SJCRH NCT00703820 (AML08) Initial version, dated: 04/03/2008, Submitted to CPSRMC 04/07/08. Resubmitted: 4/25/08 and 5/13/2008. Resubmitted to IRB 5/28/2008 and June 12, 2008. (IRB Approved: June 14, 2008) Activation Date: August 1, 2008 Amendment 1.0, dated: August 28, 2008 (IRB Approved: September 23, 2008) Amendment 2.0, dated: December 24, 2008 (IRB Approved: February 13, 2009) Amendment 3.0, dated: June 26, 2009 (IRB Approved: August 11, 2009). Activated: August 17, 2009 Amendment 4.0, dated: January 21, 2010 (IRB approved: March 11, 2010). Activated: March 19, 2010 Revision 4.1, dated April 13, 2010 (IRB approved: April 27, 2010). Activated: May 12, 2010 Revision 4.2, dated May 17, 2010 (IRB approved: June 1, 2010). Activated: June 7, 2010 Letter of Amendment #1: Deletion of Mylotarg, dated June 22, 2010 (IRB Approved: June 23, 2010). Activated: July 12, 2010 Amendment 5.0, dated July 8, 2010 (IRB Approved: August 26, 2010). Activated: August 31, 2010 Amendment 6.0, dated April 05, 2011(IRB Approved: May 26, 2011). Activated: June 8, 2011 Amendment 7.0, dated August 22, 2011(IRB Approved: October 3, 2011). Revision 7.1, dated October 05, 2011 (IRB Approved: October 24, 2011) Revision 7.2, dated February 01, 2012 (IRB Approved: February 8, 2012). Activated: March 1, 2012 Amendment 8.0, dated October 1, 2012 (IRB Approved: January 18, 2013) Activated: M arch 6, 2013 Revision 8.1, dated March 15, 2013 (IRB approved March 21, 2013) Activated: March 27, 2013 Amendment 9.0, dated June 13, 2013. Resubmitted to IRB July 12, 2013 (IRB approved: July 15, 2013). Revision 9.1, dated July 18, 2013. (IRB approved: July 19, 2013) Activated: August 28, 2013 Amendment 10.0: February 10, 2014. (IRB approved: February 12, 2014) Activated: February 18, 2014 Letter of Amendment #4, dated May 29, 2015 (IRB approved: May 29, 2015) Activated: June 1, 2015 Revision 10.1: June 2, 2016. (IRB approved: June 7, 2016) Activated: July 5, 2016 AML08: A PHASE III RANDOMIZED TRIAL OF CLOFARABINE PLUS CYTARABINE VERSUS CONVENTIONAL INDUCTION THERAPY AND A PHASE II STUDY OF NATURAL KILLER CELL TRANSPLANTATION IN PATIENTS WITH NEWLY DIAGNOSED ACUTE MYELOID LEUKEMIA Principal Investigator Jeffrey E. Rubnitz, MD, PhD1 Other St. Jude Investigators James Downing, MD3 Stanley Pounds, PhD4 Aditya Gaur, MD, MBBS5 Ching-Hon Pui, MD1 Randall Hayden, MD3 Susana Raimondi, PhD3 Hiroto Inaba, MD, PhD1 Raul Ribeiro, MD1 John Choi, MD, PhD3 Brandon Triplett, MD2 Sima Jeha, MD1 St. Jude Children's Research Hospital 262 Danny Thomas Place Memphis, Tennessee 38105-2794 Telephone: (901) 595-3300 Additional contact information for St. Jude Principal Investigator: Office: 901-595-2388, Page operator: 901-595-3300 Pager: 901-595-3578, #0713, Cell phone: 901-216-1878 FAX: 901-521-9005, Email: [email protected] Departments of 1Oncology, 2Bone marrow Transplant & Cellular Therapy, 3Pathology, 4Biostatistics, 5Infectious Diseases Contents of this document may not be extracted without permission from the Principal Investigator. Revision 10.1, dated: 06-02-2016 IRB Approval date: 06-07-2016 Protocol document date: 06-02-2016 External Co-Investigators (Collaborating Institutions): Stanford University Medical Center Children’s Hospital of Michigan Pediatric Hematology/Oncology 3901 Beaubien Blvd. Packard Children’s Hospital Detroit, MI 48201 725 Welch Road Jeffrey Taub, MD Palo Alto, CA 94304 Gary Dahl, MD Dana-Farber Cancer Institute and Norman Lacayo, MD Children’s Hospital, Boston Pediatric Oncology Cook Children’s Medical Center 44 Binney Street Hematology/Oncology Boston, MA 02115 901 Seventh Avenue Barbara Degar, MD Suite 220 Fort Worth, TX 76104 Paul Bowman, MD Ken Heym, M.D. University of Chicago National University Health System, Pediatric Hematology/Oncology MC4060 Singapore University of Chicago Paediatric Hematology/Oncology/BMT 5841 S. Maryland Avenue University Children's Medical Institute Chicago, IL 60637 5 Lower Kent Ridge Road Singapore 119074 John Cunningham, M.D. Republic of Singapore Rady Children’s Hospital San Diego Allen Eng-Juh Yeoh, M.D. 3020 Children’s Way San Diego, CA 92123 Deborah E. Schiff, M.D. External Scientific Collaborators National University of Singapore Dario Campana, MD, PhD Elaine Coustan-Smith, MSc Revision 10.1, dated: 06-02-2016 IRB Approval date: 06-07-2016 Protocol document date: 06-02-2016 AML08: A PHASE III RANDOMIZED TRIAL OF CLOFARABINE PLUS CYTARABINE VERSUS CONVENTIONAL INDUCTION THERAPY AND A PHASE II STUDY OF NATURAL KILLER CELL TRANSPLANTATION IN PATIENTS WITH NEWLY DIAGNOSED ACUTE MYELOID LEUKEMIA Letter of Amendment January 9, 2014 This letter is being sent as clarification that collaborating sites may choose to not participate in the vorinostat exploratory objective of this study, as proposed with amendment 9.0. If the decision is made that a site will opt out, then all applicable patients at that site will receive standard therapy for Induction II with LD-ADE alone. Since this objective is exploratory and does not require a specific number of patients, this will not adversely affect the study analyses. This information will be forthcoming with the next protocol amendment; however, sites may choose to opt out at any time. Revision 10.1, dated: 06-02-2016 IRB Approval date: 06-07-2016 Protocol document date: 06-02-2016 AML08: A PHASE III RANDOMIZED TRIAL OF CLOFARABINE PLUS CYTARABINE VERSUS CONVENTIONAL INDUCTION THERAPY AND A PHASE II STUDY OF NATURAL KILLER CELL TRANSPLANTATION IN PATIENTS WITH NEWLY DIAGNOSED ACUTE MYELOID LEUKEMIA Letter of Amendment November 20, 2013 Rationale This letter is being sent as clarification that if Erwinia asparaginase is given (see Section 4.5 of protocol), it may be administered according to local institutional guidelines, either IV or IM. Currently, the protocol and consent state IV administration. These will be revised to IV or IM with the next protocol amendment. Collaborating sites may follow local administration guidelines for the administration of this commercially available agent. The following St. Jude guidelines may be used, but are not required: Administration For IV administration, Erwinia asparaginase will be diluted in 50 mL NS to infuse over 30 minutes to 1 hour via syringe. Erwinia asparaginase should be administered to run concurrently with IVF. (NS at TKO is sufficient.) Erwinia asparaginase should be administered at least 2 hours after an LP/IT since some cases of over sedation were reported when given “simultaneously” with sedation and/or an LP/IT at other institutions. Further, it is desirable to avoid asparaginase directly before an IT because asparaginase could possibly interfere with the efficacy of methotrexate. Erwinia asparaginase may also be administered IM. Monitoring and concerns for anaphylaxis Obtain vital signs pre infusion, and then remain at the patient’s bedside for the first 5 minutes. Visually observe the patient at 10 minutes, and directly observe and obtain vital signs at 15 minutes and at the end of the infusion. Repeat vital signs at discharge. Patients must remain in Revision 10.1, dated: 06-02-2016 IRB Approval date: 06-07-2016 Protocol document date: 06-02-2016 the Medicine Room for 1 hour after administration to be observed for adverse effects. Keep NS at TKO during the 1 hour post watch time unless otherwise ordered. To prepare for anaphylaxis: Have oxygen, suction and pulse oximetry at bedside during and after infusion Have readily available* the following medications: o Diphenhydramine 1 mg/kg (max 50 mg) for IV administration o Epinephrine (1:1000) 0.01 mL/kg (max 0.3 mL) for SQ administration o Hydrocortisone 100 mg/m2 for IV administration o NS for IV administration *Readily available means in the general area – such as the emergency medication box in the medicine room or inpatient areas. Revision 10.1, dated: 06-02-2016 IRB Approval date: 06-07-2016 Protocol document date: 06-02-2016 Revision 10.1, dated: 06-02-2016 IRB Approval date: 06-07-2016 Protocol document date: 06-02-2016 Table of Contents 1.0 OBJECTIVES ......................................................................................................... 1 1.1 Primary objective ................................................................................................ 1 1.2 Secondary objective ............................................................................................ 1 2.0 BACKGROUND AND RATIONALE ................................................................... 2 2.1 Background and rationale for therapy................................................................. 2 2.2 Background and rationale for correlative and biologic studies ........................ 20 3.0 ELIGIBILITY CRITERIA AND STUDY ENROLLMENT ............................... 27 3.1 Diagnostic criteria ............................................................................................. 27 3.2 Inclusion criteria – all participants .................................................................... 28 3.3 Exclusion criteria – all participants................................................................... 28 3.4 Criteria for randomization................................................................................. 28 3.5 Enrollment on study .......................................................................................... 29 4.0 TREATMENT PLAN ........................................................................................... 29 4.1 General overview .............................................................................................