 
Gonzalez JD, Liso V, Esteve J, Ferrara F, Bolufer P, Bernasconi C, Gonzalez M, Rodeghiero F, 
Colomer D, Petti MC, Ribera JM, Mandelli F. Definition of relapse risk and role of nonanthracycline 
drugs for consolidation in patients with acute promyelocytic leukemia: a joint study of the PETHEMA 
and GIMEMA cooperative groups. Blood 96:1247-1253, 2000. 
2. 
Burnett AK, Grimwade D, Solomon E, Wheatley K, Goldstone AH. Presenting white blood cell count 
and kinetics of molecular remission predict prognosis in acute promyelocytic leukemia treated with 
all-trans retinoic acid: result of the Randomized MRC Trial.  Blood 93:4131-4143, 1999. 
3. 
Fenaux P, Chastang C, Chevret S, Sanz M, Dombret H, Archimbaud E, Fey M, Rayon C, Huguet F,
Sotto JJ, Gardin C, Makhoul PC, Travade P, Solary E, Fegueux N, Bordessoule D, Miguel JS, Link 
H, Desablens B, Stamatoullas A, Deconinck E, Maloisel F, Castaigne S, Preudhomme C, Degos L.  
A randomized comparison of all transretinoic acid (ATRA) followed by chemotherapy and ATRA plus 
chemotherapy and the role of maintenance therapy in newly diagnosed acute promyelocytic 
leukemia. The European APL Group.  Blood 94:1192-1200, 1999. 
4. 
Tallman MS, Nabhan C, Feusner JH, Rowe JM. Acute promyelocytic leukemia: evolving therapeutic 
strategies.  Blood 99:759-767, 2002. 
5. 
Sanz MA, Martin G, Vellenga E, Bolufer P, Gonzalez M, Rayon C, de la Serna J, Parody R, Bergua J, 
Negri S, Rivas C. Risk-adapted treatment of acute promyelocytic leukemia: updated results of the 
Spanish PETHEMA LPA99 trial using ATRA and anthracycline monochemotherapy. J Clin Oncol 23
(Part 1):563a, #6515, 2005. (Abstract)
6. 
de la Serna J, Martin G, Vellenga E, Rayon C, Rivas C, Deben G, Gonzalez M, Tormo M, Bergua J, 
Diaz-Mediavilla J, Leon A, Esteve J, Parody R, Amutio E, Gonzalez JD, Negri S, Capote FJ, Bueno 
J, Perez-Encina M, Novo A, Rodriguez A, Sanz MA. Causes of induction failure in newly diagnosed 
acute promyelocytic leukemia patients treated with simultaneous ATRA and idarubicin (AIDA).  Blood 
104 (Part 1):253a, #887, 2004. (Abstract)
7. 
Au WY, Chim JC, Lie AK, Kumana CR, Leung AY, Tse EW, Ma SY, Liang RH, Kwong YL. Treatment 
of relapsed acute promyelocytic leukemia by arsenic-based strategies without hematopoietic stem 
cell transplantation in Hong Kong: a seven-year experience.  Blood 104 (Part 1):116a, #395, 2004. 
(Abstract)
8. 
Ghavamzadeh A, Alimoghaddam K, Ghaffari H, Rostami S, Mortazavi Y, Mousavi A, Tootonchi M, 
Jahani M, Hosseini R, Iravani M, Bahar B, Aghdami, N. Treatment of new cases of acute 
promyelocytic leukemia by arsenic trioxide.  Blood 104 (Part 1):116a, #396, 2004. (Abstract)
9. 
Petti MC, Pinazzi MB, Diverio D, Romano A, Petrucci MT, De Santis S, Meloni G, Tafuri A, Mandelli 
F, Lo CF. Prolonged molecular remission in advanced acute promyelocytic leukemia after treatment 
with gemtuzumab ozogamicin (Mylotarg CMA-676).  Br J Haematol 115:63-65, 2001. 
10. 
Lo-Coco F, Cimino G, Breccia M, Noguera NI, Diverio D, Finolezzi E, Pogliani EM, Di Bona E, 
Micalizzi C, Kropp M, Venditti, A, Tafuri A, Mandelli F. Gemtuzumab ozogamicin (Mylotarg) as a 
single agent for molecularly relapsed acute promyelocytic leukemia.  Blood 104:1995-1999, 2004. 
11. 
Estey EH, Giles FJ, Beran M, O'Brien S, Pierce SA, Faderl SH, Cortes JE, Kantarjian HM. 
Experience with gemtuzumab ozogamycin ("mylotarg") and all-trans retinoic acid in untreated acute
promyelocytic leukemia.  Blood 99:4222-4224, 2002.
12.
Estey E, Garcia-Manero G, Ferrajoli A, et al.  Use of ALL-transretinoic acid + arsenic trioxide as an 
alternative to chemotherapy in untreated acute promyelocytic leukemia.  Blood 107:3469-3479, 2006.
 


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APPENDIX
18.1
Determination of Expedited Adverse Event Reporting Requirements
18.2
Writing Committee
18.3
Intake Calendar
18.4
Cancer Trials Support Unit (CTSU) Participation Procedures
 
 
 
 


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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 16.0.
Reporting requirements may include the following considerations: 1) whether the patient 
has received an investigational or commercial agent; 2) the characteristics of the adverse 
event including the grade (severity), the relationship to the study therapy (attribution), and 
the prior experience (expectedness) of the adverse event; 3) the Phase (I, II, or III) of the 
trial; and 4) whether or not hospitalization or prolongation of hospitalization was 
associated with the event. 
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.
x
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.
x
Sequential administration: When a study includes an investigational agent(s) and 
a commercial agent(s) on the same study arm, but the commercial agent(s) is 
given for a period of time prior to starting the investigational agent(s), expedited 
reporting of adverse events that occur prior to starting the investigational agent(s) 
would follow the guidelines for commercial agents. Once therapy with the 
investigational agent(s) is initiated, all expedited reporting of adverse events 
should follow the investigational guidelines.
Steps to determine if an adverse event is to be reported in an expedited manner
Step 1: 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. All appropriate 
treatment locations should have access to a copy of the CTCAE.
Step 2: Grade the event using the NCI CTCAE version specified.
Step 3: Determine whether the adverse event is related to the protocol therapy 
(investigational or commercial). Attribution categories are as follows: Unrelated, 
Unlikely, Possible, Probable, and Definite.
 
 


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Step 4: Determine the prior experience of the adverse event. Expected events are those 
that have been previously identified as resulting from administration of the agent. 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 
x
the current NCI Agent-Specific Adverse Event List (for treatments using agents 
provided under an NCI-held IND);
x
the drug package insert (for treatments with commercial agents only);
x
Section 3.0 of this protocol.
Step 5: Review Table 16.1 in the protocol to determine if there are any protocol-specific 
requirements for expedited reporting of specific adverse events that require special 
monitoring.
Step 6: Determine if the protocol treatment given prior to the adverse event included an 
investigational agent(s), a commercial agent(s), or a combination of investigational and 
commercial agents.
NOTE: This includes all events that occur within 30 days of the last dose of protocol 
treatment. Any event that occurs more than 30 days after the last dose of treatment and is 
attributed possibly, probably, or definitely to the agent(s) must be reported according to 
the instructions above. 
 
 


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18.2
Writing Committee
A Writing Committee will be responsible for the publication of a manuscript that will 
describe the results of this study in a peer-reviewed journal.  The members of this writing 
committee will be the co-authors of this manuscript.  Dr. Lancet, the Study Chair, will be 
the primary author.  Ms. Holly Gundacker, the SWOG statistician, will be the 2nd author; 
and Dr. Appelbaum, the Leukemia Committee Chair of the SWOG, will be the senior (last)
author.  The three laboratory investigators who will perform RT-PCR assays to determine 
eligibility on this trial (Drs. Willman, Gallagher, and Stock) will also be members of the 
writing committee.
The other members of the writing committee will be determined according to the level of 
participation in the study as measured by patient accrual from each group.  The number 
of investigators on the Writing Committee from each participating cooperative group (e.g., 
SWOG, CALGB, ECOG, NCIC CTG, COG) will be based on the following accrual 
formula.  Each group that enrolls at least 5% of the entire study population will have one 
member on the writing committee.  Each group will be entitled to an additional member of 
the Writing Committee for each additional 10% of the overall accrual.  For example, if a 
group enrolled 15% of the study patients, that group would have 2 co-authors on the 
committee; if 25% of the study patients were enrolled, that group would have 3 co-
authors.  The SWOG will be assigned additional members of the Writing Committee only 
after that group accrues > 25% of the total study patients.  It will be the responsibility of 
each cooperating group to name the individual clinical or laboratory investigators to fill 
their allotted positions.  By this method, it is anticipated that the final Writing Committee 
will include approximately 12-14 of the clinical and/or laboratory investigators who have 
most involved in the design, conduct, and analysis of this study.  
A smaller number of individuals (such as Disease Committee or Correlative Science 
Committee chairs) may warrant acknowledgment (with their group affiliation) in the final 
manuscript for their support of the conduct of the study and for their critical review of this 
manuscript.  The participation of each cooperative group that enrolls any patients on this 
intergroup study will be acknowledged in the final manuscript with their respective grant 
support.
 


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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
Cancer Trials Support Unit (CTSU) Participation Procedures
REGISTRATION/RANDOMIZATION
Prior to the recruitment of a patient for this study, investigators must be registered 
members of the CTSU.  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 (FDA Form 1572 with original signature, 
current CV, Supplemental Investigator Data Form with signature, and Financial Disclosure
Form with original signature) to the Pharmaceutical Management Branch, CTEP, DCTD, 
NCI.  These forms are available on the CTSU registered member Web site or by calling 
the PMB at 301-496-5725 Monday through Friday between 8:30 a.m. and 4:30 p.m. 
Eastern time.
Each CTSU 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 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 member web site at www.ctsu.org.
All forms and documents associated with this study can be downloaded from the S0535
Web page on the CTSU registered member Web site (www.ctsu.org).  Patients can be 
registered only after pre-treatment evaluation is complete, all eligibility criteria have been 
met, and the study site is listed as ‘approved’ in the CTSU RSS. 
Requirements for S0535 site registration:
x
CTSU IRB Certification
x
CTSU IRB/Regulatory Approval Transmittal Sheet
Pre-study requirements for patient enrollment on S0535
In order to participate in S0535, subjects must be enrolled on ancillary protocols as 
detailed below:
x
Patient must meet all inclusion criteria, and no exclusion criteria should apply
x
Patient has signed and dated all applicable consents and authorization forms
x
All baseline laboratory tests and prestudy evaluations (including bone marrow 
aspirate and blood samples) performed within the time period specified in the 
protocol.
x
CALGB sites:
CALGB patients must be registered on CALGB 8461
and CALGB 
9862 prior to registration to S0535,
x
ECOG sites: PRIOR to registering a patient to S0535, ECOG institutions must either 
register the patient to E3903 through ECOG.  The ECOG patient number will be 
required by the CTSU at the time of S0535 registration.
x
All other non-SWOG sites:
Effective with Revision #5, registration on SWOG-9007
and S9910 is no longer required, although cytogenetic studies and RT-PCR testing 
must be performed as described in Section 15.2.
 


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CTSU Procedures for Patient Enrollment
Registration (Step 1) Induction 
Patients must be registered prior to Induction no more than one working day prior 
to the planned start of treatment
1. 
Contact the CTSU Patient Registration Office by calling 1-888-462-3009 between 
9:00 a.m. and 5:30 p.m. Eastern Time, Mon-Fri. Leave a voicemail to alert the 
CTSU Patient Registrar that an enrollment is forthcoming. For immediate 
registration needs, e.g. Within one hour, call the registrar cell phone at 1-301-
704-2376.
2. 
Complete the following forms:
x
CTSU Patient Enrollment Transmittal Form
x
Eligibility Criteria Checklist (Section 5.1 of the protocol)
x
Registration Form for Registration Step 1
3. 
Fax these forms to the CTSU Patient Registrar at 1-888-691-8039 between the 
hours of 9:00 a.m. and 5:30 p.m., Mon-Fri, Eastern Time (excluding holidays); 
however, please be aware that registrations received after 5:00 p.m. will be 
processed the next day. The CTSU registrar will check the investigator and site 
information to ensure that all regulatory requirements have been met. The 
registrar will also check that forms are complete and will follow-up with the site to 
resolve any discrepancies.
4. 
Once investigator eligibility is confirmed and enrollment documents are reviewed 
for compliance, the CTSU registrar will contact the Southwest Oncology Group, to
obtain assignment of a unique patient ID (to be used on all future forms and 
correspondence).  The CTSU registrar will confirm registration by fax. 
Registration (Step 2) Consolidation
1. 
After completing Induction, patients will be registered for Consolidation therapy 
provided that they were eligible for the initial registration and satisfy the additional 
criteria outlined in Section 5.2 of the protocol.
2. 
Complete the following forms:
x
CTSU Patient Enrollment Transmittal Form
x
Eligibility Criteria Checklist for Consolidation (Section 5.2 of the protocol)
x
Registration Form for Registration Step 2
3. 
Fax these forms to the CTSU Patient Registrar at 1-888-691-8039 between the 
hours of 9:00 a.m. and 5:30 p.m., Mon-Fri, Eastern Time (excluding holidays).  A 
confirmation fax will be sent to the enrolling site upon successful registration.
Registration (Step 3) Maintenance Therapy
1.
After completing Consolidation, patients will be registered for Maintenance 
therapy provided that they were eligible for the initial registration; and were eligible
for and completed protocol consolidation therapy and satisfy the additional criteria 
outlined in Section 5.3 of the protocol.
2. 
Complete the following forms:
x
CTSU Patient Enrollment Transmittal Form
x
Eligibility Criteria Checklist for Maintenance Therapy (Section 5.3 of the 
protocol)
x
Registration Form for Registration Step 3
 


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3. 
Fax these forms to the CTSU Patient Registrar at 1-888-691-8039 between the 
hours of 9:00 a.m. and 5:30 p.m., Mon-Fri, Eastern Time (excluding holidays).  A 
confirmation fax will be sent to the enrolling site upon successful registration.
DATA SUBMISSION AND reconciliation
1. 
All case report forms (CRFs) associated with this study must be downloaded from 
the S0535 Web page located on the CTSU registered member Web site 
(www.ctsu.org). Sites must use the current form versions and adhere to the 
instructions and submission schedule outlined in the protocol.
2. 
Submit all completed CRFs (with the exception of patient enrollment forms), 
clinical reports, and transmittals directly to the SWOG Data Operations Center.  
The preferred method of sending data is via fax at 800/892-4007.  Do NOT 
include a cover sheet for faxed data. Do not send study data to the CTSU.
3. 
The SWOG Data Operations Center will send query notices and delinquency 
reports directly to the site for reconciliation. Please fax query responses and 
delinquent data to the SWOG Data Operations Center and do not copy the CTSU 
Data Operations. When faxing data, include the query sheet that was originally 
sent from SWOG.
4. 
Each site should have a designated CTSU Administrator and Data Administrator 
and must keep their CTEP AMS account contact information current. This 
will ensure timely communication between the clinical site and the SWOG data 
center.
Special Materials or Substudies
Cytogenetic studies and PCR as outlined in Section 15.0 are mandatory.  The collection 
of pre-treatment specimens as outlined in Section 15.0 must be completed prior to 
registration to S0535.  Additional submission time points are listed in Section 15.0.
Submissions must be made utilizing one of the following mechanisms:
CALGB sites: Cytogenetic studies and RT-PCR testing must be obtained as described in 
Section 15.4.
ECOG sites: Submissions outlined in Section 15.3.  It is required that baseline 
submissions be via E3903, ECOG’s baseline submission and repository protocol.
All other sites: Submissions outlined in Sections 15.1 and 15.2.  Submissions be made to 
a CLIA-approved laboratory.
All other sites:  Requirements for cytogenetic studies and RT-PCR testing are outlined in 
Sections 15.1 and 15.2.  Cytogenetic studies must be performed at each institution’s 
preferred cytogenetics laboratory. RT-PCR testing must be performed at CLIA-approved 
laboratories.
SERIOUS Adverse Event (AE) Reporting (SECTION 16.1)
1. 
CTSU sites must comply with the expectations of their local Institutional Review 
Board (IRB) regarding documentation and submission of adverse events.  Local 
IRBs must be informed of all reportable serious adverse reactions. 
 


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2. 
CTSU sites will assess and report adverse events according to the guidelines and 
timelines specified in the protocol. You may navigate to the CTEP Adverse Event 
Reporting System (CTEP-AERS) from either the Adverse Events tab of the CTSU 
member homepage (www.ctsu.org) or by selecting Adverse Event Reporting 
Forms from the document center drop down list on the protocol number Web 
page. 
3. 
Do not send adverse event reports to the CTSU.
4. 
Secondary AML/MDS/ALL reporting: Report occurrence of secondary AML, MDS, 
or ALL via the NCI/CTEP AML-MDS Report Form in lieu CTEP-AERS. Submit the 
completed form and supporting documentation as outlined in the protocol.  
Drug Procurement (SECTION 3.0)
 
Commercial agents: All Trans Retinoic Acid (Trentinoin), Arsenic Trioxide (Trisenox®), 
Daunomycin 
(Cerubidine)(daunorubicin 
hydrochloride),
Gemtuzumab
Ozogamicin
(Mylotarg®), 6-Mercaptopurine, Methotrexate
1. 
Information on drug formulation, procurement, storage and accountability, 
administration, and potential toxicities are outlined in Section 3.0 of the protocol.  
2. 
You may navigate to the drug forms by selecting Pharmacy Forms from the 
document center drop down list on the S0535 Web page.  
REGULATORY AND MONITORING
Study Audit
To assure compliance with Federal regulatory requirements [CFR 21 parts 50, 54, 56, 
312, 314 and HHS 45 CFR 46] and National Cancer Institute (NCI)/ Cancer Therapy 
Evaluation Program (CTEP) Clinical Trials Monitoring Branch (CTMB) guidelines for the 
conduct of clinical trials and study data validity, all protocols approved by NCI/CTEP that 
have patient enrollment through the CTSU are subject to audit.
Responsibility for assignment of the audit will be determined by the site’s primary 
affiliation with a Cooperative Group or CTSU. For Group-aligned sites, the audit of a 
patient registered through CTSU will become the responsibility of the Group receiving 
credit for the enrollment. For CTSU Independent Clinical Research Sites (CICRS), the 
CTSU will coordinate the entire audit process.
For patients enrolled through the CTSU, you may request the accrual be credited to any 
Group for which you have an affiliation provided that Group has an active clinical trials 
program for the primary disease type being addressed by the protocol. Per capita 
reimbursement will be issued by the credited Group provided they have endorsed the trial,
or by the CTSU if the Group has not endorsed the trial.
 


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Details on audit evaluation components, site selection, patient case selection, materials to 
be reviewed, site preparation, on-site procedures for review and assessment, and results 
reporting and follow-up can be found in the CTMB Monitoring Guidelines and are 
available for download from the CTEP web page
http://ctep.cancer.gov/monitoring/guidelines.html.
Health Insurance Portability and Accountability Act of 1996 (HIPAA)
The HIPAA Privacy Rule establishes the conditions under which protected health 
information may be used or disclosed by covered entities for research purposes. 
Research is defined in the Privacy Rule referenced in HHS 45 CFR 164.501. Templated 
language addressing NCI-U.S. HIPAA guidelines are provided in the HIPAA Authorization 
Form located on the CTSU website. 
The HIPAA Privacy Rule does not affect participants from outside the United States. 
Authorization to release Protected Health Information is NOT required from patients 
enrolled in clinical trials at non-US sites.
Clinical Data System–Web (CDS-Web) Monitoring
This study will be monitored by the Clinical Data System (CDS-Web). The sponsoring 
Group fulfills this reporting obligation by transmitting the CDS data collected from the 
study-specific case report forms, via the Web to the NCI Center for Biometrics (NCICB). 
Cumulative CDS data are submitted quarterly.
 


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Informed Consent Model for S0535
*NOTES FOR LOCAL INSTITUTION INFORMED CONSENT AUTHORS: 
This model informed consent form has been reviewed by the DCT/NCI and is the official 
consent document for this study. Local IRB changes to this document are allowed.  (Institutions 
should attempt to use sections of this document that are in bold type in their entirety.)  Editorial 
changes to these sections may be made as long as they do not change information or intent.  If 
the institutional IRB insists on making deletions or more substantive modifications to the risks or 
alternatives sections, they may be justified in writing by the investigator and approved by the 
IRB.  Under these circumstances, the revised language, justification and a copy of the IRB 
minutes must be forwarded to the Southwest Oncology Group Operations Office for approval 
before a patient may be registered to this study.  
Please particularly note that the questions related to banking of specimens for future study 
are in bolded type and may not be changed in any way without prior approval from the 
Southwest Oncology Group Operations Office.
Readability Statistics:  
Flesch Reading Ease
61.8 (targeted above 55)
Flesch-Kincaid Grade Level 8.6 (targeted below 8.5)
x
Instructions and examples for informed consent authors are in [italics].
x
A blank line,  __________, indicates that the local investigator should provide the 
appropriate information before the document is reviewed with the prospective 
research participant. 
x
The term "study doctor" has been used throughout the model because the local 
investigator for a cancer treatment trial is a physician.   If this model is used for a 
trial in which the local investigator is not a physician, another appropriate term 
should be used instead of "study doctor".
x
The dates of protocol updates in the header and in the text of the consent is for 
reference to this model only and should not be included in the informed consent 
form given to the prospective research participant. 
x
The local informed consent must state which parties may inspect the research 
records. This includes the NCI, the drug manufacturer for investigational studies, 
any companies or grantors that are providing study support (these will be listed in 
the protocol's model informed consent form) and the Southwest Oncology Group. 
The "Southwest Oncology Group" must be listed as one of the parties that may 
inspect the research records in all protocol consent forms for which patient 
registration is being credited to the Southwest Oncology Group.  This includes 
consent forms for studies where all patients are registered directly through the 
Southwest Oncology Group Data Operations Office, all intergroup studies for 
which the registration is being credited to the Southwest Oncology Group (whether 
the registration is through the SWOG Data Operations Office or directly through 
the other group), as well as consent forms for studies where patients are registered 
via CTSU and the registration is credited to the Southwest Oncology Group.
 


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x
When changes to the protocol require revision of the informed consent document, 
the IRB should have a system that identifies the revised consent document, in order 
to preclude continued use of the older version and to identify file copies.  An 
appropriate method to identify the current version of the consent is for the IRB to 
stamp the final copy of the consent document with the approval date.  The stamped 
consent document is then photocopied for use.  Other systems of identifying the 
current version of the consent such as adding a version or approval date are allowed 
as long as it is possible to determine during an audit that the patient signed the most 
current version of the consent form. 
*NOTES FOR LOCAL INVESTIGATORS: 
x
The goal of the informed consent process is to provide people with sufficient 
information for making informed choices.   The informed consent form provides a 
summary of the clinical study and the individual's rights as a research participant.  It
serves as a starting point for the necessary exchange of information between the 
investigator and potential research participant.  This model for the informed consent 
form is only one part of the larger process of informed consent. For more 
information about informed consent, review the "Recommendations for the 
Development of Informed Consent Documents for Cancer Clinical Trials" prepared 
by the Comprehensive Working Group on Informed Consent in Cancer Clinical 
Trials for the National Cancer Institute.  The Web site address for this document is 
http://cancer.gov/clinicaltrials/understanding/simplification-of-informed-consent-
docs/
x
A blank line,  __________, indicates that the local investigator should provide the 
appropriate information before the document is reviewed with the prospective 
research participant. 
x
Suggestion for Local Investigators:  An NCI pamphlet explaining clinical trials is 
available for your patients.  The pamphlet is titled: "If You Have Cancer…What 
You Should Know about Clinical Trials".  This pamphlet may be ordered on the 
NCI Web site at https://cissecure.nci.nih.gov/ncipubs or call 1-800-4- CANCER (1-
800-422-6237) to request a free copy. 
x
Optional feature for Local Investigators: Reference and attach drug sheets, 
pharmaceutical information for the public, or other material on risks.  Check with 
your local IRB regarding review of additional materials.
*These notes for authors and investigators are instructional and should not be included in the 
informed consent form given to the prospective research participant. 
 


S0535
Page 3
Version Date 12/26/14
Revised 10/5/10
S0535, "A Phase II Study of ATRA, Arsenic Trioxide and Gemtuzumab 
Ozogamicin in Patients With Previously Untreated High-Risk Acute 
Promyelocytic Leukemia"
This is a clinical trial, a type of research study.  Your study doctor will explain the clinical trial to 
you.  Clinical trials include only people who choose to take part. Please take your time to make 
your decision about taking part.  You may discuss your decision with your friends and family.  
You can also discuss it with your health care team.  If you have any questions, you can ask your 
study doctor for more explanation. 
You are being asked to take part in this study because you have high-risk acute promyelocytic 
leukemia (APL) that has never been treated.
Why is this study being done?
The purpose of this study is to learn about the effects of treating your APL with 
chemotherapy.  The chemotherapy for APL has three parts:  induction therapy, 
consolidation therapy, and maintenance therapy.  The purpose of the induction therapy is 
to eliminate the signs and symptoms of your APL from your body.  If this happens, your 
APL will be in "remission".  Consolidation therapy and maintenance therapy are intended 
to make your remission last as long as possible.
One of the main purposes of this trial is to study the effects, good and/or bad, of a unique 
combination and schedule of chemotherapy drugs for people who have difficult-to-treat 
APL. One of these chemotherapy drugs, gemtuzumab ozogamicin, is experimental.
(sentence added 10/5/10)
How many people will take part in the study?
About 70 people will take part in this study.  
What will happen if I take part in this research study?  
Before you begin the study …
You may need to have the following exams, tests or procedures to find out if you can be in the 
study.  These exams, tests or procedures are part of regular cancer care and may be done even if 
you do not join the study.  If you have had some of them recently, they may not need to be 
repeated.  This will be up to your study doctor.
x
Medical history and examination
x
Blood tests, including tests for your kidneys and liver 
x
A bone marrow aspirate and biopsy
x
A chest x-ray
x
Scans/tests of your heart function
 


Revised 5/30/08
S0535
Revised 3/25/10
Page 4
Version Date 12/26/14
During the study …
If the exams, tests and procedures show that you can be in the study, and you choose to take part, 
then you will need the following tests and procedures.  They are part of regular cancer care. 
x Physical exam.  This will take place twice per week during induction 
chemotherapy and once per month during the consolidation and maintenance 
chemotherapy.
x Blood tests, including test for your kidneys and liver.  This will take place twice 
per week during induction chemotherapy and once per week during the 
consolidation and maintenance chemotherapy.
x Bone marrow aspirate and biopsy.  This will take place on Day 42, then every 2
weeks during induction chemotherapy, before the first and third cycles of 
consolidation chemotherapy, before maintenance chemotherapy, and every 3 
months during maintenance chemotherapy.
You will need these tests and procedures that are part of regular cancer care.   They are being 
done more often because you are in this study.  
x
Heart scans/tests
You will need these tests and procedures that are either being tested in this study or being done to
see how the study is affecting your body.
x
Bone marrow specimens from the aspirates and biopsies will be sent to a special 
lab for research purposes.  This is required as part of the study.  (NOTE to 
institutions:  This refers to the mandatory cytogenetic studies and RT-PCR 
testing.) (3/25/10)
Induction Chemotherapy with ATRA, Gemtuzumab Ozogamicin, and Arsenic Trioxide
You will take ATRA by mouth twice every day with food starting on Day 1 until visible signs of 
your leukemia go away.  Gemtuzumab ozogamicin will be given into your vein over two hours 
on Day 1. Arsenic Trioxide will be given into your vein starting on Day 10 over two hours every 
day for five days each week until your leukemia starts getting better.  Samples of your bone 
marrow will be taken 42 days after beginning ATRA.  Samples of your bone marrow then will be 
taken every two weeks if needed until signs of your leukemia are decreased or gone.  If signs of 
your leukemia are decreased or are gone, you will go on to consolidation therapy.
(section added 5/30/08)
Consolidation Chemotherapy
After your induction therapy, your bone marrow and blood samples will be tested for signs of 
APL.  This is a standard part of the treatment for APL.  You will be in complete remission (CR) 
if the signs of your APL are gone. If you are in CR after your remission induction therapy, you 
will receive six cycles of consolidation chemotherapy.
Drug
How Drug is Given
How Often
For How Long
ATRA
by mouth
2 times a day
until visible signs of leukemia are 
gone
Gemtuzumab 
ozogamicin
IV for 2 hours
once
on Day 1 only
Arsenic Trioxide
IV for 2 hours
5 days per week, 
starting on Day 10
until visible signs of leukemia are 
gone
 


Revised 5/30/08
S0535
Page 5
Version Date 12/26/14
Consolidation #1 and #2 Chemotherapy with Arsenic Trioxide
You will receive arsenic trioxide into your vein over 2 hours 5 days per week for 5 weeks.  You 
will then have 2 weeks of rest.  You will then receive arsenic trioxide into your vein over 2 hours 
5 days per week for 5 weeks.  
(section added 5/30/08)
Drug
How Drug is Given
How Often
For How Long
Arsenic 
Trioxide
IV for 2 hours
5 days per week
five weeks of taking drug, two weeks 
of rest, five more weeks of taking drug
Consolidation #3 and #4 Chemotherapy with ATRA and Daunomycin
You will take ATRA by mouth twice each day with food on Days 1 - 7.  Daunomycin will be 
given into your vein either in a very short time period or over an hour each day on Days 1 - 3.
You will then have 2-8 weeks of rest.  You will then take ATRA by mouth twice each day with 
food on Days 1 – 7.  Daunomycin will be given into your vein either in a very short time period 
or over an hour each day on Days 1 – 3.
(section added 5/30/08)
Drug
How Drug is Given
How Often
For How Long
ATRA
by mouth
2 times a day
take  drug for 7 days, rest for 2-8
weeks, then take drug again for 7 days
Daunomycin
IV (for up to 1 hour)
once daily
take drug for 3 days, rest for 2-8
weeks, take drug again for 3 days
Consolidation #5 and #6 Chemotherapy with Gemtuzumab Ozogamicin
You will receive gemtuzumab ozogamicin into your vein over 2 hours on Day 1.  You will then 
have 2-8 weeks of rest and receive gemtuzumab ozogamicin once again.  Samples of your bone 
marrow will be taken to see if you can go on to maintenance chemotherapy.
(section added 5/30/08)
Drug
How Drug is 
Given
How Often
For How Long
Gemtuzumab 
ozogamicin
IV for 2 hours
once
take drug for 1 day, rest for 2-8
weeks, take drug again for 1 day
Maintenance Chemotherapy
You will take ATRA by mouth twice each day with food for 7 days repeated every other week 
for 1 year.  You will take 6-mercaptopurine by mouth each day for 1 year.  You will take 
methotrexate by mouth once a week for 1 year.  Samples of your bone marrow will be taken 
every 3 months during maintenance chemotherapy.
(section added 5/30/08)
Drug
How Drug is Given
How Often
For How Long
ATRA
by mouth
2 times a day
take drug for seven days, rest 
for seven days – repeat this 
cycle for one year
6-mercaptopurine
by mouth
once daily
one year
Methotrexate
by mouth
once a week
one year
 
 


S0535
Page 6
Version Date 12/26/14
Revised 11/12/08
Revised 11/1/11
How long will I be in the study?
You will be asked to take induction therapy (which could last up to 90 days unless you go into 
CR sooner), six courses of consolidation therapy (which could last about 6 months but may be 
longer if you have delays in treatment because of side effects), and maintenance therapy (for 1 
year). After you are finished with these courses of treatment, the study doctor will ask you to 
visit the office for follow-up exams every 3 months for the first year, every 6 months for the 
second year, then at 3 years from the time you finish treatment. (11/1/11) At a minimum, you
will have a physical exam and blood tests at each visit.  Also, you will have a bone marrow 
aspiration, every 3 months for 1 year, then every 6 months for 1 year, then at the end of the third 
year.
Can I stop being in the study?
Yes.  You can decide to stop at any time.  Tell the study doctor if you are thinking about 
stopping or decide to stop.  He or she will tell you how to stop safely. 
It is important to tell the study doctor if you are thinking about stopping so any risks from the
ATRA, arsenic trioxide, daunomycin, gemtuzumab ozogamicin, 6-mercaptopurine, and 
methotrexate can be evaluated by your doctor.  Another reason to tell your doctor that you are 
thinking about stopping is to discuss what follow-up care and testing could be most helpful for 
you.
The study doctor may stop you from taking part in this study at any time if he/she believes it is in 
your best interest, if you do not follow the study rules, or if the study is stopped. If you are a 
female and become pregnant while on the study, you will be taken off of protocol treatment.  
(11/12/08)
 
 
 


S0535
Page 7
Version Date 12/26/14
Revised 5/26/10
What side effects or risks can I expect from being in the study? 
You may have side effects while on the study.  Everyone taking part in the study will be 
watched carefully for any side effects.  However, doctors don’t know all the side effects 
that may happen.  Side effects may be mild or very serious. Your health care team may 
give you medicines to help lessen side effects. Many side effects go away soon after you 
stop taking the study drugs.  In some cases, side effects can be serious, long lasting, or 
may never go away. 
You should talk to your study doctor about any side effects that you have while 
taking part in the study.   
Risks and side effects related to the Induction Therapy (ATRA, Gemtuzumab 
Ozogamicin, and Arsenic Trioxide) include those that are:
Likely
x
Decreased number of a type of white blood cell 
(neutrophil/granulocyte) (updated 5/26/10)
x
Decreased number of a type of blood cell that help to clot blood 
(platelet) (updated 5/26/10)
x
Lack of enough red blood cells (anemia) (updated 5/26/10) 
x
Fever (updated 5/26/10) 
x
Chills (updated 5/26/10) 
x
Headache or head pain (updated 5/26/10) 
x
Nausea or the urge to vomit (updated 5/26/10) 
x
Vomiting (updated 5/26/10) 
x
Diarrhea (updated 5/26/10) 
x
Loss of appetite (updated 5/26/10)  
x
Belly pain (updated 5/26/10) 
x
Constipation 
x
Irritation or sores in the lining of the mouth (updated 5/26/10) 
x
Inflammation (swelling and redness) or damage to the tissue surrounding 
where a drug was injected (updated 5/26/10) 
x
Muscle weakness of the whole body (updated 5/26/10) 
x
Shortness of breath (updated 5/26/10) 
x
Fatigue or tiredness (updated 5/26/10)
x
Difficulty sleeping or falling asleep (updated 5/26/10)
x
Depression
x
Skin rash with the presence of macules (flat discolored area) and papules 
(raised bump) (updated 5/26/10)
x
High blood pressure (updated 5/26/10)
x
Low blood pressure (updated 5/26/10)
x
Dizziness (or sensation of lightheadedness, unsteadiness, or giddiness) 
(updated 5/26/10)
 
 


Revised 5/30/08
S0535
Revised 5/26/10
Page 8
Version Date 12/26/14
x
Increased blood sugar level (updated 5/26/10)
x
(item deleted 5/26/10)
x
Decreased blood level of potassium (updated 5/26/10)
x
Low blood oxygen levels
x
Chest pain not heart related (updated 5/26/10)
x
Back pain
x
Dryness of the lips (updated 5/26/10)
x
Dry skin (updated 5/26/10)
x
Fluid collecting in the lungs
x
Sudden or traumatic injury to the kidney (updated 5/26/10)
x
Toothache
x
Sores or irritation of the lips
x
Increased blood level of a form of fat called triglyceride (5/30/08)
x
Nosebleed (5/30/08)
x
Infection (added 5/26/10)
x
Itching (updated and moved from Less Likely 5/26/10)
Less Likely
x
Weight gain
x
Fluid retention
x
Upper respiratory infection
x
Damage to the liver, which could cause yellowing of the skin and/or eyes
x
Visual disturbances, eye problems
x
Dry nose (updated 5/26/10)
x
Dry mouth (updated 5/26/10)
x
(updated and moved to Likely 5/26/10)
x
Peeling skin
x
Severe injury to liver (veno-occlusive disease (5/30/08)
x
Fever associated with dangerously low levels of a type of white blood cell 
(neutrophils) (added 5/26/10)
x
Decreased number of all blood cell types (added 5/26/10)
x
Unpleasant sensation of irregular and/or forceful beating of the heart (added 
5/26/10)
x
Fast heartbeat; regular rhythm (added 5/26/10)
x
Irregular heartbeat resulting from an abnormality in one of the lower 
chambers of the heart (ventricle) (added 5/26/10)
x
Noise in the ears, such as ringing, buzzing, roaring, clicking (added 5/26/10)
x
Swelling or feeling of fullness and tightness in the abdomen (belly) (added 
5/26/10)
x
Irritation or sores in the lining of the anus (added 5/26/10)
x
Heartburn (added 5/26/10)
x
Inflammation (swelling and redness) of the pancreas (added 5/26/10)
x
Irritation or sores in the lining of the rectum (added 5/26/10)
 
 


S0535
Page 9
Version Date 12/26/14
Revised 5/26/10
x
Irritation or sores in the lining of the small bowel (added 5/26/10)
x
Swelling of the face (added 5/26/10)
x
Swelling of the extremities (arms and/or legs) (added 5/26/10)
x
Pain (added 5/26/10)
x
Infection associated with a decrease in a type of white blood cell (lymphocyte) 
(added 5/26/10)
x
Bruising (added 5/26/10)
x
Increased blood level of a liver enzyme (ALT/SGPT) (added 5/26/10)
x
Increased blood level of a liver enzyme (AST/SGOT) (added 5/26/10)
x
Increased blood level of a liver pigment (bilirubin) often a sign of liver 
problems (added 5/26/10)
x
Increased blood level of creatinine (a substance normally eliminated by the 
kidneys into the urine) (added 5/26/10)
x
Abnormal electrical conduction within the heart (added 5/26/10)
x
Increased blood level of a liver enzyme (GGT) (added 5/26/10)
x
Increased blood level of fat-digesting enzyme (lipase) (added 5/26/10)
x
Increased blood level of a digestive enzyme (amylase) (added 5/26/10)
x
Weight loss (added 5/26/10)
x
Decrease in the total number of white blood cells (leukocytes) (added 5/26/10)
x
More acid than normal in the blood (added 5/26/10)
x
Increased blood level of potassium (added 5/26/10)
x
Decreased blood level of magnesium (added 5/26/10)
x
Joint pain (added 5/26/10)
x
Bone pain (added 5/26/10)
x
Shrinking of muscles (added 5/26/10)
x
Muscle pain (added 5/26/10)
x
Commonly known as “pins and needles”, where part of the body (typically a 
foot or hand) begins to tingle and becomes numb, or “falls asleep” (added 
5/26/10)
x
Weakness or paralysis (loss of muscle function) caused by damage to 
peripheral nerves (those nerves outside of brain and spinal cord) (added 
5/26/10)
x
Inflammation (swelling and redness) or degeneration of the peripheral 
nerves (those nerves outside of brain and spinal cord) causing numbness, 
tingling, burning (added 5/26/10)
x
Anxiety, feelings of dread or danger (added 5/26/10)
x
More protein in the urine than usual, often a sign of kidney disease (added 
5/26/10)
x
Stuffy or runny nose, sneezing (added 5/26/10)
x
Sudden constriction of the muscles in the walls of the bronchioles (small 
airways of the lung) (added 5/26/10)
x
Cough (added 5/26/10)
x
Irritation or sores in the lining of the voice box (added 5/26/10)
 
 


S0535
Page 10
Version Date 12/26/14
Revised 5/26/10
x
Irritation or sores in the lining of the throat (added 5/26/10)
x
Build up of a large amount of fluid between the layers of tissue that line the 
lungs and chest cavity (added 5/26/10)
x
A collection of symptoms including fever, difficulty breathing, chest pain, 
fluid in the lung (seen on chest X-ray), fluid around the lungs and heart, and 
lack of oxygen first seen in patients receiving the drug retinoic acid (added 
5/26/10)
x
Sore throat (added 5/26/10)
x
Irritation or sores in the lining of the windpipe (added 5/26/10)
x
Hair loss (added 5/26/10)
x
Excess sweating (added 5/26/10)
x
Area of bleeding within the skin causing a reddish purple discoloration 
(added 5/26/10)
x
Inflammation (swelling and redness) of the skin (added 5/26/10)
x
Thickening of the skin (added 5/26/10)
x
Darkening of the skin (added 5/26/10)
x
Hives (added 5/26/10)
x
Increase in the number and size of the pores in the capillaries (small blood 
vessels) which causes leakage of fluid from the blood to the tissue spaces, 
resulting in dangerously low blood pressure, swelling and multiple organ 
failure (added 5/26/10)
x
Sudden reddening of the face and/or neck (added 5/26/10)
Rare, but Serious
x
Severe allergic reaction, which could be life-threatening
x
ATRA Syndrome: a combination of heart and lung problems including 
difficulty breathing, lowered oxygen in the blood, fever, rash, inflammation 
of the lungs, fluid around the heart and/or the lungs, heart failure
x
(moved 5/30/08)
Risks and side effects related to Consolidation #1 and #2 Therapy (Arsenic Trioxide) 
include those that are:
Likely
x
(updated and moved to Less Likely 5/26/10)
x
Fatigue or tiredness (updated 5/26/10)
x
Nausea or the urge to vomit (updated 5/26/10)
x
Headache or head pain (updated 5/26/10)
x
(updated and moved to Less Likely 5/26/10)
x
Decreased number of a type of white blood cell (neutrophil/granulocyte) 
(updated 5/26/10)
x
Decreased number of a type of blood cell that help to clot blood (platelet) 
(updated 5/26/10)
x
(updated and moved to Less Likely 5/26/10)
x
Shortness of breath
 
 


S0535
Page 11
Version Date 12/26/14
Revised 5/26/10
x
(item deleted 5/26/10)
x
Diarrhea
x
(updated and moved to Less Likely 5/26/10)
x
(updated and moved to Less Likely 5/26/10)
x
(item deleted 5/26/10)
x
(updated and moved to Less Likely 5/26/10)
x
(updated and moved to Less Likely 5/26/10)
x
(updated and moved to Less Likely 5/26/10)
x
( moved to Less Likely 5/26/10)
x
(updated and moved to Less Likely 5/26/10)
x
Vomiting (added 5/26/10)
x
Fever (moved from Less Likely 5/26/10)
x
Infection (added 5/26/10)
x
Itching (moved from Less Likely 5/26/10)
x
Skin rash with the presence of macules (flat discolored area) and papules 
(raised bump) (added 5/26/10)
Less Likely
x
(moved to Likely 5/26/10)
x
Chills
x
Weight gain
x
(item deleted 5/26/10)
x
(item deleted 5/26/10)
x
(moved to Likely 5/26/10)
x
(item deleted 5/26/10)
x
Abnormal electrical conduction within the heart (updated 5/26/10)
x
Increased blood sugar level (updated and moved from Likely 5/26/10)
x
Lack of enough red blood cells (anemia) (updated and moved from Likely 
5/26/10)
x
Belly pain (updated and moved from Likely 5/26/10)
x
Chest pain not heart-related (updated and moved from Likely 5/26/10)
x
Dry skin (updated and moved from Likely 5/26/10)
x
Dry mouth (updated and moved from Likely 5/26/10)
x
Build up of a large amount of fluid between the layers of tissue that line the 
lungs and chest cavity (updated and moved from Likely 5/26/10)
x
Sudden or traumatic injury to the kidney (updated and moved from Likely 
5/26/10)
x
Toothache (moved from Likely 5/26/10)
x
Dizziness (or sensation of lightheadedness, unsteadiness, or giddiness) 
(updated and moved from Likely 5/26/10)
x
Fever associated with dangerously low levels of a type of white blood cell 
(neutrophils) (added 5/26/10)
 
 


S0535
Page 12
Version Date 12/26/14
Revised 5/26/10
x
Decreased number of all blood cell types (added 5/26/10)
x
Unpleasant sensation of irregular and/or forceful beating of the heart (added 
5/26/10)
x
Fast heartbeat; regular rhythm (added 5/26/10)
x
Irregular heartbeat resulting from an abnormality in one of the lower 
chambers of the heart (ventricle) (added 5/26/10)
x
Noise in the ears, such as ringing, buzzing, roaring, clicking (added 5/26/10)
x
Swelling or feeling of fullness and tightness in the abdomen (belly) (added 
5/26/10)
x
Irritation or sores in the lining of the anus (added 5/26/10)
x
Constipation (added 5/26/10)
x
Heartburn (added 5/26/10)
x
Irritation or sores in the lining of the mouth (added 5/26/10)
x
Inflammation (swelling and redness) of the pancreas (added 5/26/10)
x
Irritation or sores in the lining of the rectum (added 5/26/10)
x
Irritation or sores in the lining of the small bowel (added 5/26/10)
x
Swelling of the face (added 5/26/10)
x
Swelling of the extremities (arms and/or legs) (added 5/26/10)
x
Inflammation (swelling and redness) or damage to the tissue surrounding 
where a drug was injected (added 5/26/10)
x
Pain (added 5/26/10)
x
Infection associated with a decrease in a type of white blood cell (lymphocyte) 
(added 5/26/10)
x
Bruising (added 5/26/10)
x
Increased blood level of a liver enzyme (ALT/SGPT) (added 5/26/10)
x
Increased blood level of a liver enzyme (AST/SGOT) (added 5/26/10)
x
Increased blood level of a liver pigment (bilirubin) often a sign of liver 
problems (added 5/26/10)
x
Increased blood level of creatinine (a substance normally eliminated by the 
kidneys into the urine) (added 5/26/10)
x
Increased blood level of a liver enzyme (GGT) (added 5/26/10)
x
Increased blood level of a fat-digesting enzyme (lipase) (added 5/26/10)
x
Increased blood level of a digestive enzyme (amylase) (added 5/26/10)
x
Weight loss (added 5/26/10)
x
Decrease in the total number of white blood cells (leukocytes) (added 5/26/10)
x
Loss of appetite (added 5/26/10)
x
More acid than normal in the blood (added 5/26/10)
x
Increased blood level of potassium (added 5/26/10)
x
Decreased blood level of potassium (added 5/26/10)
x
Decreased blood level of magnesium (added 5/26/10)
x
Joint pain (added 5/26/10)
x
Bone pain (added 5/26/10)
x
Muscle weakness of the whole body (added 5/26/10)
x
Shrinking of muscles (added 5/26/10)
x
Muscle pain (added 5/26/10)
 
 


S0535
Page 13
Version Date 12/26/14
Revised 5/26/10
x
Commonly known as “pins and needles”, where part of the body (typically a 
foot or hand) begins to tingle and becomes numb, or “falls asleep” (added 
5/26/10)
x
Weakness or paralysis (loss of muscle function) caused by damage to the 
peripheral nerves (those nerves outside of brain and spinal cord) (added 
5/26/10)
x
Inflammation (swelling and redness) or degeneration of the peripheral 
nerves (those nerves outside of brain and spinal cord) causing numbness, 
tingling, burning (added 5/26/10)
x
Anxiety, feelings of dread or danger (added 5/26/10)
x
Difficulty sleeping or falling asleep (added 5/26/10)
x
More protein in the urine than usual, often a sign of kidney disease (added 
5/26/10)
x
Stuffy or runny nose, sneezing (added 5/26/10)
x
Sudden constriction of the muscles in the walls of the bronchioles (small 
airways of the lung) (added 5/26/10)
x
Cough (added 5/26/10)
x
Nose bleed (added 5/26/10)
x
Irritation or sores in the lining of the voice box (added 5/26/10)
x
Irritation or sores in the lining of the throat (added 5/26/10)
x
A collection of symptoms including fever, difficulty breathing, chest pain, 
fluid in the lung (seen on chest X-ray), fluid around the lungs and heart, and 
lack of oxygen first seen in patients receiving the drug retinoic acid (added 
5/26/10)
x
Sore throat (added 5/26/10)
x
Irritation or sores in the lining of the windpipe (added 5/26/10)
x
Hair loss (added 5/26/10)
x
Excess sweating (added 5/26/10)
x
Area of bleeding within the skin causing a reddish purple discoloration 
(added 5/26/10)
x
Inflammation (swelling and redness) of the skin (added 5/26/10)
x
Thickening of skin (added 5/26/10)
x
Darkening of skin (added 5/26/10)
x
Hives (added 5/26/10)
x
Increase in the number an size of the pores in the capillaries (small blood 
vessels) which causes leakage of fluid from the blood to the tissue spaces, 
resulting in dangerously low blood pressure, swelling and multiple organ 
failure (added 5/26/10)
x
Sudden reddening of the face and/or neck (added 5/26/10)
x
High blood pressure (added 5/26/10)
x
Low blood pressure (added 5/26/10) 
 
 


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Risks and side effects related to Consolidation #3 and #4 Therapy (ATRA and 
Daunomycin) include those that are:
Likely
x
Lower white blood count that may lead to infection, which could be life-
threatening
x
Lower platelets, which may lead to bruising or bleeding and could be life-
threatening.  This side effect may require you to receive a transfer of blood 
platelets from a donor.
x
Lower red blood counts that may cause you to feel tired or have shortness of 
breath and require a transfer of red blood cells from a donor.  Low red blood 
counts could be life-threatening.
x
Nausea, vomiting, abdominal pain, or diarrhea
x
Loss of appetite
x
Sores in the mouth and/or rectum.  The sores in the mouth may cause 
difficulty in swallowing or a sore throat.
x
Headache
x
Hair loss
x
Skin rash
x
Fever
x
Bone pain
x
Flu-like symptoms
x
Changes in nail growth
x
Taste changes
x
Fatigue
 
 


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x
Rash
x
Red urine and/or tears while receiving daunomycin
x
Eye problems, visual disturbances (5/30/08)
x
Increased blood level of a fat called triglyceride (11/12/08)
Less Likely 
x
Heart damage, which could lead to irregular heart beats or heart failure
x
Dryness of the skin and lips
x
Damage to the liver, which could cause yellowing of the skin and/or eyes
x
Damage to the kidneys, which could result in the need for dialysis
x
Chills 
x
Itching, inflammation, and redness of the skin on the palms of the hands or 
soles of the feet
x
Muscle pain
x
Bleeding from the nose, gums, or skin
x
Mood changes
x
Problems with coordination, speech impairment, seizures, or paralysis
Rare but Serious
x
Inflammation of the lining of the bowel, which could lead to abdominal pain 
and swelling and require surgery
x
ATRA Syndrome: a combination of heart and lung problems including 
difficulty breathing, lowered oxygen in the blood, fever, rash, inflammation 
of the lungs, fluid around the heart and/or the lungs, heart failure
Risks and side effects related to Consolidation #5 and #6 Therapy (Gemtuzumab 
Ozogamicin) include those that are:
Likely
x
Lower white blood count that may lead to infection which could be life-
threatening
x
Lower platelets, which may lead to bruising or bleeding and could be life-
threatening.  This side effect may require you to receive a transfer of blood 
platelets from a donor.
x
Lower red blood counts that may cause you to feel tired or have shortness of 
breath and require a transfer of red blood cells from a donor.  Low red blood 
counts could be life-threatening. 
x
Fever, chills, headache 
x
Nausea, vomiting, diarrhea 
x
Loss of appetite, abdominal pain 
x
Constipation 
x
Low levels of potassium in the blood, which may affect the heartbeat or cause 
muscle cramps 
x
Sores in the mouth 
x
Pain at the site of injection/local reaction 
x
Weakness
 
 


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x
Difficulty breathing 
x
Fatigue
x
Difficulty sleeping
x
Fluid in the lungs
x
Depression
x
Rash
x
Changes in blood pressure
x
Dizziness
Less Likely
x
Damage to the liver, which could cause yellowing of the skin and/or eyes
x
Severe injury to the liver (veno-occlusive disease), which could be life-
threatening
Rare, but Serious
x
Severe allergic reaction, which could be life-threatening
Risks and side effects related to Maintenance Therapy with ATRA, 6-mercaptopurine, and 
Methotrexate include those that are:
Likely
x
Lower white blood count that may lead to infection, which could be life-
threatening
x
Lower platelets, which may lead to bruising or bleeding and could be life-
threatening.  This side effect may require you to receive a transfer of blood 
platelets from a donor.
x
Lower red blood counts that may cause you to feel tired or have shortness of 
breath and require a transfer of red blood cells from a donor.  Low red blood 
counts could be life-threatening.
x
Headache
x
Nausea
x
Stomach and/or intestinal ulcers
x
Vomiting of blood
x
Joint pain
x
Hair loss
x
Skin changes
x
Cough
x
Sensitivity to light
Less Likely
x
Dryness of the skin and lips
x
Bladder irritation and blood in urine (this may be prevented with drinking 
lots of fluids and/or getting them in an IV and/or with medicine)
x
Eye problems, visual disturbances
x
Dryness of the skin and lips
 
 


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Revised 11/12/08
Revised 1/28/09
Revised 10/5/10
x
Itching, inflammation, and redness of the skin on the palms of the hands or 
soles of the feet
x
Muscle pain
x
Bleeding from the nose, gums, or skin
x
Mood changes
x
Weight loss
x
Diarrhea
(moved 1/28/09)
(Section deleted 5/30/08)
Rare but Serious (added 1/28/09)
x
ATRA Syndrome:  A combination of heart and lung problems including 
difficulty breathing, lowered oxygen in the blood, fever, rash, inflammation 
of the lungs, fluid around the heart and/or lungs, heart failure. (11/12/08)
(moved 1/28/09)
In a recent clinical trial using gemtuzumab ozogamicin, in a higher dose than is used in 
this study and combined with a different chemotherapy, no benefit was seen and there 
was a higher rate of early death.  Due to these findings, the company that makes 
gemtuzumab ozogamicin has withdrawn the drug from the market.  However, every 
effort will be made to ensure availability of gemtuzumab ozogamicin for this trial.  
Currently there is no evidence that gemtuzumab ozogamicin at a lower dose (as used in 
this trial) in combination with ATRA and/or arsenic trioxide causes increased toxicity, 
although experience is limited.  The safety of the study therapy in patients on this trial 
will continue to be closely monitored. (paragraph added 10/5/10)
 
 


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(Section deleted 5/30/08)
Reproductive risks:  You should not become pregnant or father a baby while on this study 
because the drugs in this study can affect an unborn baby.  Women should not breastfeed a 
baby while on this study.  It is important you understand that you need to use birth control 
while on this study.  Check with your study doctor about what kind of birth control 
methods to use and how long to use them.  Some methods might not be approved for use in 
this study.  
Pregnancy testing is required for women with reproductive potential before induction and 
is strongly recommended before the third course of consolidation therapy and before 
maintenance therapy.
Women should be fully counseled on the serious risk to the fetus should they become 
pregnant while undergoing treatment with ATRA.  An effective form of contraception 
should be used for at least one month before and also throughout ATRA therapy, and two 
months after.  If pregnancy does occur during treatment, you should discuss this with your 
doctor immediately, and you will be removed from protocol therapy.  (11/12/08)
For more information about risks and side effects, ask your study doctor.
Are there benefits to taking part in the study?
Taking part in this study may or may not make your health better.  While doctors hope the 
treatment used in this study will be more useful against APL compared to the usual 
treatment, there is no proof of this yet. We do know that the information from this study 
will help doctors learn more about using these drugs as a treatment for APL.  This 
information could help future cancer patients.
What other choices do I have if I do not take part in this study?
Your other choices may include:
x
Getting treatment or care for your cancer without being in a study
x
Taking part in another study
x
Getting no treatment
x
Getting comfort care, also called palliative care.  This type of care helps reduce pain, 
tiredness, appetite problems and other problems caused by the cancer.  It does not 
treat the cancer directly, but instead tries to improve how you feel.  Comfort care 
tries to keep you as active and comfortable as possible.  
Talk to your doctor about your choices before you decide if you will take part in this study.
 
 


Revised 5/30/08
Revised 4/6/11
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Revised 4/25/13
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Will my medical information be kept private? 
We will do our best to make sure that the personal information in your medical record will be 
kept private.  However, we cannot guarantee total privacy.  Your personal information may be 
given out if required by law.  If information from this study is published or presented at scientific 
meetings, your name and other personal information will not be used. 
Organizations that may look at and/or copy your medical records for research, quality assurance, 
and data analysis include:
x
The Southwest Oncology Group 
x
A qualified representative from Pfizer, Inc., the manufacturer of gemtuzumab ozogamicin 
(added 1/28/09) (4/6/11)
x
The National Cancer Institute (NCI) and other government agencies, like the Food and 
Drug Administration (FDA), involved in keeping research safe for people
x
(For patients registered via the CTSU) The Cancer Trials Support Unit (CTSU), a
research group sponsored by the National Cancer Institute (NCI) to provide greater access 
to clinical trials.  (added 5/30/08)
[Note to Local Investigators: The NCI has recommended that HIPAA regulations be addressed 
by the local institution.  The regulations may or may not be included in the informed consent 
form depending on local institutional policy.]
What are the costs of taking part in this study?
You and/or your health plan/ insurance company will need to pay for some or all of the costs of 
treating your cancer in this study.  Some health plans will not pay these costs for people taking 
part in studies.  Check with your health plan or insurance company to find out what they will pay 
for.  Taking part in this study may or may not cost your insurance company more than the cost of 
getting regular cancer treatment. 
Administration of the drugs will be (provided free of charge/charged in the usual way). The 
parts of the research consisting of keeping research records will be paid by those organizing and 
conducting the research.  The research requires that you receive certain standard medical tests 
and examinations.  These standard tests and examinations will be (charged in the usual 
way/provided at a reduced rate). (local institutions must choose the option that best fits the 
hospital's situation)
All trans retinoic acid, arsenic trioxide, daunomycin, 6-mercaptopurine and methotrexate are 
commercially available. (1/28/09)
Gemtuzumab ozogamicin is investigational and will be provided free of charge by Pfizer, Inc. for 
this study. (added 1/28/09) (4/6/11)
You will not be paid for taking part in this study.
For more information on clinical trials and insurance coverage, you can visit the National Cancer 
Institute’s Web site at http://cancer.gov/clinicaltrials/learningabout/payingfor/how-insurance-
companies-decide. (updated 4/25/13)You can print a copy of the "Clinical Trials and Insurance 
Coverage" information from this Web site.
 
 


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Another way to get the information is to call 1-800-4-CANCER (1-800-422-6237) and ask them 
to send you a free copy.
What happens if I am injured because I took part in this study?
It is important that you tell your study doctor, __________________ [investigator’s name(s)], if 
you feel that you have been injured because of taking part in this study.  You can tell the doctor 
in person or call him/her at __________________ [telephone number].
You will get medical treatment if you are injured as a result of taking part in this study.  You 
and/or your health plan will be charged for this treatment.   The study will not pay for medical 
treatment.  
What are my rights if I take part in this study?
Taking part in this study is your choice.  You may choose either to take part or not to take part in 
the study.  If you decide to take part in this study, you may leave the study at any time.   No 
matter what decision you make, there will be no penalty to you and you will not lose any of your 
regular benefits.  Leaving the study will not affect your medical care.  You can still get your 
medical care from our institution.   
We will tell you about new information or changes in the study that may affect your health or 
your willingness to continue in the study.
In the case of injury resulting from this study, you do not lose any of your legal rights to seek 
payment by signing this form.  
Who can answer my questions about the study?
You can talk to your study doctor about any questions or concerns you have about this study.  
Contact your study doctor __________________ [name(s)] at __________________ [telephone 
number].
For questions about your rights while taking part in this study, call the 
________________________ [name of center] Institutional Review Board (a group of people 
who review the research to protect your rights) at __________________ (telephone number).
[Note to Local Investigator: Contact information for patient representatives or other 
individuals in a local institution who are not on the IRB or research team but take calls 
regarding clinical trial questions can be listed here.]   
*You may also call the Operations Office of the NCI Central Institutional Review Board (CIRB) 
at 888-657-3711 (from the continental US only).   [*Only applies to sites using the CIRB.]
 
 


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Please note:  This section of the informed consent form is about additional 
research studies that are being done with people who are taking part in the main 
study.   You may take part in these additional studies if you want to.  You can still 
be a part of the main study even if you say 'no' to taking part in any of these 
additional studies.
You can say "yes" or "no" to each of the following studies.  Please mark your 
choice for each study.  
1.
Future Contact
I agree to allow my study doctor, or someone approved by my study doctor, to 
contact me regarding future research involving my participation in this study. 
Yes
No
2.
Banking of specimens for future research 
[The following example of tissue consent has been taken from the NCI Cancer Diagnosis 
Program’s model tissue consent form found at the following url       
http://www.cancerdiagnosis.nci.nih.gov/specimens/model.pdf ]
[Note to investigators:  This section is applicable only to CALGB and ECOG 
institutions.] (sentence added 3/25/10)
About Using Bone Marrow and/or Peripheral Blood for Research 
If you participate in this study, your doctor will remove some blood and bone marrow 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. As described above, some of your bone marrow will be used for 
research that is part of this study.
We would like to keep some of the blood and/or bone marrow that is left over for future 
research. If you agree, this blood and/or bone marrow will be kept and may be used in 
research to learn more about cancer and other diseases. Please read the information sheet 
called "How are Specimens Used for Research?" to learn more about tissue research. 
The research that may be done with your blood and/or bone marrow is not designed 
specifically to help you. It might help people who have cancer and other diseases in the 
future. 
Reports about research done with your blood and/or bone marrow will not be given to 
you or your doctor. These reports will not be put in your health record. The research will 
not have an effect on your care. 
Things to Think About 
The choice to let us keep the left over blood and/or bone marrow for future research is up 
to you. No matter what you decide to do, it will not affect your care. 
 
 


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If you decide now that your blood and/or bone marrow can be kept for research, you can 
change your mind at any time. Just contact us and let us know that you do not want us to 
use your blood and/or bone marrow. Then any blood and/or bone marrow that remains 
will no longer be used for research. 
In the future, people who do research may need to know more about your health. While 
the Southwest Oncology Group may give them reports about your health, it will not give 
them your name, address, phone number, or any other information that will let the 
researchers know who you are. 
Sometimes blood and/or bone marrow is used for genetic research (about diseases that are 
passed on in families). Even if your blood and/or bone marrow is used for this kind of 
research, the results will not be put in your health records. 
Your blood and/or bone marrow will be used only for research and will not be sold. The 
research done with your tissue may help to develop new products in the future. 
Benefits
The benefits of research using blood and/or bone marrow include learning more about 
what causes cancer and other diseases, how to prevent them, and how to treat them. 
Risks 
The greatest risk to you is the release of information from your health records. We will do 
our best to make sure that your personal information will be kept private. The chance 
that this information will be given to someone else is very small. 
Making Your Choice 
Please read each sentence below and think about your choice. After reading each 
sentence, circle "Yes" or "No."  If you have any questions, please talk to your doctor or 
nurse, or call our research review board at IRB's phone number. 
No matter what you decide to do, it will not affect your care.
1.
My specimens may be kept for use in research to learn about, prevent, treat 
or cure cancer.
Yes
No
2.
My specimens may be kept for use in research about other health problems 
(for example: diabetes, Alzheimer's disease, or heart disease). 
Yes
No
3.
Someone may contact me in the future to ask me to allow other uses of my 
specimens.
Yes
No
 
 


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Revised 3/25/10
(section deleted 3/25/10)
[For patients participating through ECOG use the following]  (section added 5/30/08)
If you decide to withdraw your specimens from an Eastern Cooperative Oncology 
Group Repository in the future, a written withdrawal of consent should be submitted 
through your treating physician to the Eastern Cooperative Oncology Group 
Coordinating Center.  Upon withdrawal of consent, your specimens will not be 
considered for use in any future research projects.
Where can I get more information?
You may call the National Cancer Institute's Cancer Information Service at: 
1-800-4-CANCER (1-800-422-6237) or TTY: 1-800-332-8615
You may also visit the NCI Web site at http://cancer.gov/
x
For NCI’s clinical trials information, go to: http://cancer.gov/clinicaltrials/
x
For NCI’s general information about cancer, go to http://cancer.gov/cancerinfo/
You will get a copy of this form.    If you want more information about this study, ask your study 
doctor.
Signature
I have been given a copy of all _____ [insert total of number of pages] 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 ________________________________
Date _____________________________________
 
 


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Specimen Consent Supplemental Sheets
How are Specimens Used for Research?
Where do specimens come from?
A specimen may be from a blood sample or from bone marrow, skin, toenails or other body materials.  
People who are trained to handle specimens and protect donors' rights make sure that the highest 
standards of quality control are followed by the Southwest Oncology Group.  Your doctor does not work for 
the Southwest Oncology Group, but has agreed to help collect specimens from many patients.  Many 
doctors across the country are helping in the same way.  
Why do people do research with specimens?
Research with specimens can help to find out more about what causes cancer, how to prevent it, how to 
treat it, and how to cure it.  Research using specimens can also answer other health questions.  Some of 
these include finding the causes of diabetes and heart disease, or finding genetic links to Alzheimer's.
What type of research will be done with my specimen?
Many different kinds of studies use specimens.  Some researchers may develop new tests to find 
diseases.  Others may develop new ways to treat or even cure diseases.  In the future, some of the 
research may help to develop new products, such as tests and drugs.  Some research looks at diseases 
that are passed on in families (called genetic research).  Research done with your specimen may look for 
genetic causes and signs of disease.
How do researchers get the specimen?
Researchers from universities, hospitals, and other health organizations conduct research using 
specimens.  They contact the Southwest Oncology Group and request samples for their studies.  The 
Southwest Oncology Group reviews the way that these studies will be done, and decides if any of the 
samples can be used. The Southwest Oncology Group gets the specimen and information about you from 
your hospital, and sends the specimen samples and some information about you to the researcher.  The 
Southwest Oncology Group will not send your name, address, phone number, social security number or 
any other identifying information to the researcher.
Will I find out the results of the research using my specimen?
You will not receive the results of research done with your specimen.  This is because research can take a 
long time and must use specimen samples from many people before results are known.  Results from 
research using your specimen may not be ready for many years and will not affect your care right now, but 
they may be helpful to people like you in the future.
Why do you need information from my health records?
In order to do research with your specimen, researchers may need to know some things about you.  (For 
example:  Are you male or female?  What is your race or ethnic group? How old are you?  Have you ever 
smoked?)  This helps researchers answer questions about diseases.  The information that will be given to 
the researcher may include your age, sex, race, diagnosis, treatments and family history.  This information 
is collected by your hospital from your health record and sent to the Southwest Oncology Group.  If more 
information is needed, the Southwest Oncology Group will send it to the researcher.
Will my name be attached to the records that are given to the researcher?
No.  Your name, address, phone number and anything else that could identify you will be removed before 
they go the researcher.  The researcher will not know who you are.
 
 


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Revised 4/25/13
How could the records be used in ways that might be harmful to me?
Sometimes, health records have been used against patients and their families.  For example, insurance 
companies may deny a patient insurance or employers may not hire someone with a certain illness (such 
as AIDS or cancer).  The results of genetic research may not apply only to you, but to your family 
members too.  For disease caused by gene changes, the information in one person's health record could 
be used against family members.
How am I protected?
The Southwest Oncology Group is in charge of making sure that information about you is kept private.  
The Southwest Oncology Group will take careful steps to prevent misuse of records.  Your name, 
address, phone number and any other identifying information will be taken off anything associated with 
your specimen before it is given to the researcher.  This would make it very difficult for any research 
results to be linked to you or your family.  Also, people outside the research process will not have access 
to results about any one person which will help to protect your privacy.
Where will my specimens be kept?
Your blood and/or bone marrow will be kept at:
(deleted 4/25/13)
[For patients participating through ECOG use the following]  (section and addresses added 5/30/08)
Elisabeth Paietta, Ph.D.
Mayo Clinic Cytogenetics Laboratory
Our Lady of Mercy Cancer Center
970 Hilton
600 East 233rd Street
OR
200 First Street, S.W. 
6th Floor, Immunology Laboratory
Rochester, MN 55905
Bronx, NY 10466-2697
Tel: 507/284-2950
Tel: 718/920-9992
FAX: 507/284-0043
What if I have more questions?
If you have any questions, please talk to your doctor or nurse, or call our research review board at (Insert 
IRB's Phone Number).