Conditions: Acute Myeloid Leukemia Myelodysplastic Syndrome Myelodysplastic Syndrome/Acute Myeloid Leukemia
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 76
Healthy volunteers: no

Brief summary:
This randomized phase II/III trial studies how well azacitidine with or without nivolumab or midostaurin, or decitabine and cytarabine alone work in treating older patients with newly diagnosed acute myeloid leukemia or high-risk myelodysplastic syndrome. Drugs used in chemotherapy, such as azacitidine, decitabine, and cytarabine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Midostaurin may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving azacitidine with or without nivolumab or midostaurin, or decitabine and cytarabine alone may kill more cancer cells.

Detailed description:
PRIMARY OBJECTIVES:

I. To select, based on overall survival, any or all of the "Novel Therapeutic" regimens for further testing against azacitidine in patients age 60 and older with newly diagnosed acute myeloid leukemia (AML) or myelodysplastic syndrome with excessive blasts-2 (MDS-EB-2). (Phase II) II. To compare overall survival of the "Novel Therapeutic" regimens selected in the phase II portion of the trial to azacitidine in these patient populations. (Phase III)

SECONDARY OBJECTIVES:

I. To estimate the frequency and severity of toxicities of the regimens in these patient populations.

II. To estimate response rates, event-free survival, and relapse-free survival for these regimens in these patient populations.

TERTIARY OBJECTIVES:

I. To investigate associations between cytogenetic and molecular abnormalities (including FLT3) and outcomes for each of the regimens in these patient populations.

II. To bank specimens for future correlative studies.

OUTLINE: Patients are randomized to 1 of 4 arms.

ARM A: Patients receive azacitidine subcutaneously (SC) or intravenously (IV) daily on days 1-7 or on an interrupted schedule which ensures that all 7 days of therapy are received within a 12 day period. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

ARM B: Patients receive azacitidine as in Arm A and nivolumab IV over 30-60 minutes on days 1 and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

ARM C: Patients receive azacitidine as in Arm A and midostaurin orally (PO) twice daily (BID) on days 8-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

ARM D:

INDUCTION: Patients receive decitabine IV over 2 hours on days 1-5 and cytarabine IV continuously on days 6-11. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity.

MAINTENANCE: Patients deemed stable at the discretion of the treating physician receive decitabine as in Induction. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for the 1st year, every 6 months for the 2nd and 3rd years, then annually until 5 years after randomization.

Arms:
arm 1: Patients receive azacitidine SC or IV daily on days 1-7 or on an interrupted schedule which ensures that all 7 days of therapy are received within a 12 day period. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. arm 2: Patients receive azacitidine as in Arm A and nivolumab IV over 30-60 minutes on days 1 and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. arm 3: Patients receive azacitidine as in Arm A and midostaurin orally (PO) twice daily (BID) on days 8-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. arm 4: INDUCTION: Patients receive decitabine IV over 2 hours on days 1-5 and cytarabine IV continuously on days 6-11. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity.

MAINTENANCE: Patients deemed stable at the discretion of the treating physician receive decitabine as in Induction. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Interventions: intervention 1: Azacitidine intervention 2: Cytarabine intervention 3: Decitabine intervention 4: Laboratory Biomarker Analysis intervention 5: Midostaurin intervention 6: Nivolumab
Intervention descriptions: intervention 1: Given SC or IV intervention 2: Given IV intervention 3: Given IV intervention 4: Correlative studies intervention 5: Given PO intervention 6: Given IV

Protocol document:
Prot_SAP_000.pdf: 
Version Date: November 16, 2021
TO:
ALL NATIONAL CANCER CLINICAL TRIALS NETWORK (NCTN) MEMBERS; CTSU 
FROM:
SWOG Operations Office
RE:
S1612, “A RANDOMIZED PHASE II/III TRIAL OF “NOVEL THERAPEUTICS” VERSUS 
AZACITIDINE IN NEWLY DIAGNOSED PATIENTS WITH ACUTE MYELOID LEUKEMIA (AML) 
OR HIGH-RISK MYELODYSPLASTIC SYNDROME (MDS), AGE 60 OR OLDER”
REVISION #4
Study Chair: Laura C. Michaelis, M.D.
Phone number: 414/805-1118
E-mail: lmichaelis@mcw.edu
IRB Review Requirements
( √) 
No review required
Protocol Changes
( √)
Other: Addition of translational medicine objective 
REVISION #4
The primary purpose of this revision is to add translational medicine related to the use of duplex sequencing to determine 
measurable residual disease (MRD) in AML patients through the use of retrospective specimens collected on S1612.This 
work is funded through an approved BIQSFP proposal.
Protocol Changes
1. 
The version date of the protocol has been updated.
2. 
Table of Contents: The Table of Contents has been updated.
3. 
Section 1.4: This section has been added to include the additional translational medicine objective related to the 
use of duplex sequencing to determine measurable residual disease. A reference to Appendix 18.5 has been 
added.
4. 
Section 18.0: The new section for the translational medicine study has been added to the appendix list. The 
corresponding pages have been added to the appendix section.
Model Consent Form Changes
1. 
The version date has been updated. No other changes have been made to the consent.
This study has been reviewed and approved by the NCI’s Central Institutional Review Board (CIRB).
This memorandum serves to notify the NCI and the SWOG Statistics and Data Management Center.
cc: PROTOCOL AND INFORMATION OFFICE


S1612 
Page 1
Version Date: 
11/16/21 
 
 
PRIVILEGED COMMUNICATION 
FOR INVESTIGATIONAL USE ONLY 
 
SWOG 
 
TITLE 
A RANDOMIZED PHASE II/III TRIAL OF “NOVEL THERAPEUTICS” VERSUS AZACITIDINE IN 
NEWLY DIAGNOSED PATIENTS WITH ACUTE MYELOID LEUKEMIA (AML) OR HIGH-RISK 
MYELODYSPLASTIC SYNDROME (MDS), AGE 60 OR OLDER 
 
LEAP: LESS-INTENSE AML PLATFORM TRIAL 
NCT#TBD 
 
 
STUDY CHAIRS: 
AGENTS: 
 
Arm A (Azacitidine) and 
Commercially Available Agents: 
Arm C (Azacitidine + Midostaurin): 
Azacitidine (Vidaza®) (NSC-102816) 
Laura C. Michaelis, M.D. 
Cytarabine (AraC, Cytosine Arabinoside) 
(Medical Oncology) 
 
(NSC-63878) 
Medical College of Wisconsin 
Decitabine (NSC-127716) 
Froedtert Medical Center 
9200 W. Wisconsin Ave. 
NCI Supplied Investigational Agents: 
Milwaukee, WI 53226 
Midostaurin (NSC-656576) 
Nivolumab (BMS-936558, MDX1106, Optivo®) 
Roland B. Walter, M.D., Ph.D., M.S. 
(NSC-748726) 
(Medical Oncology) 
Fred Hutchinson Cancer Research Center 
TRANSLATIONAL MEDICINE: 
Clinical Research Division 
Jerald P. Radich, M.D. 
1100 Fairview Ave. N., D2-190 
Fred Hutchinson Cancer Research Center 
Seattle, WA 98109 
1100 Fairview Ave. N., D4-100 
Seattle, WA 98109 
S1612A@swog.org 
S1612C@swog.org 
CYTOGENETICS: 
Min Fang, M.D., Ph.D. 
Arm B (Azacitidine + Nivolumab): 
Fred Hutchinson Cancer Research Center 
Sarit Assouline, M.D.C.M., M.Sc., F.R.C.P.C. 
825 Eastlake Ave E, M/S G7-500  
(Medical Oncology) 
Seattle, WA 98109 
McGill University – Jewish General Hospital 
BIOSTATISTICIANS: 
Annette Hay, M.B., Ch.B. (Hematology) 
Megan Othus, Ph.D. (Biostatistics) 
Canadian Cancer Trials Group 
Anna Moseley, M.S. (Biostatistics) 
Queen’s University 
SWOG Statistical Center 
Fred Hutchinson Cancer Research Center 
1100 Fairview Ave. N., M3-C102 
E-mail: S1612B@swog.org 
P.O. Box 19024 
Seattle, WA 98109-1024 
Arm D (Decitabine + Cytarabine): 
Annie Im, M.D. (Medical Oncology) 
University of Pittsburgh Cancer Institute 
UPMC Cancer Centers 
 
James Foran, M.D. (Medical Oncology 
Mayo Clinic 
E-mail: S1612D@swog.org 


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


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TABLE OF CONTENTS
TITLE................................................................................................................................................................ 1
PARTICIPANTS............................................................................................................................................... 2
TABLE OF CONTENTS .................................................................................................................................. 3
CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION........................ 5
SCHEMA.......................................................................................................................................................... 6
1.0
OBJECTIVES ..................................................................................................................................... 7
1.1
Primary Objectives.............................................................................................................................. 7
1.2
Secondary Objectives......................................................................................................................... 7
1.3
Additional Objectives .......................................................................................................................... 7
2.0
BACKGROUND.................................................................................................................................. 7
2.1
General ............................................................................................................................................... 7
2.2
Arm A ...............................................................................................................................................8
2.3
Arm B ...............................................................................................................................................8
2.4
Arm C ...............................................................................................................................................8
2.5
Arm D ...............................................................................................................................................9
2.6
Inclusion of Women and Minorities.............................................................................................. 10
2.7
Accrual Targets................................................................................................................................. 10
3.0
DRUG INFORMATION..................................................................................................................... 11
4.0
STAGING CRITERIA ....................................................................................................................... 38
4.1
Diagnostic Criteria............................................................................................................................. 38
4.2
Staging Criteria ................................................................................................................................. 38
5.0
ELIGIBILITY CRITERIA................................................................................................................... 38
5.1
Registration Step 1 – Specimen Submission................................................................................... 38
5.2
Registration Step 2 – Randomization............................................................................................... 39
5.3
Treatment Arm Specific Eligibility Criteria for Active Treatment Arms............................................. 41
6.0
STRATIFICATION FACTORS ......................................................................................................... 42
7.0
TREATMENT PLAN......................................................................................................................... 42
7.1
Treatment.......................................................................................................................................... 42
7.2
Concomitant Therapies..................................................................................................................... 45
7.3
General Supportive Care Guidelines................................................................................................ 46
7.4
Criteria for Removal from Protocol Treatment ................................................................................. 47
7.5
Discontinuation of Treatment............................................................................................................ 47
7.6
Follow-Up Period .............................................................................................................................. 47
8.0
TOXICITIES TO BE MONITORED AND DOSE MODIFICATIONS................................................ 47
8.1
NCI Common Terminology Criteria for Adverse Events .................................................................. 47
8.2
Toxicity Monitoring and Dose Modification Information ................................................................... 47
8.3
Adverse Event Reporting.................................................................................................................. 63
9.0
STUDY CALENDARS...................................................................................................................... 63
9.1
STUDY CALENDAR – ARM A: AZACITIDINE (CONTROL).......................................................... 64
9.2
STUDY CALENDAR – ARM B: AZACITIDINE + NIVOLUMAB...................................................... 65
9.3
STUDY CALENDAR – ARM C – AZACITIDINE + MIDOSTAURIN ................................................ 66
9.4
STUDY CALENDAR – ARM D: DECITABINE + CYTARABINE ..................................................... 67
10.0
CRITERIA FOR EVALUATION AND ENDPOINT ANALYSIS....................................................... 68
10.1
Remission Definitions ().................................................................................................................... 68
10.2
Assessment of Transfusion Dependency, Hemoglobin, and Platelet Counts................................. 68
10.3
Hematologic Improvement (HI)......................................................................................................... 69
10.4
Cytogenetic Response...................................................................................................................... 70
10.5
Disease Progression......................................................................................................................... 70
10.6
Time-to-Event Outcomes.................................................................................................................. 70
10.7
Performance Status .......................................................................................................................... 71
11.0
STATISTICAL CONSIDERATIONS ................................................................................................ 71
11.1
Sample Size and Accrual.................................................................................................................. 71
11.2
Design and Analyses Assumptions and Parameters....................................................................... 71
11.3
Phase II Analyses ............................................................................................................................. 72
11.4
Phase III Analyses ............................................................................................................................ 72
11.5
Analysis of Other Endpoints ............................................................................................................. 73


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11.6
Data and Safety Monitoring Committee ........................................................................................... 74
12.0
DISCIPLINE REVIEW ...................................................................................................................... 74
13.0
REGISTRATION GUIDELINES ....................................................................................................... 75
13.1
Registration Timing........................................................................................................................... 75
13.2
Investigator/Site Registration............................................................................................................ 75
13.3
OPEN Registration Requirements.................................................................................................... 77
13.4
Registration Procedures ................................................................................................................... 78
13.5
Exceptions to SWOG registration policies will not be permitted...................................................... 79
14.0
DATA SUBMISSION SCHEDULE................................................................................................... 79
14.1
Data Submission Requirements....................................................................................................... 79
14.2
Master Forms.................................................................................................................................... 79
14.3
Data Submission Procedures........................................................................................................... 79
14.4
Data Submission Overview and Timepoints .................................................................................... 80
15.0
SPECIAL INSTRUCTIONS.............................................................................................................. 82
15.1
SWOG Specimen Tracking System (STS)....................................................................................... 82
15.2
FLT3 Testing (REQUIRED) .............................................................................................................. 83
15.3
Translational Medicine and Banking (Optional for Patient – Required if Patient Consents)........... 84
15.4
Cytogenetics and FISH (REQUIRED).............................................................................................. 84
16.0
ETHICAL AND REGULATORY CONSIDERATIONS..................................................................... 85
16.1
Adverse Event Reporting Requirements.......................................................................................... 87
17.0
BIBLIOGRAPHY .............................................................................................................................. 92
18.0
APPENDIX........................................................................................................................................ 94
18.1
Midostaurin Patient Drug Information Handout and Wallet Card..................................................... 95
18.2
Drugs Known to be Metabolized by CYP450 Isoenzymes 2D6 and 3A4........................................ 97
18.3
Management Algorithms for Immuno-Oncology (I-O) Therapy for Endocrinopathy,
Gastrointestinal, Hepatic, Neurological, Pulmonary, Renal and Skin Adverse Events for
Nivolumab (Arm B) Adverse Event Management .......................................................................... 101
18.4
Drugs Known to be Metabolized by CYP450 Isoenzymes 2D6 and 3A4...................................... 109
18.5
Translational Medicine – Duplex Sequencing for Determining Measurable Residual Disease….113


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CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION
CONTACT INFORMATION
For regulatory requirements:
For patient enrollments:
For study data submission:
Regulatory documentation must
be submitted to the CTSU via
the Regulatory Submission
Portal:
Regulatory Submission Portal
(Sign in at www.ctsu.org, and
select the Regulatory
Submission sub-tab under the
Regulatory tab.)
Institutions with patients waiting
that are unable to use the Portal
should alert the CTSU
Regulatory Office immediately
at 866-651-2878 to receive
further information and support.
Contact the CTSU Regulatory
Help Desk at 866-651-2878 for
regulatory assistance.
Please refer to the patient
enrollment section of the protocol
for instructions on using the
Oncology Patient Enrollment
Network (OPEN) which can be
accessed at
https://www.ctsu.org/OPEN_SYS
TEM/ or https://OPEN.ctsu.org.
Contact the CTSU Help Desk with
any OPEN-related questions at
ctsucontact@westat.com.
Data collection for this study will
be done exclusively through
Medidata Rave. Please see the
data submission section of the
protocol for further instructions.
Other Tools and Reports:
Institutions participating through
the CTSU continue to have
access to other tools and reports
available on the SWOG
Workbench. Access this by
using your active CTEP-IAM
userid and password at the
following url:
https://crawb.crab.org/TXWB/cts
ulogon.aspx
The most current version of the study protocol and all supporting documents must be downloaded
from the protocol-specific Web page of the CTSU Member Web site located at https://www.ctsu.org.
Access to the CTSU members’ website is managed through the Cancer Therapy and Evaluation
Program - Identity and Access Management (CTEP-IAM) registration system and requires user log on
with CTEP-IAM username and password. Permission to view and download this protocol and its
supporting documents is restricted and is based on person and site roster assignment housed in the
CTSU RSS.
For patient eligibility or data submission questions contact the SWOG Data Operations Center by
phone or e-mail:
206/652-2267
leukemiaquestion@crab.org
For treatment or toxicity related questions contact the appropriate Study Chair(s) by phone or e-mail.
Study Chair information can be found on the title page.
For non-clinical questions (i.e. unrelated to patient eligibility, treatment, or clinical 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 Website is located at https://www.ctsu.org.


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SCHEMA
Results Received by SWOG a
a
Notification that FLT3 specimens have been processed will be provided via e-mail when FLT3
results are available for stratification purposes; receipt of this e-mail is an eligibility requirement
for Step 2 (randomization).
b
Arm D will open to accrual when Arms B and C have met Phase II accrual and are temporarily
closed for Phase II analysis.
c
Patients will be followed for 5 years after randomization.
Registration Step 1
Submission of Specimens for FLT3 Testing
Registration to Step 2
Randomization to Treatment
Arm A (control)
Azacitidine
Arm B 
Azacitidine +
Nivolumab
Arm C 
Azacitidine +
Midostaurin
Arm D b
Decitabine /
Cytarabine
Continue Therapy until one of the treatment arm-
specific criteria for removal from protocol therapy is met
(see Section 7.4).
Off Treatment c


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1.0
OBJECTIVES
1.1
Primary Objectives
a.
Phase II Component: To select, based on overall survival, any or all of the “Novel
Therapeutic” regimens for further testing against azacitidine in patients age 60 and
older with newly diagnosed acute myeloid leukemia (AML) or myelodysplastic
syndrome with excessive blasts-2 (MDS-EB-2).
b.
Phase III Component: To compare overall survival of the “Novel Therapeutic”
regimens selected in the Phase II portion of the trial to azacitidine in these patient
populations.
1.2
Secondary Objectives
a.
To estimate the frequency and severity of toxicities of the regimens in these patient
populations.
b.
To estimate response rates, event-free survival, and relapse-free survival for these
regimens in these patient populations.
1.3
Additional Objectives
a.
To investigate associations between cytogenetic and molecular abnormalities
(including FLT3) and outcomes for each of the regimens in these patient
populations.
b.
To bank specimens for future correlative studies.
1.4
Additional Translational Medicine Objectives Related to
Duplex Sequencing for 
Determining Measurable Residual Disease
a.
To perform duplex sequencing (DS) and to test it against flow cytometry in patients 
treated under S0106 (see Appendix 18.5)
2.0
BACKGROUND
2.1
General
Acute myeloid leukemia (AML) primarily affects older adults, for whom outcomes have not
substantially improved over the last several decades. Outside of clinical trials, this patient
population commonly receives monotherapy with a DNA-methyltransferase inhibitor such
as azacitidine or decitabine. However, this treatment option is associated with low
response rates and only modest improvements in overall survival relative to supportive
care alone. The need for new therapies is thus unquestioned. Since the modern era of
drug development brings a rapidly increasing number of novel therapeutics into the clinic,
timely identification of beneficial therapies has never been as important as today.
To this end, a randomized Phase II/III trial platform, similar to the United Kingdom’s Medical
Research Council/National Cancer Research Institute (MRC/NCRI) trial, will be conducted
for this AML patient population. (1) The trial is not designed as a “pick-the-winner” trial,
but is intended to serve as a versatile drug-testing study that allows a randomized
comparison between a novel therapy and the control (but not between individual novel
therapies), with a design allowing for accrual to one or more experimental arms at any
given time, and the possibility of subsequent addition of new experimental arms and/or
permanent closure of existing experimental arms based on interim results.


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The initial control arm will be azacitidine monotherapy because of its widespread use and 
general acceptance in the United States as a treatment regimen for patients who are 
considered unfit for conventional intensive induction chemotherapy. If another regimen is 
determined to have improved overall survival (OS) compared to azacitidine, the study will 
be modified and the control arm replaced. 


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2.2
Arm A
The initial control arm will be azacitidine monotherapy. In a Phase II study of azacitidine
(with or without valproic acid or all-transretinoic acid) in patients with AML (median age, 74
years), the rate of complete remission, CRi, and partial response was 33%, median
response duration was 6.9 months, median OS was 9.4 months, and 2-year OS was 51%.
(2)
In a study published in 2015, involving nearly 500 patients, azacitidine was compared with
other conventional care regimens in a very similar population. Patients with AML older than
age 65 years (median age, 75 years) with either de-novo or secondary AML (over 30%
marrow blasts) were randomly assigned to receive either azacitidine 75 mg/m2/day for 7
days or one of three conventional care regimens: best supportive care, LDAC, or induction
chemotherapy (i.e., daunorubicin and cytarabine). Of the 488 patients enrolled, 18% were
assigned to the best supportive care, and 18% to the intensive chemotherapy arm. Thirty-
five percent of patients had poor-risk cytogenetics and 32% had myelodysplasia-related
changes. There was a trend for an improved median OS in the azacitidine-treated patients
(10.4 vs. 6.5 months), but this did not achieve statistical significance. In a preplanned
sensitivity analysis with censoring for any subsequent AML therapy, however, there did
emerge a statistically significant improvement in OS (12.1 vs. 6.9 months) with a stratified
HR 0.76 (log-rank P = 0.0190). (3)
Additional benefits of this regimen in the target population are a high-level of familiarity with
administration and its ability to be given in the outpatient setting. If another regimen is
determined to have improved OS compared to azacitidine, the study will be modified and
the control arm replaced.
2.3
Arm B
Experimental Arm B will test the combination of nivolumab and azacitidine. There is
increased expression of programmed death (PD)-1 receptor in approximately 40% of
patients with AML, a finding that has been correlated with poor response to azacitidine (2).
Its ligand, PD-L1, is also overexpressed in AML as it is in many solid tumor and other
hematologic malignancies, allowing tumor immune evasion and growth (3). Nivolumab is
a blocking anti-PD antibody that has been widely used in both solid tumors and lymphoid
hematologic malignancies. Therefore, utilizing nivolumab may be a rational strategy to
improving AML cells’ sensitivity to azacitidine. The dosing scheme for the proposed trial is
derived from an ongoing Phase I study of azacitidine 75 mg/m2 daily for 7 days combined
with nivolumab 3 mg/kg every 2 weeks (NCT02397720) that is being conducted at the MD
Anderson Cancer Center (MDACC). Among approximately 20 patients treated to date, no
unanticipated adverse events or dose-limiting toxicities have been observed. Autoimmune
phenomena including pneumonitis, nephritis and skin rash have occurred – typically about
three weeks after treatment initiation – but have responded to steroid therapy, and patients
have been successfully re-challenged with nivolumab while remaining on a low dose of
steroids. (4)
2.4
Arm C
Proposed (Experimental) Arm C will test the combination of azacitidine and midostaurin, a
multi-targeted FMS-like tyrosine kinase 3 receptor (FLT3) kinase inhibitor. Mutations in the
FLT3, either presenting as an internal tandem duplication (ITD) in the juxtamembrane
domain or a point mutation in the activation loop of FLT3, are among the most common
molecular abnormalities found in AML. In particular, for FLT3 ITD abnormalities, numerous
studies have demonstrated adverse prognostic significance. In addition, approximately
80% of AML samples overexpress either FLT3 receptor or FLT3 ligand proteins, which can
confer a proliferative growth signal and aggressive behavior even in the absence of FLT3
ITD mutations. (5) The FLT3 signaling pathway has therefore gained major attention as


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target for small molecule inhibitors. Stone et al. recently reported the final results of a large,
international, randomized study investigating the addition of midostaurin to conventional
induction and post-remission chemotherapy and, subsequently, as maintenance in patients
with newly diagnosed FLT3-mutated AML and found statistically significantly improved
event-free and overall survival in the experimental arm (abstract #6 [plenary session], 2015
annual meeting of the American Society of Hematology). Of note, the magnitude in
outcome improvement with midostaurin was similar in patients with FLT3 point mutations
or ITD and independent of the ITD allelic burden, suggesting that at least part of the
observed benefit was due to effects on kinases other than FLT3. This possibility is
supported by recent studies demonstrating that kinase inhibitors targeting FLT3 can have
efficacy in patients with wildtype FLT3. (6,7) Together, these observations provide the
rationale for the inclusion of patients into this experimental arm regardless of the FLT3
mutational status. Of note, the combination of azacitidine and midostaurin has been tested
in two small, single agent phase I studies. (8,9) Safety has been documented with
azacitidine given in standard dosing combined with midostaurin administered at a dose of
50mg BID beginning on day 8 and continuing until day 21 for a 28-day cycle.
2.5
Arm D
Experimental Arm D is based on a study designed by Dr. Annie Im at the University of
Pittsburgh. Preclinical studies suggest that “epigenetic priming” using decitabine followed
by cytarabine increases the cytotoxicity of cytarabine, possibly due to the reactivation of
genes that have been silenced in AML cells. The treatment scheme will include decitabine
20 mg/m2 intravenously (IV) x 5 days followed by cytarabine 100 mg/m2 continuous IV
infusion x 5 days for 1-2 cycles of induction therapy. This is followed by maintenance with
decitabine monotherapy in patients who achieve a complete or partial remission. Results
from the pilot study of this trial show a 12-month overall survival of 48% (65% 1 year
survival for those achieving CR/CRi, which was 67% of all the patients) with encouraging
responses and minimal toxicities in patients over the age of 70 years and patients with
secondary disease (10).
Strict Biologic Rationale:
In attempts to improve the efficacy of hypomethylating  agents in  AML, combination
strategies based on potential synergistic mechanisms of action have been explored. The
combination of decitabine and cytarabine administered both concurrently and sequentially
has been studied in experiments using human leukemic cell lines. It was shown that the
sequential administration led to synergistic induction of cell death. (11). Specifically, the
cytotoxicity of cytarabine was increased when given after decitabine, and cytarabine
preferentially killed hypomethylated cells. The conclusion was that decitabine-induced
hypomethylation sensitizes leukemia cells to the cytotoxicity of cytarabine, with the
hypothesis that this was likely due to reactivation of genes involved in the mechanism.
There have been small case series and a Phase 1 study evaluating this strategy of
“epigenetic priming” in AML, MDS, and ALL, showing promising efficacy without a signal
of increased toxicity. (12;13;14;15)
There is rationale for sequential as opposed to concurrent administration with this
combination. First, both agents are activated by the same enzyme (deoxycytidine kinase),
and thus competition is avoided with sequential use. In addition, both agents are
incorporated into DNA during the S-phase, again with potential for competition if
administered concurrently. Also, cytarabine leads to cell cycle arrest, and decitabine is
only active during the cell cycle, again limiting availability of the drug with concurrent
administration. Finally, it is well understood that adequate hypomethylation and gene re-
expression require time for multiple DNA replication cycles, and thus sequential
administration allows for more time for adequate epigenetic priming.
NOTE: Experimental Arm D is planned for activation when experimental Arms B and C
have met Phase II accrual and Arms B and C are temporarily closed while the data matures


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for the Phase II analyses. This will allow for the trial to continue to register and randomize
patients even while some arms are temporarily closed.
2.6
Inclusion of Women and Minorities
This study was designed to include women and minorities, but was not designed to
measure differences of intervention effects. The anticipated accrual in the ethnicity/race
and sex categories is shown in the table below.
2.7
Accrual Targets
The tables below present anticipated accrual based on prior SWOG studies S0432, S0703,
and S1117. The tables present anticipated accrual for treatment arms A, B, and C, based
on the Phase III total sample size (334 patients per treatment arm). Due to the dynamic
nature of this trial, investigators expect to accrue more than 334 patients to the control arm,
because only concurrently randomized eligible patients will be used in analyses.
DOMESTIC PLANNED ENROLLMENT REPORT (per treatment arm)
Racial
Categories
Ethnic Categories
Total
Not Hispanic or Latino
Hispanic or Latino
Female
Male
Female
Male
American
Indian/ Alaska
Native
0
0
0
0
0
Asian
15
25
5
0
45
Native
Hawaiian or
Other Pacific
Islander
5
0
0
0
5
Black or
African
American
25
10
0
0
35
White
480
880
5
20
1385
More Than
One Race
0
0
0
0
0
Total
525
915
10
20
1470
INTERNATIONAL (including Canadian participants) PLANNED ENROLLMENT REPORT
Racial
Categories
Ethnic Categories
Total
Not Hispanic or Latino
Hispanic or Latino
Female
Male
Female
Male
American
Indian/ Alaska
Native
0
0
0
0
0
Asian
0
5
0
0
5
Native
Hawaiian or
Other Pacific
Islander
0
0
0
0
0
Black or
African
American
5
0
0
0
5
White
65
120
0
5
190
More Than
One Race
0
0
0
0
0
Total
70
125
0
5
200


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3.0
DRUG INFORMATION
Investigator Brochures
For information regarding Investigator Brochures, please refer to SWOG Policy 15.
For this study azacitidine, cytarabine, and decitabine are commercially available; therefore,
Investigator Brochures are not applicable to these drugs. Information about commercial drugs is
publicly available in the prescribing information and other resources.
For this study, midostaurin and nivolumab are being provided by and IND held by the National
Cancer Institute. The current versions of the Investigator Brochures for these agents will be
accessible to site investigators and research staff through the PMB Online Agent Order Processing
(OAOP) application. Access to OAOP requires the establishment of a CTEP Identity and Access
Management (IAM) account and the maintenance of an “active” account status and a “current”
password. Questions about IB access may be directed to the PMB IB coordinator via e-mail.
3.1
Azacitidine (Vidaza®) (NSC-102816)
a. PHARMACOLOGY
Mechanism of Action: Azacitidine is a pyrimidine nucleoside analog of cytidine.
Azacitidine
is
believed
to
exert
its
antineoplastic
effects
by
causing
hypomethylation of DNA and direct cytotoxicity on abnormal hematopoietic cells in
the bone marrow. The concentration of azacitidine required for maximum inhibition
of DNA methylation in vitro does not cause major suppression of DNA synthesis.
Hypomethylation may restore normal function to genes that are critical for
differentiation and proliferation. The cytotoxic effects of azacitidine cause the death
of rapidly dividing cells, including cancer cells that are no longer responsive to
normal
growth
control
mechanisms.
Non-proliferating
cells
are
relatively
insensitive to azacitidine.
b.
PHARMACOKINETICS
1.
Absorption: The absorption of azacitidine after subcutaneous injection is
rapid with the peak plasma concentration occurring in 0.5 hour. The
bioavailability of subcutaneous azacitidine relative to IV azacitidine is
approximately 89%, based on area under the curve.
2.
Distribution: Mean volume of distribution following IV dosing is 76 ± 26 L.
3.
Metabolism: Multiple metabolites have been found with unspecified
activity.
4.
Elimination: Primary route of excretion is through the kidney at 85% of the
total dose. The mean elimination half-life of both IV and subcutanous
dosing is 4 hours. Less than 1% of drug is excreted through the feces.
c.
ADVERSE EFFECTS
1.
Adverse Effects: The Comprehensive Adverse Events and Potential Risks
list (CAEPR) provides a single list of reported and/or potential adverse
events (AE) associated with an agent using a uniform presentation of
events by body system. In addition to the comprehensive list, a subset, the
Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in
a separate column and is identified with bold and italicized text. This
subset of AEs (SPEER) is a list of events that are protocol specific


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exceptions to expedited reporting to NCI (except as noted below). Refer
to the 'CTEP, NCI Guidelines: Adverse Event Reporting Requirements'
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/
aeguidelines.pdf for further clarification.
Frequency is provided based on 1470 patients. Below is the CAEPR for
azacitidine.
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted
in parentheses next to the AE in the SPEER. If this CAEPR is part of a
combination protocol using multiple investigational agents and has an AE
listed on different SPEERs, use the lower of the grades to determine if
expedited reporting is required.
Version 2.6, July 27, 20171
Adverse Events with Possible
Relationship to Azacitidine
(CTCAE 4.0 Term)
[n= 1470]
Specific Protocol
Exceptions to Expedited
Reporting (SPEER)
Likely (>20%)
Less Likely
(<=20%)
Rare but
Serious (<3%)
BLOOD AND LYMPHATIC SYSTEM DISORDERS
Anemia
Anemia (Gr 3)
Febrile
neutropenia
Febrile neutropenia (Gr 3)
CARDIAC DISORDERS
Heart failure
Heart failure (Gr 2)
Pericardial
effusion
Pericardial effusion (Gr 2)
Sinus
tachycardia
Sinus tachycardia (Gr 2)
Supraventricular
tachycardia
Supraventricular
tachycardia (Gr 2)
EYE DISORDERS
Conjunctivitis
Conjunctivitis (Gr 2)
GASTROINTESTINAL DISORDERS
Abdominal pain
Abdominal pain (Gr 32)
Colitis
Colitis (Gr 2)
Constipation
Constipation (Gr 2)
Diarrhea
Diarrhea (Gr 3)
Dyspepsia
Esophagitis
Esophagitis (Gr 2)
Gastrointestinal
hemorrhage2
Mucositis oral
Mucositis oral (Gr 2)
Nausea
Nausea (Gr 3)
Vomiting
Vomiting (Gr 3)
GENERAL DISORDERS AND ADMINISTRATION
SITE CONDITIONS
Chills
Chills (Gr 2)
Edema limbs
Edema limbs (Gr 2)
Fatigue
Fatigue (Gr 3)
Fever
Fever (Gr 3)


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Adverse Events with Possible
Relationship to Azacitidine
(CTCAE 4.0 Term)
[n= 1470]
Specific Protocol
Exceptions to Expedited
Reporting (SPEER)
Likely (>20%)
Less Likely
(<=20%)
Rare but
Serious (<3%)
Injection site
reaction
Injection site reaction (Gr
2)
Malaise
Non-cardiac
chest pain
Pain
IMMUNE SYSTEM DISORDERS
Allergic
reaction
Allergic reaction (Gr 2)
Anaphylaxis
INFECTIONS AND INFESTATIONS
Infection3
Infection3 (Gr 4)
INJURY, POISONING AND PROCEDURAL
COMPLICATIONS
Bruising
Bruising (Gr 2)
INVESTIGATIONS
Alanine
aminotransferas
e increased
Alanine aminotransferase
increased (Gr 4)
Alkaline
phosphatase
increased
Alkaline phosphatase
increased (Gr 2)
Aspartate
aminotransferas
e increased
Aspartate
aminotransferase
increased (Gr 4)
Blood bilirubin
increased
Blood bilirubin increased
(Gr 2)
GGT increased
GGT increased (Gr 2)
Lymphocyte
count decreased
Lymphocyte count
decreased (Gr 4)
Neutrophil count
decreased
Neutrophil count
decreased (Gr 4)
Platelet count
decreased
Platelet count decreased
(Gr 4)
Weight loss
Weight loss (Gr 2)
White blood cell
decreased
White blood cell
decreased (Gr 4)
METABOLISM AND NUTRITION DISORDERS
Acidosis
Acidosis (Gr 2)
Anorexia
Anorexia (Gr 2)
Hypokalemia
MUSCULOSKELETAL AND CONNECTIVE TISSUE
DISORDERS
Arthralgia
Arthralgia (Gr 2)
Back pain
Back pain (Gr 2)


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Adverse Events with Possible
Relationship to Azacitidine
(CTCAE 4.0 Term)
[n= 1470]
Specific Protocol
Exceptions to Expedited
Reporting (SPEER)
Likely (>20%)
Less Likely
(<=20%)
Rare but
Serious (<3%)
Generalized
muscle
weakness
Generalized muscle
weakness (Gr 2)
Myalgia
Myalgia (Gr 2)
Pain in extremity
Pain in extremity (Gr 2)
NERVOUS SYSTEM DISORDERS
Dizziness
Dizziness (Gr 2)
Headache
Headache (Gr 2)
Peripheral motor
neuropathy
Peripheral motor
neuropathy (Gr 2)
Somnolence
Somnolence (Gr 2)
PSYCHIATRIC DISORDERS
Anxiety
Confusion
Confusion (Gr 2)
Depression
Insomnia
RENAL AND URINARY DISORDERS
Acute kidney
injury
RESPIRATORY, THORACIC AND MEDIASTINAL
DISORDERS
Bronchopulmo
nary
hemorrhage
Cough
Cough (Gr 2)
Dyspnea
Dyspnea (Gr 4)
Epistaxis
Epistaxis (Gr 2)
Pharyngolaryng
eal pain
Postnasal drip
Postnasal drip (Gr 2)
Respiratory,
thoracic and
mediastinal
disorders - Other
(abnormal
breath sounds)4
Respiratory, thoracic and
mediastinal disorders -
Other (abnormal breath
sounds)4 (Gr 2)
SKIN AND SUBCUTANEOUS TISSUE
DISORDERS
Alopecia
Alopecia (Gr 2)
Hyperhidrosis
Pruritus
Pruritus (Gr 2)
Purpura
Purpura (Gr 2)
Rash maculo-
papular
Rash maculo-papular (Gr
3)


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Adverse Events with Possible
Relationship to Azacitidine
(CTCAE 4.0 Term)
[n= 1470]
Specific Protocol
Exceptions to Expedited
Reporting (SPEER)
Likely (>20%)
Less Likely
(<=20%)
Rare but
Serious (<3%)
Skin and
subcutaneous
tissue disorders
- Other (skin
lesion)
VASCULAR DISORDERS
Hematoma
Hematoma (Gr 2)
Hypotension
Hypotension (Gr 3)
Vascular
disorders - Other
(pallor)
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
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.
3 Infection
may
include any
of
the
75
infection
sites
under
the
INFECTIONS AND INFESTATIONS SOC.
4 Abnormal breath sounds includes rales and rhonchi.
Adverse events reported on azacitidine trials, but for which there is
insufficient evidence to suggest that there was a reasonable
possibility that azacitidine caused the adverse event:
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic
system disorders - Other (agranulocytosis); Blood and lymphatic system
disorders - Other (lymphadenopathy); Blood and lymphatic system
disorders - Other (pancytopenia); Blood and lymphatic system disorders -
Other (splenomegaly); Blood and lymphatic system disorders - Other
(transfusion: platelets); Bone marrow hypocellular; Leukocytosis
CARDIAC DISORDERS - Acute coronary syndrome; Atrial fibrillation;
Atrial flutter; Atrioventricular block complete; Cardiac disorders - Other
(cardiac valve vegetation); Chest pain - cardiac; Myocardial infarction;
Palpitations; Pericarditis; Restrictive cardiomyopathy; Sinus bradycardia;
Ventricular fibrillation; Wolff-Parkinson-White syndrome
EAR AND LABYRINTH DISORDERS - Hearing impaired; Tinnitus
EYE DISORDERS - Eye disorders - Other (eye/conjunctival hemorrhage);
Eye disorders - Other (retina hemorrhage); Papilledema; Uveitis
GASTROINTESTINAL DISORDERS - Abdominal distension; Duodenal
ulcer; Dysphagia; Enterocolitis; Esophageal pain; Esophageal ulcer;
Flatulence; Gastritis; Gastrointestinal disorders - Other (diverticulitis);


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Gastrointestinal
disorders
-
Other
(inguinal
hernia,
obstructive);
Gastrointestinal disorders - Other (intestinal ischemia); Gastrointestinal
disorders
-
Other
(intussusception);
Hemorrhoids;
Pancreatitis;
Periodontal disease; Small intestinal obstruction
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS -
Death NOS; Flu like symptoms; Gait disturbance; General disorders and
administration site conditions - Other (general weakness); General
disorders and administration site conditions - Other (Sweet's Syndrome);
General disorders and administration site conditions - Other (systemic
inflammatory response syndrome); Multi-organ failure; Sudden death
NOS
HEPATOBILIARY
DISORDERS
-
Cholecystitis;
Hepatic
failure;
Hepatobiliary disorders - Other (bile duct stone); Hepatobiliary disorders -
Other (hepatic cirrhosis)
IMMUNE SYSTEM DISORDERS - Autoimmune disorder
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Burn;
Fall; Hip fracture; Injury, poisoning and procedural complications - Other
(excoriation); Postoperative hemorrhage; Injury, poisoning and procedural
complications - Other (transfusion reaction); Wound dehiscence
INVESTIGATIONS - Activated partial thromboplastin time prolonged;
Creatinine increased; Electrocardiogram QT corrected interval prolonged;
INR
increased;
Investigations
-
Other
(blood
LDH
increased);
Investigations - Other (blood urea increased); Investigations - Other
(cardiac murmur); Investigations - Other (coagulopathy); Investigations -
Other (protein total decreased); Lipase increased; Serum amylase
increased
METABOLISM   AND   NUTRITION   DISORDERS   -   Dehydration;
Hyperglycemia;
Hyperkalemia;
Hyperuricemia;
Hypoalbuminemia;
Hypocalcemia; Hypomagnesemia; Hyponatremia; Hypophosphatemia;
Metabolism and nutrition disorders - Other (fluid overload); Metabolism
and nutrition disorders - Other (hypovolemia); Metabolism and nutrition
disorders - Other (low carbon dioxide); Tumor lysis syndrome
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS -
Arthritis; Bone pain; Chest wall pain; Flank pain; Muscle weakness lower
limb; Musculoskeletal and connective tissue disorder - Other (chondritis);
Musculoskeletal and connective tissue disorder - Other (intervertebral disc
protrusion); Musculoskeletal and connective tissue disorder - Other
(muscle cramps); Musculoskeletal and connective tissue disorder - Other
(muscle spasms); Musculoskeletal and connective tissue disorder - Other
(musculoskeletal stiffness); Neck pain
NEOPLASMS  BENIGN,  MALIGNANT  AND
UNSPECIFIED  (INCL
CYSTS AND POLYPS) - Myelodysplastic syndrome; Neoplasms benign,
malignant and unspecified (incl cysts and polyps) - Other (colonic polyp,
vaginal polyp); Treatment related secondary malignancy
NERVOUS
SYSTEM
DISORDERS
-
Dysesthesia;
Dysgeusia;
Hydrocephalus; Intracranial hemorrhage; Lethargy; Memory impairment;
Nervous system disorders - Other (head injury); Paresthesia; Peripheral
sensory neuropathy; Seizure; Sinus pain; Syncope
PSYCHIATRIC DISORDERS - Psychiatric disorders - Other (mental
status changes)
RENAL AND URINARY DISORDERS - Hematuria; Proteinuria; Renal and
urinary disorders - Other (calculus urinary); Renal calculi; Urinary
frequency; Urinary retention; Urinary tract pain
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Erectile
dysfunction; Reproductive system and breast disorders - Other (benign
prostatic hyperplasia); Uterine hemorrhage; Vaginal hemorrhage
RESPIRATORY,  THORACIC  AND  MEDIASTINAL  DISORDERS  -
Atelectasis; Hypoxia; Nasal congestion; Pleural effusion; Pleuritic pain;


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Pneumonitis;
Pneumothorax;
Productive
cough;
Pulmonary
edema;
Respiratory failure; Respiratory, thoracic and mediastinal disorders - Other
(chronic
obstructive
pulmonary
disease);
Respiratory,
thoracic
and
mediastinal disorders - Other (oropharyngeal pain); Respiratory, thoracic
and mediastinal disorders - Other (pharyngeal erythema); Respiratory,
thoracic and mediastinal disorders - Other (pneumonia legionella);
Wheezing
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Dry skin; Palmar-
plantar erythrodysesthesia syndrome; Skin and subcutaneous tissue
disorders - Other (ecthyma gangrenosum); Skin and subcutaneous tissue
disorders - Other (skin laceration); Skin and subcutaneous tissue
disorders - Other (skin nodule); Skin induration; Urticaria
VASCULAR DISORDERS - Flushing; Hypertension; Thromboembolic
event; Vascular disorders - Other (poor venous access); Vasculitis;
Visceral arterial ischemia
Note: Azacitidine 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.
2.
Pregnancy and Lactation: Pregnancy Category D. It is not known whether
azacitidine
or
its
metabolites
are
excreted
in
human
milk
and
administration of azacitidine is not recommended.
3.
Drug
Interactions:
No
formal
clinical
assessments
of
drug-drug
interactions between azacitidine and other agents have been conducted.
Refer to the current FDA-approved package insert.
d.
DOSING & ADMINISTRATION
See Section 7.1a, Treatment Plan.
e.
HOW SUPPLIED
Azacitidine is commercially available and will not be supplied. Refer to the current
FDA-approved package insert.
f.
STORAGE, PREPARATION & STABILITY
Refer to the current FDA-approved package insert.
3.2
Cytarabine (AraC, Cytosine Arabinoside) (NSC-63878)
a.
DESCRIPTION
AraC is chemically 4-amino-1-S-D-arabino-furanosyl-2(1H)-primidinone. AraC is
metabolized to its active form, ara-CTP. The ara-CTP functions as an inhibitor of
DNA polymerase. Ara-C exhibits cell phase specificity, killing cells undergoing
DNA synthesis (S phase) and may also block cells from progressing to S phase
from G1. Extensive chromosomal damage, including chromatid breaks, occurs.
AraC appears to be most effective in tumors with high growth fraction.
b.
TOXICOLOGY
Human Toxicology: Side effects of AraC include myelosuppression, nausea,
vomiting, diarrhea, anorexia, anal ulceration, stomatitis, rash, headache, fever,
myalgia, malaise, bone pain, chest pain, hepatic and renal dysfunction, and


 
 
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alopecia. Central nervous system toxicity, i.e., significant cerebral and cerebellar 
dysfunction, progression to coma, has been seen with high doses. Severe 
cardiomyopathy has been reported with high dose AraC in combination with 
cyclophosphamide. Progressive ascending paralysis has occurred in two patients 
receiving IV and intrathecal AraC. Marked keratoconjunctivitis has also occurred 
with high doses. 
 
The most frequently reported reactions after intrathecal administration were 
nausea, vomiting and fever. Paraplegia and meningitis have been reported with 
intrathecal administration. AraC given intrathecally may cause systemic toxicity 
and careful monitoring of the hemopoietic system is indicated. If used intrathecally 
or if high dose therapy is used, do not use a diluent containing benzyl alcohol. 
AraC can cause fetal harm when administered to a pregnant woman, however, 
there are no adequate and well controlled studies in pregnant women. 
 
c. 
PHARMACOLOGY 
 
Kinetics: AraC is metabolized by deoxycytidine kinase and related kinases to 
nucleotide triphosphate, which is an active inhibitor of DNA polymerase. 
Deoxycytidine prevents or delays cytotoxic activity. The active form is converted 
to nontoxic uracil derivatives by pyrimidine nucleoside deaminases. The balance 
of kinase and deaminase levels appears to be an important factor in 
sensitivity/resistance of the cell to AraC. After IV injection, plasma disappearance 
of ara-C is biphasic. Initial half-life is 10 minutes, delayed half-life is 1 - 3 hours. 
After 24 hours, 80% is excreted in the urine as its inactive metabolite, AraI. After a 
single IV administration of AraC, levels in CSF are low. With intrathecal 
administration, half-life is 2 hours. There is little conversion to AraU because of low 
CSF levels of deaminase. Drug interaction of AraC has been reported with digoxin, 
gentamycin and fluorocytocine. 
 
Formulation: AraC is supplied as a sterile powder in 100 mg and 500 mg vials for 
injection. AraC is also available in 1 and 2 gram vials. The drug should be 
reconstituted with sterile water for injection. 
 
Storage and Stability: The sterile powder should be stored at room temperature 
15° - 30°C (59° - 86°). The resulting solution has a stability of 48 hours if stored at 
ROOM TEMPERATURE. Do not use if even a slight haze develops. The 
reconstituted solution may be further diluted in 5% Dextrose or sodium chloride 
injection. 
 
d. 
DOSING & ADMINISTRATION 
See Section 7.1d, Treatment Plan. 
e. 
HOW SUPPLIED 
 
Supplier: AraC is commercially available and therefore should be purchased by a 
third party. This drug will NOT be supplied by the NCI. 
 
Please refer to the package insert for complete information. 
 
3.3 
Decitabine (Dacogen®, 5-aza-2’-deoxycitidine) (NSC-) 
 
a. 
PHARMACOLOGY 
 
Mechanism of Action: After phosphorylation, decitabine is incorporated into DNA 
and inhibits DNA methyltransferase. Decitabine causes hypomethylation of DNA 
and subsequent cell death. The formation of covalent adducts between DNA 


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methyltransferase and decitabine may also contribute to cytotoxicity in rapidly
dividing cells. Decitabine-induced hypomethylation may restore normal function of
genes needed for cell growth.
b.
PHARMACOKINETICS
1.
Absorption: N/A
1.
Distribution: Plasma protein binding of decitabine is less than 1%
2.
Metabolism: The metabolism and route of elimination is unknown. One
possible pathway appears to be deamination by cytidine deaminase,
primarily found in the liver, granulocytes, intestinal epithelium, and whole
blood.
3.
Elimination: The mean half life was 0.62 hr in patients who received 15
mg/m2 of decitabine IV over 3 hr and 0.54 hr in patients who received 20
mg/m2 of decitabine IV over 1 hr.
c.
ADVERSE EFFECTS
1.
Possible Side Effects of Decitabine: Refer to the current FDA-approved
package insert for the most comprehensive and up to date information on
adverse reactions.
The Comprehensive Adverse Events 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. Frequency is provided based on 1832 patients. Below is the
CAEPR for Decitabine (5-aza-2'-deoxycytidine).
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted
in parentheses next to the AE in the SPEER. If this CAEPR is part of a
combination protocol using multiple investigational agents and has an AE
listed on different SPEERs, use the lower of the grades to determine if
expedited reporting is required.
Version 2.4, January 4, 2017
Adverse Events with Possible
Relationship to Decitabine (5-aza-2'-deoxycytidine)
(CTCAE 4.0 Term)
[n= 1832]
Likely (>20%)
Less Likely (<=20%)
Rare but Serious (<3%)
BLOOD AND LYMPHATIC SYSTEM DISORDERS
Anemia
Febrile neutropenia
GASTROINTESTINAL DISORDERS
Nausea
Abdominal pain
Anal mucositis
Constipation
Diarrhea
Mucositis oral
Rectal mucositis
Small intestinal
mucositis


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Adverse Events with Possible
Relationship to Decitabine (5-aza-2'-deoxycytidine)
(CTCAE 4.0 Term)
[n= 1832]
Likely (>20%)
Less Likely (<=20%)
Rare but Serious (<3%)
Vomiting
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS
Fatigue
Chills
Fever
Edema limbs
Non-cardiac chest pain
Pain
IMMUNE SYSTEM DISORDERS
Autoimmune disorder
INFECTIONS AND INFESTATIONS
Infection2
INJURY, POISONING AND PROCEDURAL COMPLICATIONS
Bruising
INVESTIGATIONS
Neutrophil count
decreased
Alanine
aminotransferase
increased
Platelet count
decreased
Aspartate
aminotransferase
increased
White blood cell
decreased
Blood bilirubin
increased
Creatinine increased
Lymphocyte count
decreased
METABOLISM AND NUTRITION DISORDERS
Anorexia
Hyperglycemia
Hyperuricemia
Hypoalbuminemia
Hypocalcemia
Hypokalemia
Hypomagnesemia
Hyponatremia
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS
Arthralgia
Back pain
Bone pain
Pain in extremity
NERVOUS SYSTEM DISORDERS
Dizziness
Intracranial hemorrhage
Headache
Somnolence


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Adverse Events with Possible
Relationship to Decitabine (5-aza-2'-deoxycytidine)
(CTCAE 4.0 Term)
[n= 1832]
Likely (>20%)
Less Likely (<=20%)
Rare but Serious (<3%)
PSYCHIATRIC DISORDERS
Anxiety
Insomnia
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS
Cough
Dyspnea
Laryngeal mucositis
Pharyngeal mucositis
Pharyngolaryngeal
pain
Respiratory
hemorrhage3
Tracheal mucositis
SKIN AND SUBCUTANEOUS TISSUE DISORDERS
Alopecia
Pruritus
Purpura
Rash maculo-papular
VASCULAR DISORDERS
Hematoma
Phlebitis
Vascular disorders -
Other (hemorrhage
with decreased
platelets)
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
may
include any
of
the
75
infection sites
under
the
INFECTIONS AND INFESTATIONS SOC.
3 Respiratory
hemorrhage
includes
Bronchopulmonary
hemorrhage,
Epistaxis, Laryngeal hemorrhage, Mediastinal hemorrhage, Pharyngeal
hemorrhage, and Pleural hemorrhage under the RESPIRATORY,
THORACIC AND MEDIASTINAL DISORDERS SOC.
4 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.
5 Gastrointestinal obstruction includes Colonic obstruction, Duodenal


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obstruction,
Esophageal
obstruction,
Ileal
obstruction,
Jejunal
obstruction, Obstruction gastric, Rectal obstruction, and Small intestinal
obstruction under the GASTROINTESTINAL DISORDERS SOC.
Adverse events
reported
on
decitabine
(5-aza-2'-deoxycytidine)
trials, but for which there is insufficient evidence to suggest that
there
was
a
reasonable
possibility
that
decitabine
(5-aza-2'-
deoxycytidine) caused the adverse event:
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic
system disorders - Other (coagulaopathy); Blood and lymphatic system
disorders - Other (lymphadenopathy); Blood and lymphatic system
disorders - Other (pancytopenia); Bone marrow hypocellular; Hemolysis;
Leukocytosis; Spleen disorder
CARDIAC DISORDERS - Acute coronary syndrome; Atrial fibrillation;
Atrial flutter; Atrioventricular block complete; Cardiac arrest; Cardiac
disorders - Other (cardiac murmur); Cardiac disorders - Other (dilation
atrial); Chest pain - cardiac; Heart failure; Myocardial infarction; Restrictive
cardiomyopathy; Sinus bradycardia; Sinus tachycardia; Supraventricular
tachycardia; Ventricular arrhythmia
EAR AND LABYRINTH DISORDERS - Ear pain; Vertigo
EYE
DISORDERS -
Blurred
vision;
Eye
disorders
-
Other
(eye
hemorrhage); Eye disorders - Other (eye swelling); Eye pain
GASTROINTESTINAL DISORDERS - Abdominal distension; Ascites;
Dyspepsia; Dysphagia; Enterocolitis; Esophagitis; Flatulence; Gastritis;
Gastroesophageal reflux disease; Gastrointestinal disorders - Other (anal
fissure); Gastrointestinal disorders - Other (diverticulitis); Gastrointestinal
disorders - Other (mouth ulceration); Gastrointestinal disorders - Other
(oral mucosal blistering); Gastrointestinal hemorrhage4; Gastrointestinal
obstruction5;  Gastrointestinal  pain;  Hemorrhoids;  Ileus;  Oral  pain;
Periodontal disease; Proctitis; Rectal pain; Toothache; Typhlitis
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS -
Edema face; Gait disturbance; Infusion related reaction; Injection site
reaction; Localized edema; Malaise; Multi-organ failure
HEPATOBILIARY
DISORDERS
-
Cholecystitis;
Hepatic
failure;
Hepatobiliary disorders - Other (cholethiasis); Hepatobiliary disorders -
Other (hepatomegaly)
IMMUNE SYSTEM DISORDERS - Allergic reaction
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Fall;
Fracture; Injury, poisoning and procedural complications - Other (catheter
site pain); Injury, poisoning and procedural complications - Other (hernia);
Injury, poisoning and procedural complications - Other (procedural pain);
Injury, poisoning and procedural complications - Other (stent occlusion)
INVESTIGATIONS - Activated partial thromboplastin time prolonged;
Alkaline phosphatase increased; CPK increased; Cardiac troponin I
increased; Ejection fraction decreased; Electrocardiogram QT corrected
interval prolonged; Fibrinogen decreased; GGT increased; INR increased;
Investigations - Other (blood bicarbonate decreased); Investigations -
Other (blood bicarbonate increased); Investigations - Other (blood bilrubin
decreased);
Investigations
-
Other
(blood
chloride
decreased);
Investigations - Other (blood chloride increased); Investigations - Other
(blood lactate dehydrogenase increased); Investigations - Other (blood
urea increased); Investigations - Other (elevated ammonia); Investigations
- Other (eosinophilia); Investigations - Other (platelet count increase);
Investigations - Other (protein total decreased); Lipase increased; Serum
amylase increased; Weight loss
METABOLISM AND NUTRITION DISORDERS - Acidosis; Dehydration;


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Hypercalcemia;
Hyperkalemia;
Hypermagnesemia;
Hypoglycemia;
Hypophosphatemia;
Metabolism
and
nutrition
disorders
-
Other
(hyperphosphatemia);
Metabolism
and
nutrition
disorders
-
Other
(malnutrition)
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS -
Chest wall pain; Generalized muscle weakness; Musculoskeletal and
connective tissue disorder - Other (muscle spasms); Myalgia
NEOPLASMS  BENIGN,  MALIGNANT  AND  UNSPECIFIED  (INCL
CYSTS AND POLYPS) - Leukemia secondary to oncology chemotherapy;
Tumor pain
NERVOUS SYSTEM DISORDERS - Amnesia; Aphonia; Ataxia; Cognitive
disturbance;
Dysesthesia;
Dysgeusia;
Ischemia
cerebrovascular;
Lethargy; Paresthesia; Peripheral sensory neuropathy; Seizure; Stroke;
Syncope; Transient ischemic attacks
PSYCHIATRIC
DISORDERS
-
Confusion;
Delirium;
Depression;
Personality change
RENAL AND URINARY DISORDERS - Acute kidney injury; Cystitis
noninfective;
Hematuria;
Urinary
fistula;
Urinary
frequency;
Urinary
retention; Urinary tract pain; Urinary urgency
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Breast pain;
Uterine hemorrhage; Vaginal hemorrhage
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Adult
respiratory
distress
syndrome;
Allergic
rhinitis;
Atelectasis;
Bronchospasm;
Hypoxia;
Nasal 
congestion;
Pleural
effusion;
Pneumonitis; Postnasal drip; Pulmonary edema; Respiratory failure;
Respiratory, thoracic and mediastinal disorders - Other (breath sounds
abnormal/decreased); Respiratory, thoracic and mediastinal disorders -
Other (crepitations); Respiratory, thoracic and mediastinal disorders -
Other (pulmonary congestion); Sinus disorder; Wheezing
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Bullous dermatitis;
Dry skin; Erythema multiforme; Hyperhidrosis; Skin and subcutaneous
tissue disorders - Other (hyperkeratosis); Skin and subcutaneous tissue
disorders - Other (Sweet's Syndrome); Skin hyperpigmentation; Skin
hypopigmentation; Skin ulceration; Stevens-Johnson syndrome; Urticaria
VASCULAR  DISORDERS  -  Flushing;  Hypertension;  Hypotension
;Thromboembolic event; Vascular disorders - Other (aortic anyeurism);
Vascular disorders - Other (catheter site hemorrhage); Vascular disorders
- Other (circulatory collapse); Vascular disorders - Other (hemorrhage);
Vascular disorders - Other (splenic infarct vs hemorrhage/rupture);
Vascular disorders - Other (veno-occlusive disease); Vasculitis
Note: Decitabine (5-aza-2'-deoxycytidine) 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.
Pregnancy and Lactation: Pregnancy category D. Decitabine can cause
fetal harm when administered to a pregnant woman. There are no
adequate and well-controlled studies of decitabine use in pregnant
women. Adverse events were observed in animal reproduction studies.
Based on the mechanism of action, decitabine may cause fetal harm if
administered during pregnancy. Women of childbearing potential should
be advised to use effective contraception to avoid pregnancy during
treatment and for 1 month after treatment. In addition, males should be
advised to avoid fathering a child while on decitabine therapy and for 2
months after treatment. Because of the potential for serious adverse
reactions in the nursing infant, a decision should be made to discontinue
nursing or the drug, taking into account the importance of treatment to the


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mother.
2.
Drug Interactions: Drug interaction studies with decitabine have not been
conducted. According to in vitro studies, decitabine is unlikely to inhibit or
induce cytochrome P450 enzymes. In vitro studies also suggested that
decitabine is not a substrate for cytochrome P450 enzymes.
d.
DOSING & ADMINISTRATION
See Section 7.1d, Treatment Plan.
e.
HOW SUPPLIED
Decitabine is commercially available and will not be supplied. Refer to the current
FDA-approved package insert for the most comprehensive and up to date
information.
3.4
Midostaurin (NSC-656576)
a.
PHARMACOLOGY
Mechanism of Action: Midostaurin is an inhibitor of several PKC isoforms of the
tyrosine kinase of the VEGF receptor, and most importantly of the Class III tyrosine
kinase FLT3 and KIT which are involved in hematopoiesis and play a key role in
certain hematopoietic disorders. Midostaurin binds to the catalytic domain of these
kinases and inhibits the mitogenic signaling of the respective growth factors in cells
and results in growth arrest. The FLT3 signaling pathway is frequently ligand-
independently activated in AML cells through point mutation in the catalytic domain
of the receptor or through insertions in the juxta-membrane (JM) domain. Similarly,
the
KIT
signaling
pathway
is
frequently
ligand-independently
activated
in
neoplastic diseases including GIST and mast-cell disease.
b.
PHARMACOKINETICS
1.
Absorption:
Midostaurin
maximum
concentrations
(Tmax)
occurred
between 1-3 hours post dose in a fasted state. Midostaurin exposure
increased 1.2-fold when co-administered with a standard meal and
increased 1.6-fold when co-administered with a high-fat meal compared to
when administered in a fasted state.
2.
Distribution: The estimated mean volume of distribution (% coefficient of
variation) is 95.2 L (31%). Midostaurin and its metabolites are distributed
mostly in plasma in vitro. Midostaurin, CGP62221, and CGP52421 are
greater than 99.8% bound to plasma protein in vitro.
3.
Metabolism: Midostaurin is primarily metabolized by CYP3A4. CGP62221
and CPG52424 (mean +/- standard deviation) account for 28 +/- 2.7% and
38 +/- 6.6% of the total circulating radioactivity.
4.
Elimination: Fecal excretion accounts for 95% of the recovered dose, with
91% of the recovered dose excreted as metabolites and 4% as unchanged
midostaurin. 5% of the recovered dose was found in the urine. The
geometric mean terminal half-life (% coefficient of variation) is 21 hours
(19%) for midostaurin, 32 hours (31%) for CGP62221, and 482 hours
(25%) for CGP52421.


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c.
ADVERSE EFFECTS
1.
Adverse Effects:
Comprehensive Adverse Events and Potential Risks list (CAEPR) for
Midostaurin (NSC 656576)
The Comprehensive Adverse Events and Potential Risks list (CAEPR)
provides a single list of reported and/or potential adverse events (AE)
associated with an agent using a uniform presentation of events by body
system. In addition to the comprehensive list, a subset, the Specific
Protocol Exceptions to Expedited Reporting (SPEER), appears in a
separate column and is identified with bold and italicized text. This subset
of AEs (SPEER) is a list of events that are protocol specific exceptions to
expedited reporting to NCI (except as noted below). Refer to the 'CTEP,
NCI
Guidelines:
Adverse
Event
Reporting
Requirements'
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/
aeguidelines.pdf for further clarification. Frequency is provided based on
684 patients. Below is the CAEPR for Midostaurin (NSC 656576).
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted
in parentheses next to the AE in the SPEER. If this CAEPR is part of a
combination protocol using multiple investigational agents and has an AE
listed on different SPEERs, use the lower of the grades to determine if
expedited reporting is required.
Version 2.1, June 28, 20181
Adverse Events with Possible
Relationship to Midostaurin
(CTCAE 5.0 Term)
[n= 684]
Specific Protocol
Exceptions to
Expedited
Reporting (SPEER)
Likely (>20%)
Less Likely
(<=20%)
Rare but
Serious
(<3%)
BLOOD AND LYMPHATIC SYSTEM DISORDERS
Anemia
Anemia (Gr 3)
Febrile
neutropenia
GASTROINTESTINAL DISORDERS
Abdominal pain
Constipation
Diarrhea
Diarrhea (Gr 2)
Nausea
Nausea (Gr 2)
Vomiting
Vomiting (Gr 2)
GENERAL DISORDERS AND ADMINISTRATION
SITE CONDITIONS
Edema limbs
Fatigue
Fatigue (Gr 3)
Fever
INFECTIONS AND INFESTATIONS
Infection2
INVESTIGATIONS


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Alanine
aminotransferase
increased
Lipase increased
Neutrophil count
decreased
Platelet count
decreased
Platelet count
decreased (Gr 4)
MUSCULOSKELETAL AND CONNECTIVE
TISSUE DISORDERS
Back pain
NERVOUS SYSTEM DISORDERS
Headache
Headache (Gr 2)
RESPIRATORY, THORACIC AND MEDIASTINAL
DISORDERS
Dyspnea
SKIN AND SUBCUTANEOUS TISSUE DISORDERS
Pruritus
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
INFESTATION SOC.
Adverse events reported on midostaurin trials, but for which there is
insufficient evidence to suggest that there was a reasonable possibility that
midostaurin caused the adverse event:
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Disseminated
intravascular coagulation; Leukocytosis
CARDIAC DISORDERS - Atrial fibrillation; Atrial flutter; Atrioventricular
block complete; Cardiac arrest; Cardiac disorders - Other (cardiomegaly);
Cardiac disorders - Other (ventricular dysfunction); Heart failure; Left
ventricular systolic dysfunction; Mitral valve disease; Myocardial infarction;
Pericardial effusion; Sinus bradycardia; Sinus tachycardia; Ventricular
arrhythmia
EAR AND LABYRINTH DISORDERS - Ear pain; Vertigo
ENDOCRINE DISORDERS – Endocrine disorders – Other (diabetes
mellitus); Hyperthyroidism
EYE DISORDERS - Blurred vision; Dry eye; Keratitis; Periorbital edema
GASTROINTESTINAL DISORDERS - Abdominal distension; Ascites;
Belching; Bloating; Colitis; Colonic hemorrhage; Dyspepsia; Dysphagia;
Enterocolitis;
Flatulence;
Gastric
hemorrhage;
Gastric
ulcer;
Gastrointestinal disorders - Other (anorectal discomfort); Gastrointestinal
disorders - Other (cramping); Gastrointestinal disorders - Other (salivary
hypersecretion); Gingival pain; Ileus; Lower gastrointestinal hemorrhage;
Mucositis  oral;  Oral  hemorrhage;  Oral  pain;  Pancreatitis;  Rectal
hemorrhage; Rectal pain; Small intestinal obstruction; Stomach pain;
Typhlitis; Upper gastrointestinal hemorrhage; Visceral arterial ischemia
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS -
Chills; Disease progression; Edema face; Flu like symptoms; Malaise;
Multi-organ failure; Non-cardiac chest pain; Pain; Sudden death NOS
HEPATOBILIARY DISORDERS - Hepatic failure; Hepatobiliary disorders
– Other (hepatic cirrhosis); Hepatobiliary disorders - Other (hepatotoxicity)


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IMMUNE SYSTEM DISORDERS - Allergic reaction; Anaphylaxis
INJURY, POISONING AND PROCEDURAL COMPLICATIONS – Fall
INVESTIGATIONS - Activated partial thromboplastin time prolonged;
Alkaline phosphatase increased; Aspartate aminotransferase increased;
Blood bilirubin increased; Ejection fraction decreased; Electrocardiogram
QT corrected interval prolonged; Hemoglobin increased; Investigations -
Other (blast cell count increased); Lymphocyte count decreased; Serum
amylase increased; Weight gain; Weight loss; White blood cell decreased
METABOLISM    AND    NUTRITION    DISORDERS    -    Anorexia;
Hypercalcemia;
Hyperglycemia;
Hypernatremia;
Hyperuricemia;
Hypoalbuminemia;  Hypokalemia;  Hyponatremia;  Hypophosphatemia;
Metabolism and nutrition disorders - Other (failure to thrive)
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS -
Arthralgia;
Arthritis;
Bone
pain;
Generalized
muscle
weakness;
Musculoskeletal and connective tissue disorder - Other (osteomylitis and
tenosynovitis L hand); Myalgia; Neck pain; Pain in extremity; Trismus
NEOPLASMS  BENIGN,  MALIGNANT  AND  UNSPECIFIED  (INCL
CYSTS AND POLYPS) - Leukemia secondary to oncology chemotherapy;
Myelodysplastic syndrome; Treatment related secondary malignancy
NERVOUS
SYSTEM
DISORDERS
-
Concentration
impairment;
Dizziness;
Intracranial  hemorrhage;   Lethargy;   Memory   impairment;
Nervous system disorders - Other (possible neuroleptic malignant
syndrome); Peripheral sensory neuropathy; Syncope; Transient ischemic
attacks; Tremor
PSYCHIATRIC ISORDERS – Agitation; Anxiety; Confusion; Insomnia;
Psychiatric disorders – Other (altered mental status)
RENAL AND URINARY DISORDERS - Acute kidney injury; Cystitis
noninfective; Hematuria; Renal and urinary disorders - Other (urinary
bladder hemorrhage); Urinary retention
REPRODUCTIVE
SYSTEM
AND
BREAST
DISORDERS
–
Dysmenorrhea; Vaginal hemorrhage
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Adult
respiratory
distress
syndrome;
Allergic
rhinitis;
Atelectasis;
Bronchopulmonary hemorrhage; Cough; Epistaxis; Hiccups; Hypoxia;
Laryngeal edema; Oropharyngeal pain; Pharyngolaryngeal pain; Pleural
effusion;
Pneumonitis;
Pulmonary
edema;
Respiratory
failure;
Respiratory, thoracic and mediastinal disorders - Other (bronchitis);
Respiratory, thoracic and mediastinal disorders - Other (pulmonary
nodules);
Respiratory,
thoracic
and
mediastinal
disorders
-
Other
(tachypnea); Sinus disorder
SKIN AND SUBCUTANEOUS TISSUE DISORDERS – Dry skin;
Erythroderma; Hyperhidrosis; Purpura; Rash maculo-papular; Skin and
subcutaneous tissue disorders – Other (toxic skin eruption); Skin
ulceration; Urticaria
VASCULAR
DISORDERS
-
Flushing;
Hematoma;
Hot
flashes;
Hypertension; Hypotension; Thromboembolic event
Note: Midostaurin 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.
2.
Pregnancy and Lactation: Midostaurin may cause fetal harm when
administered to pregnant women. Women must avoid breast-feeding, and
all women of childbearing potential will be required to employ a highly
effective method of birth control, which is defined as a birth control which
results in a low failure rate (i.e. less than 1% per year) when used
consistently and correctly. This has to be employed for the duration of the


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study and for three months post study for women because of the long half-
life (T1/2) of the metabolite, CGP52421 (>1 month). Acceptable methods
of birth control include implants, injectables, and hormonal contraceptives,
some IUDs (Intrauterine Devices), sexual abstinence or vasectomized
partner.
Sexually active males must use a condom during intercourse while taking
drug and for 5 months after stopping midostaurin medication to cover the
half-life of the compound metabolites and spermatogenesis. A condom is
required to be used also by vasectomized men in order to prevent delivery
of the drug via seminal fluid.
3.
Drug Interactions
Midostaurin is a substrate of CYP3A4. Midostaurin and its metabolites
inhibit CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP2E1.
Avoid concomitant administration of strong or moderate CYP3A4 inhibitors
when possible. Midostaurin and its metabolites induce CYP1A2, CYP2B6,
CYP2C8, CYP2C9, CYP2C19, and CYP3A in vitro. Avoid concomitant
use as strong CYP3A4 inducers decrease exposure to midostaurin and its
active
metabolites.
Midostaurin
inhibits
organic
anion
transporter
polypeptide (OATP) 1A1 and induces multidrug resistant protein (MRP) 1
in vitro.
Due to potential drug interactions, a complete patient medication list,
including midostaurin, should be screened prior to initiation of and during
treatment with midostaurin. See Section 8.0 Toxicities to be Monitored and
Dosage Modifications. In addition, refer to the current FDA-approved
package insert.
d.
DOSING & ADMINISTRATION
See Section 7.1c, Treatment Plan.
e.
HOW SUPPLIED
1.
Appearance: Midostaurin is currently prepared as 25 mg soft gelatin
capsule.
Midostaurin will be supplied as soft gelatin capsules to be taken orally. The
study drug will be packed in child resistant blisters. The drug should be
stored in the blister pack until use and no further preparation of the study
drug is needed. Upon opening a blister pack, patients may notice a
pungent odor. The odor is due to ethyl thioglycolate that forms when
ethanol in the capsules interacts with the thermostabilizer in the foil. The
capsules are not affected, and the odor will dissipate. Each capsule
contains 25 mg of midostaurin.
2.
Distributor: Midostaurin is supplied by Novartis and distributed by the
Pharmaceutical Management Branch, CTEP/DCTD/NCI as 25 mg soft
gelatin capsules individually sealed in a blister card. Each blister card
contains 8 capsules and each box contains 8 blister cards for a total of 64
capsules.


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f.
STORAGE, PREPARATION & STABILITY
Storage condition: Soft gelatin capsule: Do not store above 25°C.
g.
DRUG ORDERING & ACCOUNTABILITY
See Section 3.6.
3.5
Nivolumab (BMS-936558, MDX1106, Optivo®) (NSC-748726)
a.
PHARMACOLOGY
Mechanism of Action: Nivolumab is human monoclonal antibody which targets the
programmed death–1 (PD-1, cluster of differentiation 279 [CD279]) cell surface
membrane receptor. PD-1 is a negative regulatory receptor expressed by activated
T and B lymphocytes. Binding of PD-1 to its ligands, programmed death–ligand 1
(PD-L1) and 2 (PD-L2), results in the down-regulation of lymphocyte activation.
Nivolumab inhibits the binding of PD-1 to PD-L1 and PD-L2. Inhibition of the
interaction between PD-1 and its ligands promotes immune responses and
antigen-specific T-cell responses to both foreign antigens as well as self-antigens.
b.
PHARMACOKINETICS
1.
Distribution: Nivolumab has linear pharmacokinetics after single and
multiple dosing within the range 0.1 mg/kg to 10 mg/kg. The volume
distribution (Vd) is 8L.
2.
Elimination: Clearance is independent of dose in the range 0.1 mg/kg to
10 mg/kg. The total body clearance is 9.5 mL/hr, and the elimination half-
life of is approximately 26.7 days. Body weight normalized dosing showed
approximately constant trough concentrations over a wide range of body
weights.
c.
ADVERSE EFFECTS
1.
Adverse Effects: The Comprehensive Adverse Events and Potential Risks
list (CAEPR) provides a single list of reported and/or potential adverse
events (AE) associated with an agent using a uniform presentation of
events by body system. In addition to the comprehensive list, a subset, the
Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in
a separate column and is identified with bold and italicized text. This
subset of AEs (SPEER) is a list of events that are protocol specific
exceptions to expedited reporting to NCI (except as noted below). Refer
to the 'CTEP, NCI Guidelines: Adverse Event Reporting Requirements'
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/
aeguidelines.pdf for further clarification. Frequency is provided based on
2069 patients. Below is the CAEPR for BMS-936558 (Nivolumab, MDX-
1106).
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted
in parentheses next to the AE in the SPEER. If this CAEPR is part of a
combination protocol using multiple investigational agents and has an AE
listed on different SPEERs, use the lower of the grades to determine if
expedited reporting is required.


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Version 2.3, June 18, 20181
Adverse Events with Possible
Relationship to BMS-936558 (Nivolumab, MDX-1106)
(CTCAE 5.0 Term)
[n= 2069]
Specific Protocol
Exceptions to
Expedited Reporting
(SPEER)
Likely (>20%)
Less Likely
(<=20%)
Rare but
Serious (<3%)
BLOOD AND LYMPHATIC SYSTEM DISORDERS
Anemia
Anemia (Gr 2)
CARDIAC DISORDERS
Cardiac
disorders - Other
(cardiomyopathy
)
Myocarditis
Pericardial
tamponade2
Pericarditis
ENDOCRINE DISORDERS
Adrenal
insufficiency3
Hypophysitis3
Hyperthyroidism3
Hypothyroidism3
EYE DISORDERS
Blurred vision
Dry eye
Eye disorders -
Other (diplopia)3
Eye disorders -
Other (Graves
ophthalmopathy)
3
Eye disorders -
Other (optic
neuritis
retrobulbar)3
Uveitis
GASTROINTESTINAL DISORDERS
Abdominal pain
Abdominal pain (Gr
2)
Colitis3
Colonic
perforation3
Diarrhea
Diarrhea (Gr 3)
Dry mouth
Dry mouth (Gr 2)
Gastritis
Mucositis oral
Nausea
Nausea (Gr 2)
Pancreatitis4


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Adverse Events with Possible
Relationship to BMS-936558 (Nivolumab, MDX-1106)
(CTCAE 5.0 Term)
[n= 2069]
Specific Protocol
Exceptions to
Expedited Reporting
(SPEER)
Likely (>20%)
Less Likely
(<=20%)
Rare but
Serious (<3%)
GENERAL DISORDERS AND ADMINISTRATION SITE
CONDITIONS
Fatigue
Fatigue (Gr 3)
Fever
Fever (Gr 2)
Injection site
reaction
Injection site reaction
(Gr 2)
IMMUNE SYSTEM DISORDERS
Allergic reaction
Autoimmune
disorder3
Cytokine release
syndrome5
Immune system
disorders - Other
(GVHD in the
setting of
allotransplant)3,6
Immune system
disorders - Other
(sarcoid
granuloma)3
INJURY, POISONING AND PROCEDURAL
COMPLICATIONS
Infusion related
reaction7
INVESTIGATIONS
Alanine
aminotransferase
increased 3
Alanine
aminotransferase
increased3 (Gr 3)
Aspartate
aminotransferase
increased 3
Aspartate
aminotransferase
increased3 (Gr 3)
Blood bilirubin
increased 3
Blood bilirubin
increased3 (Gr 2)
Creatinine
increased
Lipase increased
Lymphocyte count
decreased
Lymphocyte count
decreased (Gr 2)
Neutrophil count
decreased
Platelet count
decreased
Serum amylase
increased
METABOLISM AND NUTRITION DISORDERS
Anorexia
Hyperglycemia
Hyperglycemia (Gr 2)


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Adverse Events with Possible
Relationship to BMS-936558 (Nivolumab, MDX-1106)
(CTCAE 5.0 Term)
[n= 2069]
Specific Protocol
Exceptions to
Expedited Reporting
(SPEER)
Likely (>20%)
Less Likely
(<=20%)
Rare but
Serious (<3%)
Metabolism and
nutrition
disorders - Other
(diabetes
mellitus with
ketoacidosis)3
MUSCULOSKELETAL AND CONNECTIVE TISSUE
DISORDERS
Arthralgia
Musculoskeletal
and connective
tissue disorder -
Other
(polymyositis)
Rhabdomyolysis
Myositis
NERVOUS SYSTEM DISORDERS
Encephalopathy3
Facial nerve
disorder3
Guillain-Barre
syndrome3
Myasthenia
gravis3
Nervous system
disorders - Other
(demyelination
myasthenic
syndrome)
Nervous system
disorders - Other
(encephalitis)3
Nervous system
disorders - Other
(meningoenceph
alitis)
Nervous system
disorders - Other
(meningoradi-
culitis)3
Nervous system
disorders - Other
(myasthenic
syndrome)
Peripheral motor
neuropathy
Peripheral
sensory
neuropathy


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Adverse Events with Possible
Relationship to BMS-936558 (Nivolumab, MDX-1106)
(CTCAE 5.0 Term)
[n= 2069]
Specific Protocol
Exceptions to
Expedited Reporting
(SPEER)
Likely (>20%)
Less Likely
(<=20%)
Rare but
Serious (<3%)
Reversible
posterior
leukoencephalo
pathy syndrome3
RENAL AND URINARY DISORDERS
Acute kidney
injury3
RESPIRATORY, THORACIC AND MEDIASTINAL
DISORDERS
Pleural effusion3
Pneumonitis3
Respiratory,
thoracic and
mediastinal
disorders - Other
(bronchiolitis
obliterans with
organizing
pneumonia)3
SKIN AND SUBCUTANEOUS TISSUE DISORDERS
Erythema
multiforme3
Pruritus3
Pruritus3 (Gr 2)
Rash maculo-
papular3
Rash maculo-
papular3 (Gr 2)
Skin and
subcutaneous
disorders -Other
(bullous
pemphigoid)
Skin and
subcutaneous
disorders - Other
(Sweet’s
Syndrome)3
Skin
hypopigmentation
Stevens-
Johnson
syndrome
Toxic epidermal
necrolysis
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 Pericardial tamponade may be related to possible inflammatory reaction
at tumor site.


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3 BMS-936558 (Nivolumab, MDX-1106) being a member of class of agents
involved in the inhibition of “immune checkpoints”, may result in severe
and possibly fatal immune-mediated adverse events probably due to
T-cell activation and proliferation.
This may result in autoimmune
disorders that can include (but are not limited to) autoimmune hemolytic
anemia, acquired anti-factor VIII immune response, autoimmune aseptic
meningitis, autoimmune hepatitis, autoimmune nephritis, autoimmune
neuropathy, autoimmune thyroiditis, bullous pemphigoid, exacerbation
of Churg-Strauss Syndrome, drug rash with eosinophilia systemic
symptoms [DRESS] syndrome, facial nerve disorder (facial nerve
paralysis), limbic encephalitis, hepatic failure, pure red cell aplasia,
pancreatitis, ulcerative and hemorrhagic colitis, endocrine disorders
(e.g.,
autoimmune
thyroiditis,
hyperthyroidism,
hypothyroidism,
autoimmune hypophysitis/hypopituitarism, thyrotoxicosis, and adrenal
insufficiency), sarcoid granuloma, myasthenia gravis, polymyositis, and
Guillain-Barre syndrome.
4 Pancreatitis may result in increased serum amylase and/or more
frequently lipase.
5
Cytokine
release
syndrome
may
manifest
as
hemophagocytic
lymphohistocytosis with accompanying fever and pancytopenia.
6 Complications including hyperacute graft-versus-host disease (GVHD),
some fatal, have occurred in patients receiving allo stem cell trancplant
(SCT) after receiving BMS-936558 (Nivolumab, MDX-1106). These
complications may occur despite intervening therapy between receiving
BMS-936558 (Nivolumab, MDX-1106) and allo-SCT.
7 Infusion reactions, including high-grade hypersensitivity reactions which
have been observed following administration of nivolumab, may
manifest as
fever,
chills,
shakes,
itching, rash,
hypertension
or
hypotension, or
difficulty
breathing
during
and immediately
after
administration of nivolumab.
Adverse events reported on BMS-936558 (Nivolumab, MDX-1106)
trials, but for which there is insufficient evidence to suggest that
there was a reasonable possibility that BMS-936558 (Nivolumab,
MDX-1106) caused the adverse event:
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Leukocytosis
CARDIAC DISORDERS - Atrial fibrillation; Atrioventricular block
complete; Heart failure; Ventricular arrhythmia
EAR AND LABYRINTH DISORDERS - Vestibular disorder
EYE DISORDERS - Eye disorders - Other (iridocyclitis); Optic nerve
disorder; Periorbital edema
GASTROINTESTINAL DISORDERS - Constipation; Duodenal ulcer;
Flatulence; Gastrointestinal disorders - Other (mouth sores); Vomiting
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS -
Chills; Edema limbs; Malaise; Pain
HEPATOBILIARY DISORDERS - Bile duct stenosis
IMMUNE SYSTEM DISORDERS - Anaphylaxis; Immune system
disorders - Other (autoimmune thrombotic microangiopathy); Immune
system disorders - Other (limbic encephalitis)
INFECTIONS AND INFESTATIONS - Bronchial infection; Lung infection;
Sepsis; Upper respiratory infection
INVESTIGATIONS - Blood lactate dehydrogenase increased; GGT
increased; Investigations - Other (protein total decreased); Lymphocyte
count increased; Weight loss
METABOLISM AND NUTRITION DISORDERS - Dehydration;
Hyperuricemia; Hypoalbuminemia; Hypocalcemia; Hyponatremia;


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Hypophosphatemia
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS -
Back pain; Musculoskeletal and connective tissue disorder - Other
(musculoskeletal pain); Musculoskeletal and connective tissue disorder -
Other (polymyalgia rheumatica); Myalgia; Pain in extremity
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL
CYSTS AND POLYPS) - Neoplasms benign, malignant and unspecified
(incl cysts and polyps) - Other (histiocytic necrotizing lymphadenitis)
NERVOUS SYSTEM DISORDERS - Dizziness; Headache; Intracranial
hemorrhage
PSYCHIATRIC DISORDERS - Insomnia
RENAL AND URINARY DISORDERS - Hematuria; Renal and urinary
disorders - Other (tubulointerstitial nephritis)
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS -
Bronchospasm; Cough; Dyspnea; Hypoxia
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Dry
skin; Hyperhidrosis; Pain of skin; Photosensitivity; Rash acneiform; Skin
and subcutaneous tissue disorders - Other (rosacea)
VASCULAR DISORDERS - Flushing; Hypertension; Hypotension; Vasculitis
Note: BMS-936558 (Nivolumab, MDX-1106) 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.
2.
Pregnancy and Lactation:
Pregnancy: Adverse events were observed in animal reproduction studies.
Nivolumab may be expected to cross the placenta; effects to the fetus may
be greater in the second and third trimesters. Based on its mechanism of
action, nivolumab is expected to cause fetal harm if used during
pregnancy. Women of reproductive potential should use highly-effective
contraception during therapy and for at least 23 weeks after treatment has
been discontinued. Men receiving nivolumab and who are sexually active
with women of child bearing potential should adhere to contraception for a
period of 31 weeks after the last dose of nivolumab.
Lactation: It is not known if nivolumab is excreted into breast milk. Due to
the potential
for serious adverse reactions in the nursing infant, the
manufacturer recommends women to discontinue breastfeeding during
treatment with nivolumab.
3.
Drug Interactions: Nivolumab is not expected to have any effect on
cytochrome P450 or other drug metabolizing enzymes in terms of
inhibition or induction, and is, therefore, not expected to induce these
types of PK-based drug interactions.
d.
DOSING & ADMINISTRATION
See Section 7.1b, Treatment Plan
Nivolumab is to be administered as a 30-60-minute IV infusion through a 0.2
micron to 1.2 micron pore size, low-protein binding polyethersulfone membrane in-
line filter. DO NOT administer as IV push or bolus injection.


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e.
HOW SUPPLIED
1.
Nivolumab is a clear to opalescent, colorless to pale yellow liquid; light
(few) particulates may be present. The drug product is a sterile,
nonpyrogenic, single-use, isotonic aqueous solution formulated in sodium
citrate, sodium chloride, mannitol, diethylenetriamine pentacetic acid
(pentetic acid) and polysorbate 80 (Tween® 80), pH 6.0.
2.
Nivolumab is supplied by Bristol-Myers Squibb and distributed by the
Pharmaceutical Management Branch, CTEP/DCTD/NCI as 100 mg vials
(10 mg/mL) with a 0.7mL overfill. It is supplied in 10 mL type I flint glass
vials, with butyl rubber stoppers and aluminum seals.
f.
STORAGE, PREPARATION & STABILITY
1.
Vials of Nivolumab must be stored at 2°-8°C (36°-46°F) and protected from
light, freezing and shaking.
If a storage temperature excursion is
identified, promptly return nivolumab to 2°-8°C and quarantine the
supplies.
Provide
a
detailed
report
of
the
excursion
(including
documentation of temperature monitoring and duration of the excursion)
to PMBAfterHours@mail.nih.gov for determination of suitability.
2.
Nivolumab can be infused undiluted (10 mg/mL) or diluted with 0.9%
Sodium
Chloride
Injection,
USP
or
5%
Dextrose,
USP
to
drug
concentrations no less than 0.35 mg/mL. Note: Mix gently. Do not shake.
3.
Compatibility: Nivolumab infusions are compatible with polyvinyl chloride
(PVC) or polyolefin containers and infusion sets, and glass bottles.
4.
Stability: Shelf-life surveillance of the intact vials is ongoing.
The administration of undiluted and diluted solutions of Nivolumab must
be completed within 24 hours of preparation. If not used immediately, the
infusion solution may be stored up to 24 hours in a refrigerator at 2°-8°C
(36°-46°F) and a maximum of 4 hours of the total 24 hours can be at room
temperature (20°-25°C, 68°-77°F) and room light. The maximum 4-hour
period under room temperature and room light conditions includes the
product administration period.
CAUTION:
The
single-use dosage
form
contains no
antibacterial
preservative or bacteriostatic agent. Therefore, it is advised that the
product be discarded 8 hours after initial entry.
g.
DRUG ORDERING & ACCOUNTABILITY
See Section 3.6.
3.6
Drug Ordering and Accountability for NCI-Supplied Agents
a.
Drug Ordering
NCI-supplied agents may be requested by the Principal Investigator (or their
authorized
designee)
at
each
participating
institution.
Pharmaceutical
Management Branch (PMB) policy requires that drug be shipped directly to the
institution where the patient is to be treated. PMB does not permit the transfer of
agents between institutions (unless prior approval from PMB is obtained). The
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supplied investigational agents. The responsible investigator at each participating
institution must be registered with CTEP, DCTD through an annual submission of
FDA Form 1572 and a CV. If there are several participating investigators at one
institution, CTEP-supplied investigational agents for the study should be ordered
under the name of one lead investigator at that institution.
Active
CTEP-registered
investigators
and
investigator-designated
shipping
designees and ordering designees can submit agent requests through the PMB
Online Agent Order Processing (OAOP) application. Access to OAOP requires
the establishment of a CTEP Identity and Access Management (IAM) account and
the maintenance of an “active” account status and a “current” password. For
questions about drug orders, transfers, returns, or accountability, call or e-mail
PMB any time. Refer to the PMB’s website for specific policies and guidelines
related to agent management.
Patients must be randomized to a treatment arm in OPEN prior to ordering agent.
Agent orders may be expedited overnight Monday-Thursday when sites provide
expedited courier information. Initiation of treatment must occur no more than
seven working days after patient randomization.
b.
Drug Handling and Accountability
1.
Drug Accountability: The investigator, or a responsible party designated
by the investigator, must maintain a careful record of the receipt,
dispensing and final disposition of all agents received from the PMB using
the appropriate NCI Investigational Agent (Drug) Accountability Record
(DARF) available on the CTEP forms page. Store and maintain separate
NCI Investigational Agent Accountability Records for each agent, strength,
formulation and ordering investigator on this protocol.
2.
Electronic logs are allowed as long as a print version of the log process is
the exact same appearance as the current NCI DARF.
c.
Drug return and/or disposition instruction
1.
Drug Returns: All unused drug supplies should be returned to the PMB.
When it is necessary to return study drug (e.g., sealed vials remaining
when expired vials are recalled by the PMB), investigators should return
the study drug to the PMB using the NCI Return Agent Form available on
the NCI home page (http://ctep.cancer.gov).
2.
Drug Expiration: Shelf life stability studies of the intact vials of nivolumab
are on-going. Shelf life stability studies of the midostaurin capsules are
on-going.
3.
Questions about drug orders, transfers, returns or accountability should
be addressed to the PMB by calling 240/276-6575 Monday through Friday
between 8:30 am and 4:30 pm Eastern Time.
d.
Useful Links and Contacts
x
CTEP Forms, Templates, Documents: http://ctep.cancer.gov/forms/
x
NCI CTEP Investigator Registration: PMBRegPend@ctep.nci.nih.gov
x
PMB policies and guidelines:
http://ctep.cancer.gov/branches/pmb/agent_management.htm
x
PMB Online Agent Order Processing (OAOP) application: https://eapps-
ctep.nci.nih.gov/OAOP/pages/login.jspx
x
CTEP Identity and Access Management (IAM) account:


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https://eapps-ctep.nci.nih.gov/iam/
x
CTEP Associate Registration and IAM account help:
ctepreghelp@ctep.nci.nih.gov
x
PMB IB Coordinator: IBCoordinator@mail.nih.gov
x
PMB e-mail: PMBAfterHours@mail.nih.gov
PMB phone and hours of service: (240) 276-6575 Monday through Friday between
8:30 am and 4:30 pm (ET).
4.0      STAGING CRITERIA
4.1
Diagnostic Criteria
For purposes of this study Acute Myeloid Leukemia (AML) is defined by ≥20% myeloblasts
in the blood or marrow and MDS (EB-2) is defined by blast counts ≥10% and < 20% in
marrow or 5%-19% blasts in peripheral blood (if marrow is not available). Please refer to
the 2016 updated WHO Classification of Myeloid Neoplasms and Acute Leukemia for more
detailed information. (16)
4.2
Staging Criteria
Staging criteria are not applicable to this protocol.
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. For each criterion requiring test results and dates, please record this information on the
Onstudy Form and submit via Medidata Rave® (see Section 14.0). Any potential eligibility issues should
be addressed to the Data Operations Center in Seattle at 206/652-2267 or leukemiaquestion@crab.org
prior
to
registration.
NCI
policy
does
not
allow
for
waiver
of
any
eligibility
criterion
(http://ctep.cancer.gov/protocolDevelopment/policies_deviations.htm).
In calculating days of tests and measurements, the day a test or measurement is done is considered Day
0. Therefore, if a test is done on a Monday, the Monday 4 weeks later would be considered Day 28. If Day
28, 42, or 56 falls on a weekend or holiday, the limit may be extended to the next working day.
5.1
Registration Step 1 – Specimen Submission
Disease Related Criteria
a.
Patients must be suspected to have previously untreated acute myelogenous
leukemia (AML) or myelodysplastic syndrome with excess blasts-2 (MDS-EB-2).
b.
Patients must be ≥60 years of age.
c.
Patients must not be known to have AML in the CNS.
Specimen Submission Criteria
d.
Patients must have specimens submitted for FLT3 testing for  randomization
stratification. Collection of pretreatment specimens must be completed within 1
day of registration to Step 1. Specimens must be submitted via the SWOG
Specimen Tracking System as outlined in Section 15.2. FLT3 results will be used
for stratification purposes at the time of randomization. E-mail notification of
randomization assignment must be received prior to Step 2 registration.


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e.
Patients must be offered participation in specimen banking as outlined in Section
15.3.
With patient consent, pretreatment specimens must be  collected and
submitted via the SWOG Specimen Tracking System as outlined in Section 15.3.
Prior/Concurrent Therapy Criteria
f.
Patients who have received prior therapy with midostaurin, any anti-PD-1 or anti-
PD-L1 therapy, any DNA-methyltransferase inhibitor (including hypomethylating
agents such as azacitidine, decitabine, or other investigational agent that acts by
inhibiting DNA or RNA methylation) for any condition, or prior intensive cytotoxic
therapy for MDS, are not eligible.
g.
Patients must be able to swallow oral medications without crushing or chewing.
Clinical/Laboratory Criteria
h.
Prior malignancy is allowed providing it does not require concurrent therapy.
Exception: Active hormonal therapy is allowed.
i.
Patients must not be pregnant or nursing, due to the teratogenic potential of the
drugs used on this study. Women/men of reproductive potential must have agreed
to use an effective contraceptive method. A woman is considered to be of
"reproductive potential" if she has had menses at any time in the preceding 12
consecutive months. In addition to routine contraceptive methods, "effective
contraception also  includes (but is not limited to) heterosexual celibacy and
surgery intended to prevent pregnancy (or with a side-effect of pregnancy
prevention) defined as a hysterectomy, bilateral oophorectomy, bilateral tubal
ligation, or vasectomy. However, if at any point a previously celibate patient
chooses to become heterosexually active during the time period for use of
contraceptive measures outlined in the protocol, he/she is responsible for
beginning contraceptive measures.
Women must agree to avoid breast-feeding and women of child-bearing potential
(WOCBP) must agree to use highly effective contraception while receiving study
drug and for a period of 31 weeks after the last dose of study drug. Sexually-active
men must agree to use a condom while receiving study drug and for 31 weeks
after the last dose of study drug. Vasectomized men must also agree to use a
condom to avoid delivering drug in the seminal fluid.
Regulatory Criteria
j.
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.
As a part of the OPEN registration process (see Section 13.3 for OPEN access
instructions) the treating institution's identity is provided in order to ensure that the
current (within 365 days) date of institutional review board approval for this study
has been entered in the system.
5.2
Registration Step 2 – Randomization
Patients must be registered to Step 2 no more than 42 days after registration to Step 1 and
no more than 42 days after collection of specimens for FLT3 testing.


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Disease Related Criteria
a.
Patients must have morphologically confirmed, previously untreated acute myeloid
leukemia (AML) or MDS with excess blasts-2 (MDS-EB-2).
Patients with acute promyelocytic leukemia (APL), biphenotypic leukemia, blastic
transformation of chronic myelogenous leukemia (CML or BCR/ABL), are not
eligible.
Patients must have disease present in the blood or bone marrow; patients with
only extramedullary disease in the absence of bone marrow or blood involvement
are not eligible.
All tests for establishing baseline disease status eligibility must be based on blood
and/or bone marrow examination performed within 42 days prior to randomization
(registration Step 2).
b.
Patients must not be known to have AML in the CNS.
c.
Patients must be deemed, in the judgment of the treating physician, to be ineligible
for intensive induction therapy, or must have refused intensive induction therapy.
Rationale for clinical determination or notation of patient decision must be made
on the S1612 Onstudy Form.
d.
Pretreatment cytogenetics must be performed on all patients as outlined in Section
15.4.
Collection of pretreatment specimens must be completed within 42 days
prior to randomization (registration Step 2). Reports of the results must be
submitted as outlined in Sections 14.4 and 15.4.
Specimen Submission Criteria
e.
FLT3 results will be used for stratification purposes at the time of randomization.
E-mail notification that FLT3 specimens have been processed must be received
prior to randomization (registration Step 2).
Prior/Concurrent Therapy Criteria
f.
Prior treatment with hydroxyurea is permitted (see Section 7.2 for information
regarding use of hydroxyurea while on protocol therapy).
Prior ATRA for
suspected APL and prior intrathecal therapy are permitted, but must plan to be
discontinued prior to initiating protocol therapy. Patients with signs/symptoms of
hyperleukocytosis or WBC ≥50,000/mcL can be treated with leukapheresis prior
to randomization (registration to Step 2).
g.
Patients may have received non-intensive therapy for antecedent hematologic
disorders, including lenalidomide. Patients may have received prior chemotherapy
for prior cancers. These therapies must be discontinued at least 5 days prior to
randomization (registration to Step 2).
h.
Patients who are transfusion-dependent and patients receiving growth  factor
support are eligible. Patients must discontinue growth factor support prior to
initiation of protocol therapy.
Clinical/Laboratory Criteria
i.
The following tests must be performed within 14 days prior to randomization
(registration to Step 2) to establish baseline values:


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x
Performance Status
x
CBC/Differential/Platelets
x
Creatinine Clearance (Cockcroft-Gault)*
x
Total Bilirubin
x
AST and ALT
x
LDH
x
Albumin
x
Glucose
x
Fibrinogen
x
ECG (see Section 5.3b, Arm C)
*CCR = (140-age) x wt (kg) x 0.85 (if female)
72 x creatinine (mg/dl)
j.
Patients must have complete history and physical examination within 28 days prior
to randomization  (registration to Step 2).  History must include autoimmune
disease status (to determine whether patient is eligible for Arm B, see Section
5.3a).
k.
Patients must not have active infection (systemic bacterial, fungal, or viral
infection) that is not controlled (defined as exhibiting ongoing signs/symptoms
related to the infection and without improvement despite appropriate antibiotics or
other treatment).
Regulatory Criteria
l.
Patients must be eligible for at least one of the currently active investigational
treatment arms (S1612B or S1612C). If the patient does not meet eligibility criteria
for at least one active investigational arm, then the patient is not eligible for S1612.
See Section 5.3 for treatment arm specific eligibility criteria.
m.
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.
5.3
Treatment Arm Specific Eligibility Criteria for Active Treatment Arms
a.
Arm B (Azacitidine + Nivolumab)
1.
Patients must not have active autoimmune disease that has required
systemic treatment in past 2 years (i.e., with use of disease modifying
agents,
corticosteroids
or
immunosuppressive
drugs).
Replacement
therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement
therapy for adrenal or pituitary insufficiency, etc.) is not considered a form
of systemic treatment.
2.
Additional Arm-Specific Laboratory/Treatment Criteria
x
Patients must have AST and ALT ≤2.5 x IULN.
x
Patients must have total bilirubin ≤1.5 x IULN.
x
Patients must have baseline troponin test performed for eligibility;
however, no associated values must be met in order for the patient to
be eligible.


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b.
Arm C (Azacitidine + Midostaurin)
1.
Additional Arm-Specific Laboratory/Treatment Criteria
x
Patients must have total bilirubin ≤2.5 x IULN.
x
Patients must have creatinine clearance ≤ 2.5 x IULN.
x
Patients must have QTc interval < 500/msec (by Bazett’s formula) on
baseline ECG.
x
Patients must not have any history of hypersensitivity to any drugs or
metabolites of midostaurin.
c.
All tests for establishing baseline values must be completed within 14 days prior
to registration to Step 2 (randomization).
6.1
STRATIFICATION FACTORS
A dynamic allocation scheme will be used to balance the randomization (registration Step 2) on the
following stratification factors within arms between which a patient is eligible to be randomized (17):
1.
PS (PS 0-1 versus PS 2-4).
2.
FLT3-ITD status (wild type FLT3 versus mutated FLT3-ITD versus non-evaluable) based
on central laboratory results.
Baseline blast percentage (MDS-EB-2 [< 20%] versus AML [20% or higher]).
7.0
TREATMENT PLAN
For treatment or dose modification questions, please contact the Study Chairs listed for the specific
treatment arm in which the patient is enrolled. For dosing principles or questions, please consult
the SWOG Policy #38 "Dosing Principles for Patients on Clinical Trials" at http://swog.org (then
click on "Policies and Manuals" under the "Visitors" menu and choose Policy 38).
Treatment may be administered on an inpatient or outpatient basis, at the discretion of the treating
physician.
7.1
Treatment
a.
Arm A: Azacitidine (Control)
For treatment or dose modification questions, please contact Dr. Laura Michaelis
and Dr. Roland Walter (S1612A@swog.org).
Azacitidine may be administered on either a 7-day continuous schedule or a 7-day
interrupted schedule (e.g. 5-2-2: azacitidine administered Days 1-5 followed by 2
days of no treatment followed by 2 days of azacitidine
administration). Any
interrupted schedule is allowable, providing the entire 7-day dose is given within a
total of no more than 12 calendar days. The Study Chair(s) should be contacted if
there are questions regarding the dosing schedule.
Patients should continue treatment on protocol as long as they are deriving clinical
benefit in the opinion of the treating physician for up to 5 years from randomization,
or until one of the criteria in Section 7.4 has been met.


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Agent
Dose
Route
Day
Schedule*
Azacitidine
75 mg/m2/day
SC or IV
1-7#
Every 28 days
* One cycle = 28 days.
# Azacitidine may be administered continuously for 7 days (e.g., Days 1-7) or with
breaks (e.g., Days 1-5 and 8-9) within no more than 12 calendar days.
Patients receiving intravenous azacitidine may be switched to subcutaneous
administration
if
venous
access
becomes
difficult.
Patients
receiving
subcutaneous azacitidine may be switched to intravenous, at the discretion of the
treating physician.
Treatment interruptions should be documented on the
appropriate treatment summary form.
For dose delays > 45 days, the Study Chairs should be contacted to discuss
whether treatment should be continued.
b.
Arm B: Azacitidine + Nivolumab
For treatment or dose modification questions, please contact Dr. Sarit Assouline
and Dr. Annette Hay (S1612B@swog.org).
Patients should continue treatment on protocol as long as they are deriving clinical
benefit in the opinion of the treating physician for up to 5 years from randomization,
or until one of the criteria in Section 7.4 has been met.
Before starting treatment, patients should receive baseline ECHO, if clinically
indicated.
Agent
Dose
Route
Day
Schedule*
Azacitidine
75 mg/m2/day
SC or IV
1-7#
Every 28 days
Nivolumab
3 mg/kg
IV over
30-60 mins
1 and 15
Every 28 days
* One cycle = 28 days.
# Azacitidine may be administered continuously for 7 days (e.g., Days 1-7) or with
breaks (e.g., Days 1-5 and 8-9) within no more than 12 calendar days.
Patients receiving intravenous azacitidine may be switched to subcutaneous
administration
if
venous
access
becomes
difficult.
Patients
receiving
subcutaneous azacitidine may be switched to intravenous, at the discretion of the
treating physician.
Treatment interruptions should be documented on the
appropriate treatment summary form.
c.
Arm C: Azacitidine + Midostaurin
For treatment or dose modification questions, please contact Dr. Laura Michaelis
and Dr. Roland Walter (S1612C@swog.org).
Patients should continue treatment on protocol as long as they are deriving clinical
benefit in the opinion of the treating physician for up to 5 years from randomization,
or until one of the criteria in Section 7.4 has been met.


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Agent
Dose
Route
Day
Schedule*
Azacitidine
Midostaurin
75 mg/m2/day
50 mg (twice/day)^
SC or IV
orally
1-7#
8-21
Every 28 days
Every 28 days
* One cycle = 28 days.
# Azacitidine may be administered continuously for 7 days (e.g., Days 1-7) or with
breaks (e.g., Days 1-5 and 8-9) within 12 calendar days.
^ Administered with water following meals. Doses are to be separated by 12
hours. Total daily intake will be 4 capsules (2 capsules of 25 mg each every 12
hours).
Patients receiving intravenous azacitidine may be switched to subcutaneous
administration
if
venous
access
becomes
difficult.
Patients
receiving
subcutaneous azacitidine may be switched to intravenous, at the discretion of the
treating physician.
Treatment interruptions should be documented on the
appropriate treatment summary form.
d.
Arm D: Decitabine + Cytarabine
For treatment or dose modification questions, please contact Dr. Annie Im and Dr.
James Foran (S1612D@swog.org).
           Pre-Medication
Patients will receive ondansetron 8 mg PO 30 minutes prior to each dose
of decitabine and 30 minutes prior to start of administration of each 24-
hour bag of cytarabine.
Patients may receive dexamethasone 4 mg PO prior to cytarabine
administration.
           Treatment
a.
Induction
Agent
Dose
Route
Day  Schedule*
Decitabine  20mg/m2/day  IV (over 2 hrs)  1-5
Every 28 days
Cytarabine 100 mg/m2
IV (cont)
6-11 Every 28 days
* One cycle = 28 days.
Patients may receive up to 2 cycles of Induction treatment.
Patients will continue to Maintenance treatment if the patient is
deemed stable, at the discretion of the treating physician. Patients
not deriving clinical benefit in the opinion of the treating physician
within 2 cycles of Induction treatment will be removed from
protocol therapy (see Section 7.4).


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b.
Maintenance
Agent
Dose
Route
Day  Schedule*
Decitabine 20mg/m2/day  IV (over 2 hrs)  1-5
Every 28 days
* One cycle = 28 days.
During Maintenance, patients experiencing treatment delay > 8
weeks with delay in count recovery should be assessed for
relapse, with bone marrow examination at the discretion of the
treating physician. Patients should continue Maintenance therapy
as long as they are deriving clinical benefit in the opinion of the
treating physician for up to 5 years from randomization, or until
one of the criteria in Section 7.4 is met.
7.2
Concomitant Therapies
a.
Supportive Therapies
           Antiemetic and antidiarrheal medications will be used per standard
practices. It is recommended that serotonin (5-HT3) receptor antagonists
should be administered approximately 30 minutes prior to subcutaneous
administration of azacitidine.
           Antibiotic prophylaxis: Patients may receive prophylaxis directed against
gram-negative gastrointestinal infections, candidiasis, and/or herpes
simplex virus, per individual institutional practices.
           See Section 7.3c regarding use of growth factors.
           Blood product transfusions and related supportive care should be
administered per local institutional standards.
b.
Prohibited Therapies
Prohibited concomitant therapies include investigational agents, androgens,
supraphysiologic doses of corticosteroids, erythropoietin, or chemotherapeutic
agents active against MDS.
c.
Concomitant Therapy
           Concomitant Anti-Infective Prophylaxis and Treatment
It is highly recommended to avoid concomitant strong CYP3A4 inhibitors (e.g.,
ketoconazole,
itraconazole,
voriconazole,
posaconazole).
The
suggested
antifungal regimens from a drug metabolism perspective are described below:
Prophylaxis
a.
Fluconazole (moderate CYP3A4 inhibitor)
b.
Micafungin
If a patient requires active treatment for a fungal or mold infection and the only
treatment options is an azole that is a strong CYP3A4 inhibitor, then the suggested
agents from a drug metabolism and safety perspective include:


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Treatment
c.
Isavuconazole
or
d.
Voriconazole
e.
Posaconazole
           CYP Metabolization
a.
General
Isavuconazole is a moderate inhibitor of CYP34A. The other two
are both strong CYP3A4 inhibitors and will likely increase
midostaurin concentrations. With intra-patient variability with
regard to CYP3A4 inhibition and midostaurin pharmacokinetics,
the suggested approach is to avoid strong CYP3A4 inhibitors
unless there are no treatment alternatives. If CYP24A inhibitors
are used, monitor patients closely for toxicity. Elderly patients may
be particularly prone to toxicities. See Appendix 18.2, Drugs
Known to be Metabolized by CYP450 Isoenzymes 2D6 and 3A4.)
b.
Arm C (Azacitidine + Midostaurin)
Patients in Arm C should have non-essential medications that are
strong CYP3A inhibitors discontinued (see Appendix 18.4). If
these medications must be continued, then Patients in Arm C
should be monitored for adverse reactions with medications that
are strong CYP3A inhibitors, especially during the first week of
midostaurin   treatment,   according   to    the    package insert.
Information regarding concurrent administration of midostaurin
and
CYP3A
inhibitors
must
be
documented
(dates
of
administration,
the
specific
CYP3A
inhibitor(s),
duration
of
concurrent administration) and the adverse event (onset of event,
severity, duration, and details regarding PK [as available]) must
be captured
in the comments section
of the S1612
Adverse
Events Form.
7.3
General Supportive Care Guidelines
a.
Patients
receiving
hydroxyurea
prior
to
randomization
must
discontinue
hydroxyurea within 14 days of initiation of protocol therapy. It is recommended
that leukocytosis be controlled, in the judgment of the treating physician, prior to
initiation of protocol therapy.
b.
Supportive care will be given to each patient per local institutional guidelines,
unless otherwise specified for a specific treatment arm.
c.
White Blood Cell Growth Factors
If used, white blood cell growth factors, including biosimilars, must be used per
ASCO
guidelines
(http://jco.ascopubs.org/content/24/19/3187.full)
and
NCCN
Guidelines®
Myeloid
Growth
Factors
(http://www.nccn.org/professionals/physician_gls/pdf/myeloid_growth.pdf).


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7.4
Criteria for Removal from Protocol Treatment
a.
Unacceptable toxicity.
b.
The patients may withdraw from the study at any time for any reason.
c.
The treating physician may remove the patient for treatment failure, progressive
disease, or relapse, at their discretion; however, it is not required that patients be
removed from protocol therapy for disease progression or relapse, if, in the opinion
of the treating physician, remaining on protocol therapy is in the patient’s best
interest. Information regarding disease progression and relapse will be reported
in the S1612 Disease Assessment Form, per the requirements in Section 14.0.
d.
Patient becomes pregnant.
7.5
Discontinuation of Treatment
All reasons for discontinuation of treatment must be documented in the Off Treatment
Notice.
7.6
Follow-Up Period
All patients will be followed until death or 5 years after randomization (registration to Step
2), whichever occurs first. Patients not registered to Step 2 will not be followed beyond
documentation of reason for not being randomized (see Section 14.4b)
8.0
TOXICITIES TO BE MONITORED AND DOSE MODIFICATIONS
8.1
NCI Common Terminology Criteria for Adverse Events
This study will utilize the CTCAE (NCI Common Terminology Criteria for Adverse Events)
Version 5.0 for toxicity and Serious Adverse Event reporting. A copy of the CTCAE Version
5.0 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 5.0.
8.2
Toxicity Monitoring and Dose Modification Information
a.
General Considerations
           Dose modifications will be based on the toxicity requiring the largest dose
reduction.
           Dose modifications may be made for individual drugs if, in the judgment of
the treating physician, the toxicity is attributable to one drug.
           For Arm C (azacitidine + midostaurin), if patients must permanently
discontinue treatment with azacitidine, the patient must be removed from
protocol therapy; continued monotherapy with midostaurin will not be
permitted. For all other arms with multiple drugs, if either drug must be
permanently discontinued, the patient may remain on protocol treatment
with the remaining drug, at the discretion of the treating physician.


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b.
Azacitidine (Arm A, Arm B, and Arm C)
           General Considerations
a.
Both subcutaneous and IV administered azacitidine will follow the
same dose reduction schema.
b.
Each treatment cycle will be 28 calendar days, regardless of
whether treatment is held during a cycle. As needed, delays are
allowed between the end of one treatment cycle and the start of
the next treatment cycle.
c.
Dose Re-Escalation
If a patient has undergone dose reduction because of an adverse
event, and
the adverse event does not recur during
the
subsequent cycle, the dose may be re-escalated to the dose
administered when the event occurred. Patients may have their
dose re-escalated because initial adverse events commonly
associated with azacitidine may not occur as patients begin to
respond to therapy, and continued dose reduction may impact
long-term efficacy. However, if the dose of azacitidine is modified
during the course of the study and the investigator believes benefit
is demonstrated at a dose lower than 75 mg/m2, that dose may
be maintained during subsequent cycles that are given (unless
toxicity develops).
           Toxicity Monitoring and Dose Modification Information
a.
Dose Adjustments: General
Both subcutaneous and IV administered azacitidine will follow the
same dose reduction schema.
No dose adjustments will be allowed during Cycle 1.
After Cycle 1, azacitidine dose should be adjusted per the
guidelines below for non-hematologic toxicities. After cycle 2,
azacitidine dose should be adjusted per the guidelines below for
hematologic toxicities
b.
Dose Adjustment Based on Hematology Laboratory Values
Hematologic
toxicity,
including
anemia,
neutropenia,
and
thrombocytopenia, can occur with azacitidine therapy, particularly
during the first 2 cycles. Complete blood counts should be
performed per local institutional standards.
If a patient, prior to protocol treatment, does not have reduced
blood counts, (i.e. WBC is > 3.0 x 109, ANC > 1.5 x 109/L, and
platelets > 75.0 x 109/L), then the platelet count and ANC should
recover prior to the next cycle. Recovery is defined as an increase
of cell line(s) where hematological toxicity was observed of at least
half of the difference of nadir and the baseline count plus the nadir
count (i.e., blood count at recovery ≥nadir count + (0.5 x [baseline
count – nadir count]). If recovery is achieved within 14 days, no
dose adjustment is necessary. However, if recovery has not been


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achieved within 14 days, the dose should be reduced per the table
below. Following dose modifications, the cycle duration should
return to 28 days. The reduced dose should be maintained during
subsequent cycles that are given (unless toxicity develops).
Nadir Counts
% Dose in the next
Cycle if recovery1 is
not achieved in next
14 days
ANC (x 109/L)
Platelets (x 109/L)
≤ 1.0
≤ 50.0
50%
> 1.0
> 50.0
100%
1 Recovery = counts ≥Nadir Count + (0.5 x [baseline count – nadir
count]).
For subjects with reduced baseline blood counts (i.e., WBC count
< 3.0 x 109/L or ANC < 1.5 x 109/L or platelets < 75.0 x 109/L)
prior to treatment, if the decrease in WBC/ANC/platelets from that
prior to treatment is < 50%, or > 50% but with an improvement in
a different cell line, the next cycle should not be delayed and no
dose adjustment made.
If the decrease in WBC/ANC/platelets is > 50% from that prior to
treatment, with no improvement in cell line differentiation, the next
cycle of azacitidine therapy should be delayed until the platelet
count and the ANC have recovered, as defined above. If recovery
is achieved within 14 days, bone marrow cellularity should be
determined. If the bone marrow cellularity is > 50%, no dose
adjustments should be made. If bone marrow cellularity is ≤50%,
treatment should be delayed and the dose reduced per the
following table.
Bone 
Marrow
Cellularity
% Dose in the next Cycle if recovery1 is
not achieved in next 14 days
Recovery ≤21
days
Recovery > 21
days
15-50%
100%
50%
< 15%
100%
33%
1 Recovery = counts ≥nadir count + (0.5 x [baseline count – nadir
count]).
Following dose modifications, the cycle duration should return to
28 days.
The reduced dose should be maintained during
subsequent cycles that are given (unless toxicity develops).
c.
Dose Adjustment Based on Renal Function:
If creatinine clearance is > 1.5 x IULN, the azacitidine dose may
be reduced by up to 50%. Renal abnormalities ranging from
elevated creatinine clearance to renal failure and death were
reported rarely in subjects treated with intravenous azacitidine in
combination with other chemotherapeutic agents. In addition,
renal tubular acidosis, defined as a fall in serum bicarbonate to <
20 mmol/L in association with an alkaline urine and hypokalemia
(serum potassium < 3 mmol/L) developed in 5 subjects with


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chronic myelogenous leukemia (CML) treated with azacitidine and
etoposide.
If unexplained reductions in serum bicarbonate (< 20 mmol/L)
occur, the dose should be reduced by 50% on the next course.
Similarly, if unexplained elevations in creatinine clearance or
blood urea nitrogen (BUN) to ≥2-fold above baseline values and
above ULN occur, the next cycle should be delayed until values
return to normal or baseline and the dose should be reduced by
50% on the next treatment cycle. The reduced dose should be
maintained during subsequent cycles that are given (unless
toxicity develops).
d.
Additional Azacitidine Dose Modification
Toxicity
Modification
Grade 3 or 4 Non-
Hematologic
Toxicity (possibly,
probably, or
definitely related to
azacitidine)
Hold azacitidine until toxicity
resolves to ≤Grade 2 (or baseline).
If toxicity does not resolve within 3
weeks, remove patient from protocol
treatment.
Creatinine
Clearance > 1.5 x
IULN
Reduce azacitidine dose by 50%
until resolved to ≤ 1.5 x IULN, then
resume full dose.
c.
Nivolumab (Arm B)
           General Considerations
c.
Patients experiencing ≤Grade 2 adverse event related to
nivolumab may receive pre-medications at the discretion of the
treating investigator, per local institutional guidelines.
d.
No dose modifications of nivolumab will be allowed, except as
outlined
below. Adverse
events
will
be
managed
per
the
guidelines below. See Section 8.2c.4c for dose modification and
management for cardiomyopathy myocarditis.
e.
Dose interruptions will be based on adverse event severity on the
day of planned therapy.
f.
Treatment with nivolumab may be delayed for up to 56 days.
During this time, patients may continue to receive azacitidine at
the discretion of the treating physician/local investigator.
           Management Algorithms for Immuno-Oncology Agents
Immuno-oncology agents such as nivolumab are associated with AEs that
can differ in severity and duration than AEs caused by other therapeutic
classes. Early recognition and management of AEs associated with
immuno- oncology agents may mitigate severe toxicity. Management
Algorithms have been developed to assist investigators in assessing and
managing the following groups of AEs: (I-O).
See Section 8.2g for toxicity management and follow-up algorithms for
endocrinopathy, gastrointestinal, hepatic, neurological, pulmonary, renal,


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and skin adverse events. Note: Per the link below, Prednisone PO, or
other equipotent steroid, may be utilized in place of methylprednisolone
IV.
           Concomitant Corticosteroid Treatment for Management of Immune-
Related Reactions
For guidance on allowable concomitant corticosteroid treatment and
tapering of steroids, please see:
http://www.accessdata.fda.gov/drugsatfda_docs/rems/Yervoy_2012-02-
16_Full.pdf.
           Dose Delays
a.
In addition to the AEs identified in the tables below, nivolumab
dose should be delayed for any AE, laboratory abnormality or
inter-current illness which, in the judgment of the investigator,
warrants delaying the dose of study medication.
b.
Patients requiring a delay of > 8 weeks, or who experience
immune-related toxicity with inability to decrease with prednisone
< 10mg PO daily, must permanently discontinue nivolumab.
Patients who received systemic corticosteroids for management
of
any
drug-related
immunologic
toxicity
must
be
off
corticosteroids or have tapered down to an equivalent dose of
prednisone 10 mg/day
1.
Dosing delays to manage drug-related adverse events,
such as prolonged steroid tapers, are allowed.
Assessments should continue as per protocol even if
dosing is delayed.
d.
Dose Modification and Management
           Dose Modification and Management for Cardiomyopathy Myocarditis
x
Drug will be held for Grade 2 cardiac dysfunction pending evaluation
x
Drug will be permanently discontinued for Grade 3 or 4 cardiac
dysfunction and Grade 2 events that do not recover to baseline or
that reoccur
x
Treatment with steroids as clinically indicated
Cardiac *
Management/Next Dose for BMS-936558
(Nivolumab) Cardiac Toxicities
≤Grade 1
Hold dose pending evaluation and observation.**
Evaluate for signs and symptoms of CHF, ischemia,
arrhythmia or myositis. Obtain history EKG, CK (for
concomitant myositis), CK-MB. Repeat troponin, CK
and EKG 2-3 days. If troponin and labs normalize
may resume therapy. If labs worsen or symptoms
develop then treat as below. Hold pending
evaluation.
Grade >2 with
suspected
myocarditis
Hold dose.** Admit to hospital. Cardiology consult.
Rule out MI and other causes of cardiac disease.
Cardiac Monitoring. Cardiac Echo. Consider


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Cardiac *
Management/Next Dose for BMS-936558
(Nivolumab) Cardiac Toxicities
cardiac MRI and cardiac biopsy. Initiate high dose
methylprednisolone. If no improvement within 24
hours, add either infliximab, ATG or tacrolimus.
Resume therapy if there is a return to baseline and
myocarditis is excluded or considered unlikely.
Grade >2 with
confirmed
myocarditis
Off protocol therapy. Admit to CCU (consider
transfer to nearest Cardiac Transplant Unit, if
appropriate). Treat as above. Consider high dose
methylprednisolone.
Add ATG or tacrolimus if no improvement. Off
treatment.
*
Including CHF, LV systolic dysfunction, Myocarditis, CPK, and
troponin.
**
Patients with evidence of myositis without myocarditis may be
treated according as “other event”.
Note: The optimal treatment regimen for immune mediated
myocarditis has not been established. Since this toxicity has
caused patient deaths, an aggressive approach is recommended.
           Dose Modification and Management for Other Adverse Events
Treatment-related
Adverse Event
Grade of
Event
Management/Next Dose for
Nivolumab
Nephritis
≤Grade 1
No change.
Grade 2
Hold nivolumab until < Grade 2.
Grade 3
Hold nivolumab until < Grade 2.
Grade 4
Off protocol therapy.
Diarrhea (immune-
related enterocolitis)
≤Grade 1
No change.
Grade 2
Hold until < Grade 2
Grade 3
Hold nivolumab until < Grade 2.
Grade 4
Off protocol therapy.
Endocrinopathy
(hypophysitis,
adrenal 
insufficiency, Type 1
diabetes
≤Grade 1
No change.
Grade 2
Hold until < Grade 2.
Grade 3
Hold until < Grade 2.
Grade 4
Off protocol therapy.
(Note: Asymptomatic hypothyroidism does
not require dose modification.)
Neuropathy (new,
motor, sensory,
encephalitis)
≤Grade 1
No change.
Grade 2
Hold nivolumab until < Grade 2.
Grade 3
Off protocol therapy.
Grade 4
Off protocol therapy.
Drug-related uveitis,
eye pain, or blurred
vision
≤Grade 1
No change.
Grade 2
Hold nivolumab until < Grade 1.
If Grade 2 event does not
respond to topical therapy and
does not improved to Grade 1
within the re-treatment period,
patient must go off protocol
therapy.
Grade 3
Off protocol therapy.
Grade 4
Off protocol therapy.
≤Grade 1
No change.


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Treatment-related
Adverse Event
Grade of
Event
Management/Next Dose for
Nivolumab
Skin drug-related
AE
Grade 2
No change.
Grade 3
Hold nivolumab until < Grade
3.
Grade 4
Off protocol therapy.
Pneumo-nitis,
broncho-spasm,
pulmonary toxicity
or interstitial lung
disease
≤Grade 1
No change.
Grade 2
Hold nivolumab until event
resolves to baseline.
Grade 3
Off protocol therapy.
Grade 4
Off protocol therapy.
Above does not include infusion reactions. See
also: Appendix 18.3.
Other, Non-skin,
drug-related adverse
events
≤Grade 1
No change.
Grade 2
Hold nivolumab until < Grade 2.
Grade 3
Hold nivolumab until < Grade 2.
Grade 4
Off protocol therapy.
Above does not include infusion/
hypersensitivity reactions, laboratory
abnormalities or AEs otherwise indicated in this
table.
1   In event of recurrence of same Grade 3
adverse reaction, patient should be removed
from protocol therapy.
Infusion / hypersen-
sitivity reactions
(manifestation may
include: fever,
chills, rigors,
headache, rash,
pruritus, arthralgia,
hypotension,
hyperten-sion,
broncho-spasm)
≤Grade 1
Remain at bedside and
monitor subject until recovery
from symptoms. Following
prophylactic premedication is
recommended for future
infusions: diphenhydramine 50
mg (or equivalent) and/or
acetaminophen/ paracetamol
325 to 1000 mg at least 30
minutes before additional
administration. No change in
dose for future administration.
Grade 2
•
Stop infusion, begin an IV
infusion of normal saline,
and treat the subject with
diphenhydramine 50 mg IV
(or equivalent) and/or
acetaminophen/paracetam
ol 325 to 1000 mg; remain
at bedside and monitor
subject until resolution of
symptoms. Corticosteroid
(e.g. hydrocortisone 50-
100mg) and/or
bronchodilator therapy may
also be administered as
appropriate if reaction is
severe or patient not
responding to
diphenhydramine or
acetaminophen.


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Treatment-related
Adverse Event
Grade of
Event
Management/Next Dose for
Nivolumab
•
If the infusion is
interrupted, then restart the
infusion at 50% of the
original infusion rate when
symptoms resolve; if no
further complications ensue
after 30 minutes, the rate
may be increased to 100%
of the original infusion rate.
•
Monitor subject closely. If
symptoms recur, then no
further drug will be
administered at that visit.
•
Administer
diphenhydramine 50 mg IV,
and remain at bedside and
monitor the subject until
resolution of symptoms.
The amount of study drug
infused must be recorded
on the electronic case
report form (eCRF).
•
For future infusions,
following prophylactic pre-
medications are
recommended:
diphenhydramine 50 mg (or
equivalent) and/or
acetaminophen
/paracetamol 325 to 1000
mg should be administered
at least 30 minutes before
nivolumab infusions. If
necessary, corticosteroids
(up to 25 mg of
hydrocortisone or
equivalent) may be used if
premedication with
diphenhydramine and
acetaminophen is not
sufficient to prevent
infusion reactions.
Infusion / hypersen-
sitivity reactions
(manifest-ation may
include: fever, chills,
rigors, headache,
rash, pruritus,
arthralgia, hypoten-
sion, hypertension,
broncho-spasm)
Grade 3 or
Grade 4
•
Immediately discontinue
infusion. Begin an IV
infusion of normal saline
and treat the subject as
follows: Recommend
bronchodilators,
epinephrine 0.2 to 1 mg of a
1:1000 solution for
subcutaneous
administration or 0.1 to 0.25
mg of a 1:10,000 solution
injected slowly for IV
administration, and/or
diphenhydramine 50 mg IV


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Treatment-related
Adverse Event
Grade of
Event
Management/Next Dose for
Nivolumab
with methylprednisolone
100 mg IV (or equivalent),
as needed. Subject should
be monitored until the
investigator is comfortable
that the symptoms will not
recur.
•
Permanently discontinue
drug. Investigators should
follow their institutional
guidelines for the treatment
of anaphylaxis. Remain at
bedside and monitor subject
until recovery of the
symptoms.
•
In case of late-occurring
hypersensitivity symptoms,
symptomatic treatment may
be given (e.g., oral
antihistamine or
corticosteroids).
All Grade 3 or 4 infusion reactions should be
reported within 24 hours to the Arm B Study
Chairs at: S1612B@swog.org AND reported as
an SAE if criteria are met. Infusion reactions
should be graded according to NCI CTCAE
(Version 4.0) guidelines.
Note: Treatment guidelines may be modified
based upon local SOPs, as appropriate.
Thrombocytopenia*
≤Grade 1
No change.
Grade 2
Hold nivolumab until < Grade 2.
Grade 3
Hold nivolumab until < Grade 2.
Grade 3 drug-related
thrombocytopenia > 7 days and
associated with bleeding
requires discontinuation from
protocol.
Grade 4
Off protocol therapy.
Neutropenia*
≤Grade 1
No change.
Grade 2
Hold nivolumab until < Grade 2.
Grade 3
Hold nivolumab until < Grade 2.
Grade 4
Off protocol therapy.
Abnormal liver
function (AST/ALT,
Total bilirubin,
immune-related
hepatitis)
≤Grade 1
No change.
Grade 2
No change
Grade 3
Hold nivolumab until < Grade 3.
If AST/ALT>8x ULN or bilirubin
>5x ULN, off protocol therapy
Grade 4
Off protocol therapy.
Amylase or lipase,
associated with GI
symptoms
≤Grade 1
No change.
Grade 2
No change.
Grade 3
No change if asymptomatic. If
GI symptoms, hold nivolumab


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Treatment-related
Adverse Event
Grade of
Event
Management/Next Dose for
Nivolumab
until asymptomatic and <
Grade 3.
Grade 4
Off protocol therapy.
Note: Isolated Grade 4
abnormalities that are not
associated with symptoms or
clinical manifestations of
pancreatitis and decrease to <
Grade 4 within 1 week of onset,
do not require permanent
discontinuation. 1
1 Contact the Arm B Study Cha
S1612B@swog.org for consul
4 amylase or lipase abnormali
irs at:
tation on Grade
ties.
* If due to nivolumab toxicity; if due to leukemia infiltration, discuss with Study
Chair before reducing/holding drug.
e.
Midostaurin (Arm C)
Missed doses of midostaurin will not be made up.
Toxicity
Modification
Hematologic Toxicity
Grade 4 Neutropenia
Cycle 1: No modifications
Subsequent cycles: Hold midostaurin until ANC
≥1,000/mcL, then resume midostaurin at full
dose. If neutropenia persists for more than 2
weeks, discontinue midostaurin.
Pulmonary Toxicity
≥
Grade
3
pulmonary
infiltrate
Hold midostaurin until infiltrates resolve to ≤
Grade 1, then resume midostaurin at full dose.
Cardiac Toxicity
QTc interval > 450 msec
and
≤
470
msec
(by
Bazett’s formula)
Check magnesium and potassium levels and
correct any abnormalities. If possible, stop any
medication which may prolong QTc interval. No
dose reduction.
QTc interval > 470 msec
and
≤
500
msec
(by
Bazett’s formula)
Check magnesium and potassium levels and
correct any abnormalities. If possible, stop any
medication which may prolong QTc interval.
Decrease midostaurin to 50 mg once daily until
QTc improves to ≤470 msec, then resume
midostaurin at full dose.
QTc interval > 500 msec
(by Bazett’s formula)
Immediately
hold
midostaurin.
Check
magnesium and potassium levels and correct
any
abnormalities.
If
possible,
stop
any
medication which may prolong QTc interval.
If QTc interval improves to between > 470 msec
and ≤500 msec, restart midostaurin at 50 mg
once daily
Once QTc interval improves to ≤470 msec,
resume midostaurin at full dose.


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Toxicity
Modification
Hematologic Toxicity
If QTc remains > 470 for more than 3 weeks, hold
midostaurin until QTc interval improves to ≤470,
then resume midostaurin at full dose.
Other Non-Hematologic Toxicity
Grade 3 or Grade 4 non-
hematologic
toxicity,
at
least
possibly
related
to
midostaurin
Hold midostaurin until toxicity resumes to ≤
Grade 1, then resume midostaurin at full dose.
f.
Cytarabine and Decitabine (Arm D)
Dose Modifications and Delays
INDUCTION
Creatinine increase > 2.0 x
baseline or ULN (whichever is
higher)
(unless there is a reversible
etiology, e.g., no count recovery)
Delay treatment until resolved to baseline
or IULN (whichever is higher), then restart
treatment; no dose reduction required
ALT, AST, or total bilirubin > 5 x
ULN
Delay treatment until resolved to IULN,
then restart treatment; no dose reduction
required
MAINTENANCE
At the start of a new cycle, any
Grade 3 or 4 non-hematologic
toxicity that is possibly, probably,
or definitely related to decitabine
Delay treatment until resolved to ≤ Grade
2 or baseline (whichever is higher), then
restart treatment; no dose reduction is
required
Dose modifications outside of those outlined above will be allowed, but should first
be discussed with and approved by the Study Chairs.
g.
Management Algorithms for Immuno-Oncology Agents
Immuno-oncology agents such as nivolumab are associated with AEs that can
differ in severity and duration than AEs caused by other therapeutic classes. Early
recognition and management of AEs associated with immuno-oncology agents
may mitigate severe toxicity. Management Algorithms have been developed to
assist investigators in assessing and managing the following groups of AEs: (I-
O).
           Pulmonary Adverse Event Management
Toxicity
Toxicity Management and Follow-up
Pulmonary (i.e., Pneumonitis)
Any Grade
Patients should be thoroughly evaluated to rule out
non-inflammatory causes. If non-inflammatory cause
treat accordingly. Evaluate with imaging and
pulmonary consultation.
Grade 1
- Monitor for symptoms every 2-3 days
- Consider Pulmonary and Infectious Disease (ID)
consults
- Re-image at least every 3 weeks
If worsens:
- Treat as Grade 2 or 3-4


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Toxicity
Toxicity Management and Follow-up
Pulmonary (i.e., Pneumonitis)
Grade 2
- Consider Pulmonary and ID consults
- Monitor symptoms daily, consider hospitalization
- 1.0 mg/kg/day methylprednisolone IV or oral
equivalent
- Consider bronchoscopy, lung biopsy
- Re-image every 1-3 days
If improves:
- When symptoms return to near baseline, taper
steroids over at least 1 month, consider prophylactic
antibiotics
If not improving after 2 weeks or worsening:
- Treat as Grade 3-4
> Grade 3
- Hospitalize
- Pulmonary and ID consults
- 2-4  mg/kg/day methylprednisolone IV or oral
equivalent
- Add prophylactic antibiotics for opportunistic
infections
- Consider bronchoscopy, lung biopsy
If improves to baseline:
- Taper steroids over at least 6 weeks
If not improving after 48 hours or worsening:
- Add additional immunosuppression (e.g., infliximab,
cyclophosphamide, intravenous immunoglobulin
(IVIG), or mycophenolate mofetil)
           Gastrointestinal Adverse Event Management
Toxicity
Toxicity Management and Follow-up
Gastrointestinal (i.e., Diarrhea/Colitis)
Any Grade
Patients should be thoroughly evaluated to rule out
non-inflammatory causes. If non-inflammatory cause
treat accordingly. Opiates/narcotics may mask
symptoms of perforation. Infliximab should not be
used in cases of perforation or sepsis.
Grade 1
- Close monitoring for worsening symptoms.
- Educate patient to report worsening immediately
- Consider symptomatic treatment including
hydration, electrolyte replacement, dietary changes
(e.g., American Dietetic Association colitis diet), and
loperamide.
If worsens:
- Treat as Grade 2 or 3/4
Grade 2
–  Consider symptomatic treatment including
hydration, electrolyte replacement, dietary changes
(e.g., American Dietetic Association colitis diet),
and loperamide.
If persists > 5-7 days or recurs:
- 0.5-1.0 mg/kg/day methylprednisolone IV or oral
equivalent
- When symptoms improve to grade 1, taper steroids
over at least 1 month, consider prophylactic


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Toxicity
Toxicity Management and Follow-up
Gastrointestinal (i.e., Diarrhea/Colitis)
antibiotics for opportunistic infections
If worsens or persists > 3-5 days with oral steroids:
- Treat as Grade 3/4
> Grade 3
- 1.0 to 2.0 mg/kg/day methylprednisolone  IV or oral
equivalent
- Add prophylactic antibiotics for opportunistic
infections
- Consider lower endoscopy
If improves:
- Continue steroids until grade 1, then taper over at
least 1 month
If persists > 3-5 days, or recurs after improvement:
- Add infliximab 5 mg/kg (if no contraindication).
Note: Infliximab should not be used in cases of
perforation or sepsis
           Hepatic Adverse Event Management
Toxicity
Toxicity Management
Hepatic (Elevated LFTs – ALT, AST, Total Bilirubin)
Any Grade
Patients should be thoroughly evaluated to rule out
non-inflammatory causes. If non-inflammatory
cause treat accordingly. Consider imaging for
obstruction.
Grade 1
- Continue liver function tests (LFT) monitoring per
protocol
If worsens:
- Treat as Grade 2 or 3/4
Grade 2
- Increase frequency of LFT monitoring to every 3
days until resolution to baseline. Resume routine
monitoring
If elevations persist > 5-7 days or worsen:
- 0.5-1 mg/kg/day methylprednisolone IV or oral
equivalent and when LFT returns to grade 1 or
baseline, taper steroids over at least 1 month,
consider prophylactic antibiotics for opportunistic
infections
≥Grade 3
- Increase frequency of LFT monitoring to every 1-2
days
- 1.0 to 2.0 mg/kg/day methylprednisolone IV or oral
equivalent. The recommended starting dose for
Grade 4 hepatitis is 2 mg/kg/day
methylprednisolone IV.
- Add prophylactic antibiotics for opportunistic
infections
- Consult gastroenterologist
If returns to Grade 2:
- Taper steroids over at least 1 month
If does not improve in >3-5 days, worsens or
rebounds:
- Add mycophenolate mofetil 1 gram (g) twice daily


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Toxicity
Toxicity Management
(BID)
- If no response within an additional 3-5 days,
consider other immunosuppressants per local
guidelines
           Renal Adverse Event Management
Toxicity
Toxicity Management
Renal (i.e., Creatinine Increased)
Any Grade
Patients should be thoroughly evaluated to rule out
non-inflammatory causes. If non-inflammatory
cause treat accordingly.
Grade 1
- Monitor creatinine weekly until resolution to
baseline; resume routine creatinine monitoring per
protocol
If worsens:
- Treat as Grade 2 or 3/4
Grade 2-3
- Monitor creatinine every 2-3 days
- 0.5 to 1.0 mg/kg/day methylprednisolone  IV or oral
equivalent
- Consider renal biopsy
If returns to Grade 1:
- Taper steroids over at least 1 month, consider
prophylactic antibiotics for opportunistic infections
and routine creatinine monitoring per protocol
If elevations persist > 7 days or worsen:
- Treat as Grade 4
≥Grade 4
- Monitor creatinine daily
- 1.0-2.0 mg/kg/day methylprednisolone IV or oral
equivalent
- Consult nephrologist
- Consider renal biopsy
If returns to Grade 1:
- Taper steroids over at least 1 month and add
prophylactic antibiotics for opportunistic infections
           Skin Adverse Event Management
Toxicity
Toxicity Management
Skin (i.e., Rash, Macula-papular)
Any Grade
Patients should be thoroughly evaluated to rule out
non-inflammatory causes. If non-inflammatory
cause treat accordingly.
Grade 1
Consider symptomatic treatment including oral
antiprurities (e.g., diphenhydramine or hydrolyzine)
and topical therapy (e.g., urea cream).


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Toxicity
Toxicity Management
Skin (i.e., Rash, Macula-papular)
Grade 2
Consider symptomatic treatment including oral
antiprurities (e.g., diphenhydramine or hydrolyzine)
and topical therapy (e.g., urea cream).
If persists > 1-2 weeks or recurs:
- Consider skin biopsy
- Consider 0.5-1.0 mg/kg/day methylprednisolone IV
or oral equivalent. Once improving, taper steroids
over at least 1 month, consider prophylactic
antibiotics for opportunistic infections
If worsens:
- Treat as Grade 3/4
Grade 3
- Consider skin biopsy
- Dermatology Consult
- 1.0-2.0 mg/kg/day methylprednisolone IV or oral
equivalent
If improves to Grade 1:
- Taper steroids over at least 1 month and add
prophylactic antibiotics for opportunistic infections
Grade 4
- Consider skin biopsy
- Dermatology Consult
- 1.0-2.0 mg/kg/day methylprednisolone IV or oral
equivalent
If improves to Grade 1:
- Taper steroids over at least 1 month and add
prophylactic antibiotics for opportunistic infections
           Endocrinopathy Adverse Event Management
Toxicity
Toxicity Management
Endocrinopathy (Endocrine Disorders - adrenal insufficiency, ACTH
deficiency, hyper- or hypothyroidism, or glucose intolerance)
Any Grade
- Patients should be thoroughly evaluated to rule out
non-inflammatory causes. If non-inflammatory
cause treat accordingly. Consider visual field testing,
endocrinology consultation, and imaging.
- Monitor patients for signs and symptoms of
endocrinopathies. Non-specific symptoms include
headache, fatigue, behavior changes, changed
mental status, vertigo, abdominal pain, unusual
bowel habits, hypotension and weakness.
- Patients should be thoroughly evaluated to rule out
any alternative etiology (e.g., disease progression
including brain metastases, infections, etc.)
- If a patient experiences an AE that is thought to be
possibly of autoimmune nature (e.g., thyroiditis,
pancreatitis, hypophysitis, diabetes insipidus), the
investigator should send a blood sample for
appropriate autoimmune antibody testing
Grade 1
(including those with asymptomatic TSH elevation)
Monitor patient with appropriate endocrine function test
- If TSH < 0.5X LLN, or TSH >2X ULN or consistently
out of range in 2 subsequent measurements, include
FT4 at subsequent cycles as clinically indicated and
consider Endocrinology Consult.


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Toxicity
Toxicity Management
Grade 2
(including those with symptomatic endocrinopathy)
– Discuss with Study Chair
– Initiate hormone replacement as needed for
management
– Evaluate endocrine function, and as clinically
indicated, consider pituitary scan
– For patients with abnormal lab/pituitary scan work
up, consider short-term,1-2 mg/kg/day
methylprednisolone IV or oral equivalent with
relevant hormone therapy
- For patients with normal endocrine work up (lab or
MRI scans), repeat labs in 1-3 week/MRI in 1 month.
- If improves (with or without hormone replacement):
- Taper steroids over at least 1 month and consider
prophylactic antibiotics for opportunistic infections
- Patients with adrenal insufficiency may need to
continue steroids with mineral corticoid component
- Suspicion of adrenal crisis (e.g., severe dehydration,
hypotension, shock out of proportion to current
illness)
- Discuss with Study Chair
- Rule out sepsis
- Administer stress dose of IV steroids with mineral
corticoid activity
- Administer IV fluids
- Consult endocrinologist
- If adrenal crisis ruled out, then treat as above for
symptomatic endocrinopathy
Grade 3
−Discuss with Study Chair
−Initiate empiric IV corticosteroids (e.g.,
methylprednisolone IV or oral equivalent) at 1 to 2
mg/kg/day
−Administer hormone replacement therapy as
necessary
−For adrenal crisis, severe dehydration, hypotension,
or shock: immediately initiate intravenous
corticosteroids with mineralocorticoid activity
−Consult endocrinologist
- Once improving, gradually taper immunosuppressive
steroids over ≥4 weeks
Grade 4
           Neurological Adverse Event Management
Toxicity
Dose Modification
Toxicity Management
Neurological Toxicity (Nervous System Disorders)
Any Grade
Patients should be thoroughly evaluated to rule out
non-inflammatory causes. If non-inflammatory
cause treat accordingly.
Grade 1
-Continue to monitor the patient.
If worsens:
-Treat as Grade 2 or 3/4
Grade 2
−Treat symptoms per local guidelines
−Consider 0.5 to 1.0 mg/kg/day methylprednisolone
IV or oral equivalent
If worsens:
−Treat as Grade 3/4
≥Grade 3
−Obtain Neurology Consult


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Toxicity
Dose Modification
Toxicity Management
−Treat symptoms per local guidelines
−1.0-2.0 mg/kg/day methylprednisolone IV or oral
equivalent
−Add prophylactic antibiotics for opportunistic
infections
If improves to Grade 2:
−Taper steroids over at least 1 month
If worsens or atypical presentation:
−Consider IVIG or other immunosuppressive therapies
per local guidelines
Glucocorticosteroids should be used for the management of
autoimmune complications related to nivolumab. Treatment with
prednisone 1 mg/kg equivalent daily (minimum 40 mg daily) with a
taper when symptoms and signs have resolved is recommended.
Please refer to the product monograph for further details, or
Appendix 3 from the Investigator Brochure.
8.3
Adverse Event Reporting
Toxicities (including suspected reactions) that meet the expedited reporting criteria must
be reported to the Operations Office, Study Chair and NCI via CTEP-AERS, and to the IRB
per local IRB requirements.
All adverse events, regardless of grade or suspected relationship to study drug, should be
collected and analyzed per the standard adverse event reporting mechanism (see Section
14.0).
9.0
STUDY CALENDARS


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9.1
STUDY CALENDAR – ARM A: AZACITIDINE (CONTROL)
REQUIRED STUDIES
Pre-
Reg
Cycle 1
C2
C3
C4
C5
Subsequent
Cycles
Off 
Tx
Follow
Up5
W1
W2
W3
W4
History and Physical
Exam
X
X
X
X
X
X
X
X
X
Weight and
Performance Status 6
X
X
X
X
X
X
X
X
X
Toxicity Notation
X
X
X
X
X
X
X
X
X
X
X
X
LABORATORY
STUDIES
Bone Marrow
Aspirate/Biopsy1
X
X
X
X8
X8
CBC, Diff, Platelets
X
X7
X
X
X
X
X
X
X
Direct Bilirubin
X6
Creatinine Clearance
X6
X7
X
X
X
X
X
X
X
Total bilirubin
X6
X7
X
X
X
X
X
X
X
AST and ALT
X6
X7
X
X
X
X
X
LDH
X6
Albumin
X6
Glucose
X6
Fibrinogen
X6
Troponin
X6
Autoimmune Status
Clinical Assessment
X6
SCANS
ECG
X6
SPECIMEN
SUBMISSION
FLT3 2
X
Cytogenetics
and FISH 3
X
Translational Medicine
and Banking 4
X
X
X
TREATMENT
Azacitidine
X
X
X
X
X
X
1
Bone marrow biopsy will be performed at diagnosis, and after Cycles 2 and 4. Note that the Cycle 2 bone marrow
biopsy does not affect protocol treatment decisions. Additional biopsies may be performed as clinically indicated.
2
See Section 15.2.
3
See Section 15.4.
4
See Section 15.3.
5
After discontinuation of protocol therapy, patients will be followed every 3 months for the first year, every 6 months
for the second and third years, and then annually until 5 years after randomization.
6
Results of these tests do not determine eligibility but are performed prior to randomization in order to obtain
baseline measurements.
7
If the pre-registration test is performed within 7 days prior to starting treatment, the test need NOT be repeated on
Cycle 1, Day 1.
8
As clinically indicated.
NOTE: Forms are found on the protocol abstract page of the SWOG website (www.swog.org). Forms submission
guidelines are found in Section 14.0.
NOTE: Unless indicated otherwise in the protocol, scheduled procedures and assessments (treatment administration,
toxicity assessment for continuous treatment, disease assessment, specimen collection and follow-up activities) must
follow the established SWOG guidelines as outlined in
https://swog.org/Visitors/Download/QA/Best%20Practices%20update.pdf.


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9.2
STUDY CALENDAR – ARM B: AZACITIDINE + NIVOLUMAB
REQUIRED STUDIES
Pre-
Reg
Cycle 1
C2
C3
C4
C5
Subsequent
Cycles
Off 
Tx
Follow
Up5
W1
W2
W3
W4
History and Physical
Exam
X
X
X
X
X
X
X
X
X
Weight and
Performance Status 6
X
X
X
X
X
X
X
X
X
Toxicity Notation
X
X
X
X
X
X
X
X
X
X
X
X
LABORATORY
STUDIES
Bone Marrow
Aspirate/Biopsy1
X
X
X
X8
X8
CBC, Diff, Platelets
X
X7
X
X
X
X
X
X
X
Direct Bilirubin
X
X7
X
X
X
X
X
Creatinine Clearance
X6
X7
X
X
X
X
X
X
X
Total bilirubin
X6
X7
X
X
X
X
X
X
X
AST and ALT
X
X7
X
X
X
X
X
LDH
X6
Albumin
X6
Glucose
X6
Fibrinogen
X6
Amylase and Lipase
X6
X7
X
X
X
X
Troponin
X6
Autoimmune Status
Clinical Assessment
X6
SCANS
ECG
X6
ECHO
X
SPECIMEN
SUBMISSION
FLT3 2
X
Cytogenetics
and FISH 3*
X
Translational Medicine
and Banking 4
X
X
X
TREATMENT
Azacitidine
X
X
X
X
X
X
Nivolumab
X
X
X
X
X
X
X
1
Bone marrow biopsy will be performed at diagnosis, and after Cycles 2 and 4. Note that the Cycle 2 bone marrow
biopsy does not affect protocol treatment decisions. Additional biopsies may be performed as clinically indicated.
2
See Section 15.2.
3
See Section 15.4.
4
See Section 15.3.
5
After discontinuation of protocol therapy, patients will be followed every 3 months for the first year, every 6 months
for the second and third years, and then annually until 5 years after randomization.
6
Results of these tests do not determine eligibility but are performed prior to randomization in order to obtain
baseline measurements.
7
If the pre-registration test is performed within 7 days prior to starting treatment, the test need NOT be repeated on
Cycle 1, Day 1.
8
As clinically indicated.
NOTE: Forms are found on the protocol abstract page of the SWOG website (www.swog.org). Forms submission
guidelines are found in Section 14.0.
NOTE: Unless indicated otherwise in the protocol, scheduled procedures and assessments (treatment administration,
toxicity assessment for continuous treatment, disease assessment, specimen collection and follow-up activities) must
follow the established SWOG guidelines as outlined in
https://swog.org/Visitors/Download/QA/Best%20Practices%20update.pdf.


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9.3
STUDY CALENDAR – ARM C – AZACITIDINE + MIDOSTAURIN
REQUIRED STUDIES
Pre-
Reg
Cycle 1
C2
C3
C4
C5
Subsequent
Cycles
Off 
Tx
Follow
Up5
W1
W2
W3
W4
History and Physical Exam
X
X
X
X
X
X
X
X
X
Weight and Performance
Status6
X
X
X
X
X
X
X
X
X
Toxicity Notation
X
X
X
X
X
X
X
X
X
X
X
X
LABORATORY STUDIES
Bone Marrow
Aspirate/Biopsy1
X
X
X
X8
X8
CBC, Diff, Platelets
X
X7
X
X
X
X
X
X
X
Direct Bilirubin
X
X7
X
X
X
X
X
X
X
Creatinine Clearance
X
X7
X
X
X
X
X
X
X
Total bilirubin
X
X7
X
X
X
X
X
X
X
AST and ALT
X6
X7
X
X
X
X
X
LDH
X6
Albumin
X6
Glucose
X6
Fibrinogen
X6
Troponin
X6
Autoimmune Status
Clinical Assessment6
X6
SCANS
ECG
X
X9
X9
X9
X9
X9
X9
X9
SPECIMEN SUBMISSION
FLT3 2
X
Cytogenetics
and FISH 3
X
Translational Medicine
and Banking 4
X
X
X
TREATMENT
Azacitidine
X
X
X
X
X
X
Midostaurin
X
X
X
X
X
X
X
1
Bone marrow biopsy will be performed at diagnosis and after Cycles 2 and 4. Note that the Cycle 2 bone marrow
biopsy does not affect protocol treatment decisions. Additional biopsies may be performed as clinically indicated.
2
See Section 15.2.
3
See Section 15.4.
4
See Section 15.3.
5
After discontinuation of protocol therapy, patients will be followed every 3 months for the first year, every 6 months
for the second and third years, and then annually until 5 years after randomization.
6
Results of these tests do not determine eligibility but are performed prior to randomization in order to obtain
baseline measurements.
7
If the pre-registration test is performed within 7 days prior to starting treatment, the test need NOT be repeated on
Cycle 1, Day 1.
8
As clinically indicated.
9
To be performed on Days 1 and 8 of Cycle 1 (prior to initiation of treatment) and on Day 1 of each subsequent
cycle (prior to initiation of treatment).
NOTE: Forms are found on the protocol abstract page of the SWOG website (www.swog.org). Forms submission
guidelines are found in Section 14.0.
NOTE: Unless indicated otherwise in the protocol, scheduled procedures and assessments (treatment administration,
toxicity assessment for continuous treatment, disease assessment, specimen collection and follow-up activities) must
follow the established SWOG guidelines as outlined in
https://swgo.org/Visitors/Download/QA/Best%20Practices%20update.pdf.


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9.4
STUDY CALENDAR – ARM D: DECITABINE + CYTARABINE
INDUCTION8
MAINTENANCE
REQUIRED STUDIES
Pre-
Reg7
Cycle 1
C2
Cycle 1
C2
C3
Subsequent
Cycles
Off 
Tx
Follow
Up5
W 
17
W 
2
W 
3
W 
4
W 
1
W 
2
W 
3
W 
4
History and Physical Exam
X
X
X
X
X
X
X
Weight and Performance
Status 6
X
X
X
X
X
X
X
Toxicity Notation
X
X
X
X
X
X
X
X
X
X
LABORATORY STUDIES
Bone Marrow
Aspirate/Biopsy1
X
X
X
X9
X9
CBC, Diff, Platelets
X
X
X
X
X
X
X
X
X
Creatinine Clearance
X6
X
X
X
X
X
X
X
X
Direct Bilirubin
X6
X
X
Total bilirubin
X6
X
X
X
X
X
X
X
X
AST and ALT
X6
X
X
X
X
LDH
X6
X
X
X
X
Albumin
X6
X
X
X
X
Glucose
X6
X
X
X
X
Fibrinogen
X6
X
X
X
X
Troponin
X6
Autoimmune Status Clinical
Assessment
X6
SCANS
ECG
X
SPECIMEN SUBMISSION
FLT3 2
X
Cytogenetics
and FISH 3
X
Translational Medicine and
Banking 4
X
X
X
TREATMENT
Decitabine
X
X
X
X
X
Cytarabine
X
X
1
Bone marrow biopsy will be performed at diagnosis and after Cycles 2 and 4. Note that the Cycle 2 bone marrow biopsy
does not affect protocol treatment decisions. Additional biopsies may be performed as clinically indicated.
2
See Section 15.2.
3
See Section 15.4.
4
See Section 15.3.
5
After discontinuation of protocol therapy, patients will be followed every 3 months for the first year, every 6 months for the
second and third years, and then annually until 5 years after randomization.
6
Results of these tests do not determine eligibility but are performed prior to randomization in order to obtain baseline
measurements.
7
If the pre-registration test is performed within 7 days prior to starting treatment, the test need NOT be repeated prior on
Cycle 1, Day 1.
8
Patients may receive up to 2 cycles of Induction treatment. Patients deriving clinical benefit within 2 cycles will continue
to Maintenance treatment. Patients not deriving clinical benefit within 2 cycles of Induction treatment will be removed
from protocol therapy (see Section 7.1d).
9
As clinically indicated.
NOTE: Forms are found on the protocol abstract page of the SWOG website (www.swog.org). Forms submission guidelines
are found in Section 14.0.
NOTE: Unless indicated otherwise in the protocol, scheduled procedures and assessments (treatment administration, toxicity
assessment for continuous treatment, disease assessment, specimen collection and follow-up activities) must follow the
established SWOG guidelines as outlined in
https://swgo.org/Visitors/Download/QA/Best%20Practices%20update.pdf.


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10.0
CRITERIA FOR EVALUATION AND ENDPOINT ANALYSIS
10.1
Remission Definitions (18)
a.
Morphologic complete remission (CR): Bone marrow blasts < 5%; absence of
circulating blasts and blasts with Auer rods; absence of extramedullary disease;
absolute neutrophil count ≥1.0 x 109/L (1,000/mcL); platelet count ≥100 x 109/L
(100,000/mcL).
b.
Morphologic complete remission with incomplete blood count recovery (CRi): All
CR criteria except for residual neutropenia [< 1.0 x 109/L (1,000/mcL)] OR
thrombocytopenia [< 100 x 109/L (100,000/mcL)].
c.
Partial Remission (PR): All hematologic criteria of CR; decrease of bone marrow
blast percentage to 5% to 25%; and decrease from pretreatment bone marrow
blast percentage by at least 50%.
d.
Morphologic leukemia-free state (MLFS): Bone marrow blasts < 5%; absence of
blasts with Auer rods; absence of extramedullary disease; no hematologic
recovery required
e.
Marrow CR (CRm): The patient must satisfy the definition of CR for the bone
marrow examination (≤5% myeloblasts) and the marrow myeloblasts must have
decreased by ≥50% from pretreatment. NOTE: CRm may be achieved with or
without improved blood counts, with any hematologic improvement (see Section
10.3) noted separately.
f.
Stable disease (SD): Failure to achieve at least a PR, but with no evidence of
progression as defined in Section 10.3 for at least 8 weeks.
g.
Refractory disease: failure to achieve CR, CRi, PR, MLFS, or SD, excluding
patients with death in aplasia or death due to indeterminate cause.
h.
Death in aplasia: Deaths occurring ≥7 days following completion of initial treatment
while cytopenic; with an aplastic or hypoplastic bone marrow obtained within 7
days of death, without evidence of persistent leukemia.
i.
Death from indeterminate cause: Deaths occurring before completion of therapy,
or < 7 days following its completion; or deaths occurring ≥7 days following
completion of initial therapy with no blasts in the blood, but no bone marrow
examination available.
10.2
Assessment of Transfusion Dependency, Hemoglobin, and Platelet Counts
a.
Accurate counts of RBC units and platelet transfusions received before and after
starting protocol treatment are necessary to determine patients’ responses to
therapy. The numbers of RBC units and platelet transfusions during the 8 weeks
before randomization will be recorded for use as baselines. Only RBC transfusions
given for hemoglobin ≤9 g/dL or platelet transfusions for platelets < 50,000/mm3
before randomization will be considered in the RBC/platelet transfusion response
evaluation.
           Transfusion dependence: Patients who receive one or more RBC or
platelet transfusions will be considered RBC or platelet transfusion
dependent, respectively, in the absence of another explanation such as
gastrointestinal bleeding, hemolysis, etc.


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           Relevant reduction in RBC transfusion requirement: This is defined for
patients who were RBC transfusion dependent and received ≥4 units
during the 8 weeks before randomization. If, during the 8-week period after
randomization, the total number of RBC units transfused has decreased
by at least 4 units compared to the number transfused during the 8 weeks
before randomization, then the patient will have a relevant reduction in
RBC transfusion requirement.
           Transfusion independence: For assessment of response, RBC or platelet
transfusion independence requires that the patient receive no RBC or
platelet transfusions, respectively, for a period of at least 8 weeks.
b.
Accurate measurements of hemoglobin (Hgb), platelet (PLT), and ANC counts
before and after starting protocol treatment are also necessary to determine
patients’ responses to therapy. Whenever patients are transfusion dependent,
Hgb, PLT, and ANC counts must be measured immediately before transfusions,
to ensure that they reflect the patient’s true hematologic status
10.3
Hematologic Improvement (HI)
Hematologic Improvement (HI) is assessed separately for erythroid cells, platelets, and
neutrophils. For each type of response, the criteria must be satisfied for all blood
examinations performed during a period of at least 8 weeks.
a.
Erythroid response (HI-E): is defined only for patients with hemoglobin < 11 g/dL
prior to treatment.
           Response: At least a 1.5 g/dL increase in hemoglobin from pretreatment;
and, for RBC transfusion-dependent patients, achievement of transfusion
independence or a relevant reduction in the RBC transfusion requirement.
           Progression/relapse
following
HI-E:
Reduction
in
hemoglobin
concentration by at least 1.5 g/dL from maximum level during HI-E, or
becoming RBC transfusion dependent, in the absence of another
explanation such as gastrointestinal bleeding or hemolysis.
b.
Platelet response (HI-P): is defined only for patients with platelet count <
100,000/mm3 prior to treatment.
           Response: An absolute increase of ≥30,000/mm3 from pretreatment for
patients with a platelet count > 20,000/mm3 at pretreatment. For patients
with a platelet count ≤20,000/mm3 at pretreatment, an increase of at least
100% from pretreatment counts to a platelet count > 20,000/mm3. For
platelet transfusion-dependent patients, platelet transfusion independence
is also required.
           Progression/relapse following HI-P: 50% or greater decrement from
maximum platelet count achieved while HI-P, in the absence of another
explanation such as gastrointestinal bleeding or hemolysis.
c.
Neutrophil response (HI-N): is defined only for patients with ANC < 1,000/mm3 prior
to treatment.
d.
Response: ANC increase from pretreatment of at least 100%, and an absolute
increase of > 500/mm3 from pretreatment.


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e.
Progression/relapse following HI-N: 50% or greater decrement from maximum
ANC achieved while HI-N, in the absence of another explanation such as acute
infection.
10.4
Cytogenetic Response
Cytogenetic response is based on cytogenetic studies performed at local CLIA-approved
laboratories
a.
Complete cytogenetic response: is defined only for patients with preexisting clonal
cytogenetic abnormalities, and requires (1) no detection of any preexisting clonal
or nonclonal abnormality(ies) and (2) no cytogenetic evidence of any additional
clonal populations, based on a study of at least 20 metaphases. FISH may be used
as a supplement to follow a specifically defined cytogenetic abnormality.
b.
Partial cytogenetic response: is defined as a 50% reduction of preexisting clonal
cytogenetic abnormalities without evidence of any new clonal abnormalities.
c.
Cytogenetic relapse: is defined as the detection of any clonal abnormality in a
patient who previously achieved a complete cytogenetic response.
10.5
Disease Progression:
a.
Evidence for an increase in bone marrow blast percentage and/or increase of
absolute blast counts in the blood:
           > 50% increase in marrow blasts over baseline (a minimum 15% increase
is required in cases with <30% blasts at baseline; or persistent marrow
blast percentage of >70% over at least 3 months; without at least a 100%
improvement in absolute neutrophil count (ANC) to an absolute level [>
0.5 x 109/L (500/mcL), and/or platelet count to >50 x 109/L (50,000/mcL)
non-transfused]; or
           > 50% increase in peripheral blasts (WBC x % blasts) to >25 x 109/L
(>25,000/mcL) (in the absence of differentiation syndrome)
b.
New extramedullary disease
Note: Transient cytopenias during chemotherapy courses should not be considered
disease progression, as long as they recover to the previous levels. Progression
based on blood values should not be considered at all until after the post-Cycle 4
marrow draw.
10.6
Time-to-Event Outcomes
a.
Overall survival: Defined for all patients; measured from day of randomization on
study until death from any cause with observations censored on the day of last
contact for patients not known to have died.
b.
Relapse-free survival: Defined only for patients achieving complete remission
(CR), or CR with incomplete hematologic recovery (CRi); measured from the date
of achievement of a remission until the date of relapse or death from any cause;
patients not known to have relapsed or died at last follow-up are censored on the
date of last contact.
c.
Event-free survival: Defined for
all patients; measured
from the
date
of
randomization to the first of: date of primary refractory disease; date of progressive
disease; date off protocol therapy without CR or CRi; date of relapse from CR or


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CRi, or death from any cause; patients not known to have any of these events are
censored on the date of last contact.
d.
Cumulative incidence of relapse: Defined for all patients achieving CR or CRi;
measured from the date of achievement of a remission until the date of relapse or
death; patients not known to have relapsed or died are censored on the date of
last contact; patients who died without relapse have death considered a competing
cause of failure.
10.7
Performance Status
Patients will be graded according to the Zubrod performance status scale.
POINT       DESCRIPTION
0
Fully active, able to carry on all pre-disease performance without restriction.
1
Restricted in physically strenuous activity but ambulatory and able to carry out
work of a light or sedentary nature, e.g., light housework, office work.
2
Ambulatory and capable of self-care but unable to carry out any work activities;
up and about more than 50% of waking hours.
3
Capable of limited self-care, confined to bed or chair more than 50% of waking
hours.
4
Completely disabled; cannot carry on any self-care; totally confined to bed or chai.
11.0
STATISTICAL CONSIDERATIONS
11.1
Sample Size and Accrual
Based on S0432, S0703, and S1117, the anticipated accrual is approximately 40
patients/month.
Only contemporaneously randomized and eligible patients will be evaluated for each
comparison.
The design detailed below requires up to 300 eligible patients per arm. The earliest
possibility of stopping an arm is at 100 patients per arm (33% accrual, expected
approximately one year into a three-arm study). If 10% of patients are not eligible, the
maximum accrual for an experimental arm is 334 patients. Because of staggered entry
experimental arms, the control arm is expected to accrue more than 300 eligible patients.
In addition, it is expected that up to 5% of patients registered to Step 1 (specimen
submission for FLT3 testing) will not be randomized (Step 2 registration).
11.2
Design and Analyses Assumptions and Parameters
The primary objective of the Phase II study is to determine based on OS which if any of
the experimental regimens should be tested further against the control regimen
(azacitidine). Any regimen that passes the Phase II threshold will be taken forward for
Phase III testing. The Phase II analysis will not select among experimental regimens.
The primary objective of the Phase III study is to compare OS between the control arm and
experimental arm(s) selected in the Phase II study. Patients accrued during the Phase II
portion of the trial will be used in the Phase III analysis. For all analyses, only concurrently
randomized, eligible patients will be compared.


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Based on data from the French study of azacitidine in older patients with hyper-proliferative
AML, the study assumes that OS with azacitidine follows an exponential distribution with a
median OS of 10.4 months (null hypothesis). (19) The study is powered for exponential OS
in the experimental arms with a median OS of 15.6 months (corresponds to hazard ratio =
0.67, alternative hypothesis).
All testing will be stratified by the randomization stratification factors: age ≥70 AND PS 2-
4 versus age < 70 OR PS 0-1; wild type FLT3-ITD versus mutated FLT3-ITD versus
indeterminate FLT3-ITD; baseline blasts percentage (< 20% versus ≥20%).
For each experimental arm comparison versus the control arm, the study assumes equal
randomization across arms, three years of accrual, and one year of follow-up after accrual
completes. Analysis timing is event-based, so timing will adapt appropriately as the study
progresses. For each experimental arm comparison versus the control arm, the study
assumes a two-sided alpha of 5% or less.
11.3
Phase II Analyses
Up to 100 eligible patients will be enrolled to each arm for Phase II analysis. The Phase II
analysis will be done at 104 pooled-arm deaths (deaths on both control + experimental
arms). Accrual to experimental arms is expected to temporarily close to allow the OS data
to mature. The length of the temporary closure will depend on accrual; it is expected an
arm may need to be closed for up to 10 months while OS data mature. A stratified log-rank
test of the null hypothesis (HR=1) with a one-sided alpha of 15% will be used to test an
experimental arm versus azacitidine for further Phase III testing. This corresponds to
continuing to Phase III testing arms with HRs < 0.87 favoring the experimental arm. A
Phase II interim analysis for futility is scheduled for when there are 52 pooled-arm deaths.
An experimental arm that has a hazard ratio (HR) favoring an experimental arm versus
azacitidine will continue accrual. Accrual will not be held for the interim analysis.
11.4
Phase III Analyses
Up to 200 additional eligible patients will be enrolled to each arm for Phase III analysis (for
a total of 300 eligible patients per arm). 100% of expected pooled-arm events for Phase III
analysis is 414 deaths. The final Phase II analysis at 104 pooled-arm deaths corresponds
to 25% of the full Phase III control arm OS events. For arms carried forward for Phase III
testing, two additional interim analyses will be performed at 50% and 75% pooled-arm OS
deaths (at 207 and 311 deaths). At each interim analysis an efficacy test will be done (test
of the null hypothesis HR=1) using a stratified log-rank test with a one-sided alpha of 0.5%.
At each interim analysis a futility test (test of the alternative hypothesis HR=0.67) will be
done using a stratified log-rank test (modified to test the alternative HR) with a one-sided
alpha of 2.5% at the first interim analysis and a one-sided alpha of 1.0% at the second
interim analysis. The final analysis will occur at 100% pooled-arm OS deaths (414 deaths,
expected at 6 months after accrual completes), or 1.5 years after accrual to an
experimental arm completes, whichever occurs first. In order to account for interim
analyses, each final test (stratified log-rank test of the null hypothesis HR=1) of an
experimental arm versus azacitidine will be done with a two-sided alpha of 4.5%. This
design has a power of 83% for each experimental arm. The table below summarizes
properties of the design. If the event rate in the control arm is much slower than anticipated
and the final analysis occurs at 1.5 years after completion of the accrual to an experimental
arm, the power to detect the same effect size might be slightly different among the
experimental arms, as the accrual duration may differ (depending on the accrual dynamics
and how many arms are open at the same time).
If at any point an experimental arm has a positive interim or final analysis, accrual to the
study will be terminated. Pending approval by the SWOG DSMC and CTEP, all study data
will be released to the investigators.


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Table 1. Characteristics of Analysis Plan (for each experimental regimen comparison versus
azacitidine)
OS Scenario
Probability
Under
Alternative
Probability
Under Null
Probability stop for futility at Phase II interim analysis
7%
50%
Probability continue to Phase III accrual based on Phase II analysis
84%
15%
Probability stop for futility at first Phase III interim analysis
3%
4%
Probability stop for efficacy at first Phase III interim analysis
40%
< 1%
Probability stop for futility at second Phase III interim analysis
≤1%
5%
Probability stop for efficacy at second Phase III interim analysis
25%
< 1%
Probability stop early for futility
19%
94%
Probability stop early for efficacy
64%
< 1%
Probability of positive result
83%
1%
Probability of positive result ignoring futility monitoring
98%
5%
Table 2. Additional Characteristics of Interim and Final Analyses
Analysis
N Deaths
across
Pooled Arms
Alpha Level
HR
Threshold
Absolute Difference in
12-Month OS (Aza vs.
Experimental Arm)
Phase II
Analyses
Interim futility
52
N/A
1.00
45% v. 45%
Final Phase II
104
One-sided 15%
0.84
45% v. 51%
Phase III
Analyses
First interim
efficacy
207
One-sided 0.5%
0.64
45% v. 60%
First interim
futility
207
One-sided 2.5%
0.90
45% v. 49%
Second interim
efficacy
311
One-sided 0.5%
0.65
45% v. 60%
Second interim
futility
311
One-sided 1.0%
0.90
45% v. 49%
Final efficacy
414
Two-sided 4.5%
0.82
45% v. 52%
11.5
Analysis of Other Endpoints
Toxicities: For each arm, three hundred eligible patients will be sufficient to estimate toxicity
rates to within ± 6% (95% confidence interval). Any toxicity occurring with at least 1.5%
probability is likely to be seen at least once (99% probability).
The study team (Study Chairs, Study Statisticians, and Committee Chair) will review the
Cycle 1 and Cycle 2 toxicity data on the first 10 patients enrolled on the study (to any arm)
with Performance Status 4. If the study team has concerns about excess toxicity among
these patients, they will decide to continue to intensively monitor additional patients, or, in
conjunction with the NCI, whether to modify the eligibility criteria.
Response and time-to-event endpoints: Remission rates will be tabulated. Time-to-event
endpoints will be estimated using the Kaplan-Meier method or cumulative incident
endpoints and associations with time-to-event outcomes will be assessed using Cox
regression models (for cause-specific hazards as appropriate). Landmark analyses of
different response categories will be evaluated based on dates at which 75% and 90% of
patients have achieved a response (with other quantiles analyzed as needed.)
Analyses of FLT3-ITD and overall survival:
The prognostic effect of FLT3-ITD (positive versus negative or non-evaluable) with respect
to the outcome OS will be evaluated using Cox regression models. We assume accrual


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and follow-up as indicated above. Under the null hypothesis assumptions (OS following
an exponential distribution with a median of 10.4 months), if 20% of patients are FLT3-ITD
positive, each Phase 3 arm (300 patients) will have 87% power to detect a hazard ratio of
1.6 (corresponds to median OS among FLT3-ITD positive patients of 7 months and median
OS among FLT3-ITD negative/non-evaluable patients of 11.2 months) with a two-sided
alpha of 5%. The prognostic association will also be evaluable across all the arms and will
have increased power with the increased sample size.
The predictive effect of FLT3-ITD (positive versus negative/non-evaluable) with respect to
the outcome of OS and the treatments of azacitdine+midostaurin versus azacitidine will be
evaluated using a Cox regression model with treatment arm and FLT3-ITD as covariates
and including the interaction between the two covariates. If 20% of patients are FLT3-ITD
positive on each arm and OS follows an exponential distribution, 600 patients (300/arm)
will have 84% power to detect an interaction hazard ratio of 2 (corresponding to median
OS of 7 months among FLT3-ITD positive patients treated with azacitidine, median OS of
14 months among FLT3-ITD positive patients treated with azacitidine+midostaurin, median
OS of 11.2 months among FLT3-ITD negative patients on both arms) with a two-sided
alpha of 5%.
As a sensitivity analysis, the same analyses as above will be done but excluding patients
who were non-evaluable for FLT3-ITD (expected to be < 5% of patients).
As additional sensitivity analyses, the investigators will evaluate regression models with
treatment arm, FLT3-ITD allelic ratio, and FLT3-TKD mutation status.
Associations between outcomes and cytogenetic abnormalities and risk categories and
mutations: Univariate and multivariable regression models will be used assess potential
associations between outcomes (CR, OS, EFS, and RFS) and cytogenetic abnormalities
and mutation status (including FLT3-ITD). Regression models including interaction terms
with treatment arm will be fit. In addition to analyzing FLT3-ITD as categorical variable
used in randomization stratification, we will analyze FLT3-TKD also and evaluate FLT3-
ITD allelic ratio as a quantitative variable and as a binary variable using the threshold of
0.50.
Potential control arm drift: Given the dynamic nature of the trial design it is possible that
the prognostic factors of randomized patients will change over time. To control for this
potential issue, only concurrently randomized patients will be evaluated in comparisons
between arms. In addition, the patient characteristics table provided for the Data and
Safety Monitoring Committee twice a year will summarize by 6-month or 12-month intervals
based on randomization date.
11.6
Data and Safety Monitoring Committee
A Data and Safety Monitoring Committee will oversee the conduct of the study. The
Committee consists of four members from outside of SWOG, three SWOG members, three
non-voting representatives from the National Cancer Institute (NCI), and the Group
Statistician (non-voting). The members of this Committee will receive confidential reports
every six months from the SWOG Statistical Center, and will meet at the Group's bi-annual
meetings as necessary. The Committee will be responsible for decisions regarding
possible termination and/or early reporting of the study.
12.0
DISCIPLINE REVIEW
Discipline review is not necessary for this study.


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13.0
REGISTRATION GUIDELINES
13.1
Registration Timing
Specimens for FLT3 testing must be submitted at the time of registration to Step 1 using
the SWOG Specimen Tracking System (see Section 15.2) (within 1 day of Step 1
registration and within 42 days prior to randomization [Step 2]). FLT3 results will be used
for stratification purposes at the time of randomization. Upon receipt of e-mail notification
of randomization assignment, the patient must be registered to Step 2 prior to initiation of
treatment (no more than seven working days prior to planned start of treatment).
13.2
Investigator/Site Registration
Prior to the recruitment of a patient for this study, investigators must be registered members
of a Cooperative Group. Each investigator must have an NCI investigator number and
must maintain an “active” investigator registration status through the annual submission of
a complete investigator registration packet to CTEP.
a.
CTEP Investigator Registration Procedures
Food and Drug Administration (FDA) regulations and National Cancer Institute
(NCI) policy require all investigators participating in any NCI-sponsored clinical trial
to register and to renew their registration annually.
Registration requires the submission of:
x
a completed Statement of Investigator Form (FDA Form 1572) with an
original signature
x
a current Curriculum Vitae (CV)
x
a completed and signed Supplemental Investigator Data Form (IDF)
x
a completed Financial Disclosure Form (FDF) with an original signature
Fillable PDF forms and additional information can be found on the CTEP website
at <http://ctep.cancer.gov/investigatorResources/investigator_registration.htm>.
For questions, please contact the CTEP Investigator Registration Help Desk by
e-mail at <pmbregpend@ctep.nci.nih.gov>.
b.
CTEP Associate Registration Procedures
The
Cancer
Therapy
Evaluation
Program
(CTEP)
Identity
and
Access
Management (IAM) application is a web-based application intended for use by both
Investigators (i.e., all physicians involved in the conduct of NCI-sponsored clinical
trials) and Associates (i.e., all staff involved in the conduct of NCI-sponsored
clinical trials).
Associates will use the CTEP-IAM application to register (both initial registration
and annual re-registration) with CTEP and to obtain a user account.
Investigators will use the CTEP-IAM application to obtain a user account only. (See
CTEP Investigator Registration Procedures above for information on registering
with CTEP as an Investigator, which must be completed before a CTEP-IAM
account can be requested.)


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An active CTEP-IAM user account will be needed to access all CTEP and CTSU
(Cancer Trials Support Unit) websites and applications, including the CTSU
members’ website.
Additional   information   can   be   found   on   the   CTEP   website   at
<http://ctep.cancer.gov/branches/pmb/associate_registration.htm>. For
questions, please contact the CTEP Associate Registration Help Desk by e-mail
at <ctepreghelp@ctep.nci.nih.gov>.
c.
CTSU Registration Procedures
Each investigator or group of investigators at a clinical site must obtain IRB
approval for this protocol and submit IRB approval and supporting documentation
to the CTSU Regulatory Office before they can be approved to enroll patients.
Study centers can check the status of their registration packets by querying
the Regulatory Support System (RSS) site registration status page of the
CTSU
members’ website by entering credentials at https://www.ctsu.org. For sites under
the CIRB initiative, IRB data will automatically load to RSS.
Note: Sites participating on the NCI CIRB initiative and accepting CIRB approval
for the study are not required to submit separate IRB approval documentation to
the CTSU Regulatory Office for initial, continuing or amendment review. This
information will be provided to the CTSU Regulatory Office from the CIRB at the
time the site’s Signatory Institution accepts the CIRB approval. The Signatory site
may be contacted by the CTSU Regulatory Office or asked to complete information
verifying the participating institutions on the study. Other site registration
requirements (i.e., laboratory certifications, protocol-specific training certifications,
or modality credentialing) must be submitted to the CTSU Regulatory Office or
compliance communicated per protocol instructions.
           Downloading Site Registration Documents:
Site registration forms may be downloaded from the S1612 protocol page
located on the CTSU members’ website. Add if a restricted access
protocol: Permission to view and download this protocol and its supporting
documents is restricted and is based on person and site roster assignment
housed in the CTSU RSS.

Go to https://www.ctsu.org and log in to the members’ area using
your CTEP-IAM username and password

Click on the Protocols tab in the upper left of your screen

Click on the SWOG link to expand, then select S1612. Click on
the Site Registration Documents link.
           Requirements for S1612 Site Registration:

CTSU IRB Certification (for sites not participating via the NCI
CIRB)

CTSU IRB/Regulatory Approval Transmittal Sheet (for sites not
participating via the NCI CIRB)
           Submitting Regulatory Documents:
Submit completed forms along with a copy of your IRB Approval and
Model Informed Consent to the CTSU Regulatory Office, where they will
be entered and tracked in the CTSU RSS.


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Regulatory Submission Portal:
www.ctsu.org (members’ area) →
Regulatory Tab →Regulatory Submission
When applicable, original documents should be mailed to:
CTSU Regulatory Office
1818 Market Street, Suite 1100
Philadelphia, PA 19103
Institutions with patients waiting that are unable to use the Portal should
alert the CTSU Regulatory Office immediately at 866-651-2878 in order to
receive further instruction and support.
           Checking Your Site’s Registration Status:
Check the status of your site’s registration packets by querying the RSS
site registration status page of the members’ section of the CTSU
website. (Note: Sites will not receive formal notification of regulatory
approval from the CTSU Regulatory Office.)

Go to https://www.ctsu.org and log in to the members’ area using
your CTEP-IAM username and password

Click on the Regulatory tab at the top of your screen

Click on the Site Registration tab

Enter your 5-character CTEP Institution Code and click on Go
Note: the status given only reflects compliance with IRB documentation
and institutional compliance with protocol-specific requirements outlined
by the Lead Network. It does not reflect compliance with protocol specific
requirements for individuals participating on the protocol or the enrolling
investigator’s status with the NCI or their affiliated networks.
13.3
OPEN Registration Requirements
The individual registering the patient must have completed the appropriate SWOG
Registration Worksheet. The completed form must be referred to during the registration
but should not be submitted as part of the patient data.
Patient enrollment will be facilitated using the Oncology Patient Enrollment Network
(OPEN). OPEN is a web-based registration system available on a 24/7 basis. To access
OPEN, the site user must have an active CTEP-IAM account (check at < https://eapps-
ctep.nci.nih.gov/iam/index.jsp >) and a 'Registrar' role on either the LPO or participating
organization roster.
OPEN will also ask additional questions that are not present on the SWOG Registration
Worksheet. The individual registering the patient must be prepared to provide answers to
the following questions:
a.
Institution CTEP ID
b.
Protocol Number
c.
Registration Step
d.
Treating Investigator
e.
Credit Investigator


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f.
Patient Initials
g.
Patient’s Date of Birth
h.
Patient SSN (SSN is desired, but optional. Do not enter invalid numbers.)
i.
Country of Residence
j.
ZIP Code
k.
Gender (select one):
x
Female Gender
x
Male Gender
l.
Ethnicity (select one):
x
Hispanic or Latino
x
Not Hispanic or Latino
x
Unknown
m.
Method of Payment (select one):
x
Private Insurance
x
Medicare
x
Medicare and Private Insurance
x
Medicaid
x
Medicaid and Medicare
x
Military or Veterans Sponsored NOS
x
Military Sponsored (Including Champus & Tricare)
x
Veterans Sponsored
x
Self Pay (No Insurance)
x
No Means of Payment (No Insurance)
x
Other
x
Unknown
n.
Race (select all that apply):
x
American Indian or Alaska Native
x
Asian
x
Black or African American
x
Native Hawaiian or other Pacific Islander
x
White
x
Unknown
13.4
Registration Procedures
a.
All site staff will use OPEN to enroll patients to this study. OPEN is integrated with
the CTSU Enterprise System for regulatory and roster data and, upon enrollment,
initializes the patient in the Rave® database. OPEN can be accessed at
https://open.ctsu.org, from the OPEN tab on the CTSU members’ side of the
website at https://www.ctsu.org, or from the OPEN Patient Registration link on the
SWOG CRA Workbench.
b.
Prior to accessing OPEN site staff should verify the following:
x
All eligibility criteria have been met within the protocol stated timeframes
and the affirmation of eligibility on the Registration Worksheet has been
signed by the registering investigator or another investigator designate.
Site staff should refer to Section 5.0 to verify eligibility.


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x
All patients have signed an appropriate consent form and HIPAA
authorization form (if applicable).
c.
The OPEN system will provide the site with a printable confirmation of registration
and treatment information.
Please print this confirmation for your records.
d.
Further instructional information is provided on the OPEN tab on the CTSU
members’ side of the website at https://www.ctsu.org or at https://open.ctsu.org.
For any additional questions contact the CTSU Help Desk at 1-888-823-5923 or
ctsucontact@westat.com.
13.5
Exceptions to SWOG registration policies will not be permitted.
a.
Patients must meet all eligibility requirements.
b.
Institutions must be identified as approved for registration.
c.
Registrations may not be cancelled.
d.
Late registrations (after initiation of treatment) will not be accepted.
14.0
DATA SUBMISSION SCHEDULE
14.1
Data Submission 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 can be found on the protocol abstract page on the SWOG website
(www.swog.org) and (with the exception of the sample consent form and the Registration
Worksheet) must be submitted on-line via the Web; see Section 14.3 for details.
14.3
Data Submission Procedures
a.
Data collection for this study will be done exclusively through the Medidata Rave®
clinical data management system. Access to the trial in Rave® is granted through
the iMedidata application to all persons with the appropriate roles assigned in
Regulatory Support System (RSS). To access Rave® via iMedidata, you must
have
an
active
CTEP-IAM
account
(check
at
https://eapps-
ctep.nci.nih.gov/iam/index.jsp) and the appropriate Rave® role
(Rave®  CRA,
Read-Only, Site Investigator) on either the LPO or participating organization roster
at the enrolling site.
Upon initial site registration approval for the study in RSS, all persons with Rave®
roles assigned on the appropriate roster will be sent a study invitation e-mail from
iMedidata. To accept the invitation, site users must log into the Select Login
(https://login.imedidata.com/selectlogin) using their CTEP-IAM user name and
password, and click on the “accept” link in the upper right-corner of the iMedidata
page. Please note, site users will not be able to access the study in Rave® until all
required Medidata and study specific trainings are completed. Trainings will be in
the form of electronic learnings (eLearnings), and can be accessed by clicking on
the link in the upper right pane of the iMedidata screen.


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Users that have not previously activated their iMedidata/ Rave® account at the
time of initial registration approval for the study in RSS will also receive a separate
invitation from iMedidata to activate their account. Account activation instructions
are located on the CTSU website, Rave® tab under the Rave® resource materials
(Medidata Account Activation and Study Invitation Acceptance). Additional
information on iMedidata/ Rave® is available on the CTSU members’ website
under the Rave® tab at www.ctsu.org/RAVE/ or by contacting the CTSU help Desk
at 1-888-823-5923 or by e-mail at ctsucontact@westat.com
b.
You may also access Rave® via the SWOG CRA Workbench. Go to the SWOG
web site (http://swog.org) and logon to the Members Area using your SWOG
Roster ID Number and password. After you have logged on, click on Workbenches,
then CRA Workbench to access the home page for the CRA Workbench and follow
the link to Rave® provided in the left-hand navigation panel.
To access the CRA Workbench the following must be done (in order):
           You are entered into the SWOG Roster and issued a SWOG Roster ID
Number,
           You are associated as an investigator or CRA/RN at the institution where
the patient is being treated or followed,
           Your Web User Administrator has added you as a web user and has given
you the appropriate system permissions to view data for that institution.
For assistance with points 1 and 2 call the Operations Office at 210/614-8808. For
point 3, contact your local Web User Administrator (refer to the "Who is my Web
User Administrator?" function on the swog.org Members logon page).
For difficulties with the CRA Workbench, please e-mail
technicalquestion@crab.org.
c.
Institutions participating through the Cancer Trials Support Unit (CTSU), please
refer to the CTSU Participation Table.
14.4
Data Submission Overview and Timepoints
a.
WITHIN 1 DAY AFTER REGISTRATION TO STEP 1:
Submit specimens for FLT3 testing as outlined in Section 15.2.
b.
WITHIN 7 DAYS OF DECISION NOT TO RANDOMIZE PATIENT:
Submit the S1612 Notice of intention Not to Randomize
c.
WITHIN 7 DAYS AFTER RANDOMIZATION (STEP 2 REGISTRATION):
Submit the following:
S1612 Onstudy Form
S1612 Transfusion Log
Pathology Report (upload reports via the Source Documentation: Baseline form in
Rave®


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d.
WITHIN 28 DAYS AFTER RANDOMIZATION (STEP 2 REGISTRATION):
Submit the following:
S1612 Mutational Analysis and Cytogenetics Report Form
Pretreatment cytogenetics mutational analysis, FISH, and flow cytometry reports
(whichever are performed). Upload reports via the Source Documentation:
Baseline form in Rave®.
e.
WITHIN 14 DAYS AFTER EACH CYCLE OF TREATMENT:
Submit the following:
S1612 Arm-Specific Treatment Form
S1612 Adverse Event Form*
S1612 Disease Assessment Form
If applicable, S1612 Fungal Infections Form
If applicable, S1612 Mutational Analysis and Cytogenetics Report Form
If applicable, S1612 Transfusion Log
Bone marrow exam, pathology, cytogenetics and mutational analysis, FISH, and
flow cytometry reports (whichever are performed). Upload reports via the Source
Documentation: Follow-up form in Rave®.
f.
WITHIN 14 DAYS OF DISCONTINUATION OF TREATMENT:
Submit the following:
S1612 Off Treatment Notice
Final S1612 Arm-Specific Treatment Form
Final S1612 Adverse Event Form*
Final S1612 Disease Assessment Form
If applicable, S1612 Mutational Analysis and Cytogenetics Report Form
If applicable, S1612 Transfusion Log
Bone marrow exam, pathology, cytogenetics and mutational analysis, FISH, and
flow cytometry reports (whichever are performed). Upload reports via the Source
Documentation: Follow-up form in Rave®.
*All adverse events, regardless of grade or suspected relationship to study drug,
should be collected and analyzed on the study.


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g.
AFTER THE PATIENT IS OFF TREATMENT, EVERY 3 MONTHS FOR THE
FIRST YEAR, EVERY 6 MONTHS FOR THE SECOND AND THIRD YEARS,
THEN ANNUALLY UNTIL FIVE YEARS FROM RANDOMIZATION (STEP 2
REGISTRATION) AND WITHIN 28 DAYS OF KNOWLEDGE
OF  RELAPSE,
PROGRESSION, OR DEATH:
Submit the following:
S1612 Follow Up Form
Late Effects Form (if prior to treatment for progression or relapse or a second
primary, and prior to non-protocol treatment, the patient experiences any severe
[Grade ≥3] long term toxicity that has not been previously reported)
h.
WITHIN 28 DAYS OF KNOWLEDGE OF DEATH:
Submit the following:
Notice of Death
Forms listed in Section 14.4e (if the patient was still on protocol treatment) or
S1612 Follow Up Form (if the patient was off protocol treatment).
15.0
SPECIAL INSTRUCTIONS
15.1
SWOG Specimen Tracking System (STS)
Patients must be registered to Step 1 before their specimens are entered into the SWOG
Specimen Tracking System.
All specimen submissions for this study must be entered and tracked using the online
SWOG Specimen Tracking System (STS). SWOG members may log on to STS via the
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 using your
SWOG roster ID number and password, click on the CRA Workbench link to access the
home page for the CRA Workbench website. Non-SWOG members may access
SpecTrack using their CTSU UserID and password on the SpecTrack login page located
at https://crawb.crab.org/SpecTrack/Logon.aspx (select the option "SWOG - SWOG -
CTSU").
A copy of the Shipment Packing List produced by the online Specimen Tracking system
should be printed and placed in the pocket of the specimen bag if it has one, or in a
separate resealable bag. STS laboratory IDs are used to identify laboratories to which
specimens are shipped.
ALL
SPECIMENS
MUST
BE
LOGGED
VIA
THIS
SYSTEM;
THERE
ARE
NO
EXCEPTIONS.
To report technical problems with Specimen Tracking, such as database errors or
connectivity issues, please send an e-mail to technicalquestion@crab.org. For procedural
help with logging and shipping specimens, there is an introduction to the system on the
Specimen Tracking main page
(https://crawb.crab.org/SpecTrack/Documents/Instructions.pdf);  or  contact  the
Data
Operations Center at 206/652-2267 to be routed to the Data Coordinator for further
assistance.


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15.2
FLT3 Testing (REQUIRED)
Specimens for FLT3 screening testing (submitted to the Radich Laboratory [Lab #93]):
Note: Previous FLT3 testing performed outside of this study must be repeated for study
stratification.
a.
Specimen Collection and Submission Timepoints:
Specimens for FLT3 testing must be collected and submitted within 1 day of
registration to Step 1 and within 42 days prior to randomization (registration
to Step 2). FLT3 results will be used for stratification purposes at the time of
randomization. E-mail notification of randomization assignment must be received
by the site prior to patient randomization (see Section 5.2e). E-mail notification of
randomization assignment is expected within 2-3 business days from the date of
specimen receipt.
3 mL of bone marrow aspirate and 10 mL of peripheral blood must be collected
per local institutional procedures into EDTA/purple top tubes. No onsite
processing is required.
If marrow is inaspirable (dry tap), the peripheral blood submission is sufficient,
regardless of peripheral blast count. If bone marrow aspiration is not obtainable
for other logistical reasons, and the patient’s peripheral blood demonstrates at
least 25% circulating blasts, the peripheral blood submission will complete the
requirement for FLT3 specimen submission.
b.
Specimen Submission Instructions
Specimens must be submitted within 24 hours of collection. Note that Lab
#93 does not accept Sunday deliveries. Arrangements should be made to
ensure that specimens will be delivered Monday-Saturday.
Specimen collection and submission instructions can be accessed on the SWOG
specimen submission webpage
(https://swog.org/members/clinicaltrials/specimens/LeuSpecimens.asp).
Please ensure that specimens are labeled correctly per the online instructions,
and that information in the sample submission form exactly matches the
specimen label. Specimens with incorrect labeling or with discrepancies
between labels and submission forms will not be accepted by the
laboratory.
c.
Specimen collection kits are not being provided for this submission; sites will use
institutional supplies.
d.
Laboratory Controls and Results
The laboratory will use 4 controls in every FLT3-ITD run: 2 positive (high and low),
1 wt and 1 ntc. The positive controls are previously validated patient samples.
Both controls must be within the laboratory’s established acceptability
range 
before a patient’s allelic ratio will be reported.
Interpreting FLT3 Results:
x
FLT3 wt band at 328 bp = NEGATIVE
x
FLT3 wt band at 328 AND one or more FLT3 ITD bands > 328 bp =
POSITIVE
x
Allelic ratio calculation: total ITD peak height/wt peak height


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x
Duplicate samples must have allelic ratios agreeing within 10%.
x
The laboratory can detect and report any ITDs will an allelic ratio down to
0.01.
15.3
Translational Medicine and Banking (Optional for Patient – Required if Patient Consents)
Specimens for translational medicine and banking (submitted to the SWOG Specimen
Repository – Leukemia Division, Lab #200):
a.
With patient’s consent, specimens must be submitted as follows:
          3 mL of bone marrow aspirate and 10 mL of peripheral blood must be
collected per local institutional procedures into EDTA/purple top tubes. No
onsite processing is required.
If marrow is inaspirable (dry tap), submission of the peripheral blood will
suffice.
          Specimens must be submitted at the following time points:
x
Prior to randomization (within 42 days prior to registration to Step 2)
– required
x
After Cycle 2 (prior to treatment on Cycle 3)
x
After Cycle 4 (prior to treatment on Cycle 5)
b.
Specimen collection and submission instructions can be accessed on the SWOG
Specimen Submission webpage
(https://swog.org/members/clinicaltrials/specimens/LeuSpecimens.asp).
c.
Specimen collection kits are not being provided for this submission; sites will use
institutional supplies.
Banked specimens will be used for future, currently unspecified translational medicine
studies, as new and important biologic markers and assays are identified. Future
research will undergo the appropriate NCI/CTEP review process before specimens are
released and used for testing.  Specimen banking is an important component of the
clinical trial to ensure that appropriate specimens are available for future research.
15.4
Cytogenetics and FISH (REQUIRED)
Specimens for cytogenetic and FISH analysis must be performed at each institution’s
preferred CLIA-approved laboratory as outlined below. If FISH analysis is not possible,
patient may still be eligible based on cytogenetics; the reason for not performing FISH
must be noted on the S1612 Cytogenetics and FISH Analysis Form.
a.
Specimen Collection and Submission Timepoints
x
Prior to randomization (within 42 days prior to registration to Step 2) – required
x
Any other time bone marrow exam is performed cytogenetic and FISH testing
are encouraged, but not mandatory. However, if cytogenetics/FISH are
performed, then results must be submitted as outlined below.
b.
Result Reporting
The S1612 Cytogenetics Lab Report Form must be submitted to the
laboratory along with the specimen. The laboratory will then return the
completed form with the results. E-mail contact information for the Data


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Manager at the site must be provided to the lab performing cytogenetic
studies. The institution will complete the S1612 Cytogenetics and FISH
Analysis Form in Medidata Rave® using the information provided by the
lab.
16.1
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
per procedures and requirements governing the use of investigational new drugs as described in
the Code of Federal Regulations 21 CFR 312.
Publication and Industry Contact
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI under
a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical Company(ies)
(hereinafter referred to as "Collaborator(s)") and the NCI Division of Cancer Treatment and
Diagnosis.  Therefore, the following obligations/guidelines  in addition to the provisions in the
"Intellectual Property Option to Collaborator"
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm)  contained  within  the
terms of award apply to the use of the Agent in this study.
1.
Agent(s) may not be used outside the scope of this protocol, nor can Agent(s) be
transferred or licensed to any party not participating in the clinical study. Collaborator(s)
data for Agent(s) are confidential and proprietary to Collaborator(s) and shall be maintained
as such by the investigators. The protocol documents for studies utilizing Agents contain
confidential information and should not be shared or distributed without the permission of
the NCI. If a copy of this protocol is requested by a patient or patient’s family member
participating on the study, the individual should sign a confidentiality agreement. A suitable
model agreement can be downloaded from: http://ctep.cancer.gov.
2.
For a clinical protocol where there is an investigational Agent used in combination with
(an)other investigational Agent(s), each the subject of different Collaborative Agreements,
the access to and use of data by each Collaborator shall be as follows (data pertaining to
such combination use shall hereinafter be referred to as "Multi-Party Data"):
3.
NCI will provide all Collaborators with written notice regarding the existence and nature of
any agreements governing  their  collaboration  with NCI, the design  of the proposed


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combination protocol, and the existence of any obligations which would tend to restrict
NCI's participation in the proposed combination protocol.
a.
Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical
trial by any other Collaborator solely to the extent necessary to allow said other
Collaborator to develop, obtain regulatory approval or commercialize its own
investigational Agent.
b.
Any Collaborator having the right to use the Multi-Party Data from these trials must
agree in writing prior to the commencement of the trials that it will use the Multi-
Party Data solely for development, regulatory approval, and commercialization of
its own Agent.
4.
Clinical Trial Data and Results and Raw Data developed under a Collaborative Agreement
will be made available exclusively to Collaborator(s), the NCI, and the FDA, as appropriate
and unless additional disclosure is required by law or court order as described in the IP
Option to Collaborator.
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm). Additionally, all
Clinical Data and Results and Raw Data will be collected, used and disclosed consistent
with all applicable federal statutes and regulations for the protection of human subjects,
including, if applicable, the Standards for Privacy of Individually Identifiable Health
Information set forth in 45 C.F.R. Part 164.
5.
When a Collaborator wishes to initiate a data request, the request should first be sent to
the NCI, who will then notify the appropriate investigators (Group Chair for Cooperative
Group studies, or PI for other studies) of Collaborator's wish to contact them.
6.
Any data provided to the Collaborator(s) for Phase III studies must be in accordance with
the guidelines and policies of the responsible Data Monitoring Committee (DMC), if there
is a DMC for this clinical trial.
7.
Any manuscripts reporting the results of this clinical trial must be provided to CTEP by the
Group office for Cooperative Group studies or by the principal investigator for non-
Cooperative Group studies for immediate delivery to Collaborator(s) for advisory review
and comment prior to submission for publication. Collaborator(s) will have 30 days from
the date of receipt for review. Collaborator shall have the right to request that publication
be delayed for up to an additional 30 days in order to ensure that Collaborator's confidential
and proprietary data, in addition to the Collaborator(s)'s intellectual property rights, are
protected. Copies of abstracts must be provided to CTEP for forwarding to Collaborator(s)
for courtesy review as soon as possible and preferably at least three (3) days prior to
submission, but in any case, prior to presentation at the meeting or publication in the
proceedings. Press releases and other media presentations must also be forwarded to
CTEP prior to release. Copies of any manuscript, abstract and/or press release/media
presentation should be sent to:
E-mail: ncicteppubs@mail.nih.gov
8.
The Regulatory Affairs Branch will then distribute them to the Collaborator(s). No
publication, manuscript or other form of public disclosure shall contain any of the
Collaborator's confidential/proprietary information.
Monitoring
This study will be monitored by the Clinical Data Update System (CDUS) Version 3.0. Cumulative
CDUS data will be submitted quarterly to CTEP by electronic means. Reports are due January 31,
April 30, July 31 and October 31.


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Instructions for submitting data using the CDUS can be found on the CTEP Web site
(http://ctep.cancer.gov/reporting/cdus.html).
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.
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.
b.
Reporting method
This study requires that expedited adverse events be reported using the Cancer
Therapy Evaluation Program Adverse Event Reporting System (CTEP-AERS).
CTEP's guidelines for CTEP-AERS can be found at http://ctep.cancer.gov. A
CTEP-AERS report must be submitted to the SWOG Operations Office
electronically via the CTEP-AERS Web-based application located at:
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_
events.htm.
c.
When to report an event in an expedited manner
Some adverse events require 24-hour notification (refer to Table 16.1) via
CTEP-AERS.
When the adverse event requires expedited reporting, submit the report within
the number of calendar days of learning of the event, as specified in Table 16.1.
In the rare event when internet connectivity is disrupted a 24-hour notification
is made to NCI by telephone at 301-897-7497. An electronic report MUST be
submitted immediately upon re-establishment of internet connection.
Any supporting documentation should be submitted to CTEP per NCI
guidelines for AE reporting located at:
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeg
uidelines.pdf.
d.
Other recipients of adverse event reports
The SWOG Operations Office will forward reports and documentation to the
appropriate regulatory agencies and drug companies as required.
Adverse events determined to be reportable to the Institutional Review Board
responsible for oversight of the patient must be reported according to local
policy and procedures.


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


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Table 16.1:
Late Phase 2 and Phase 3 Studies: Expedited Reporting Requirements for Adverse Events
that Occur on Studies under a CTEP IND within 30 Days of the Last Administration of the
Investigational Agent/Intervention1 Midostaurin or Nivolumab
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312)
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or
not they are considered related to the investigational agent(s)/intervention (21 CFR 312.64)
An adverse event is considered serious if it results in ANY of the following outcomes:
1)
Death
2)
A life-threatening adverse event
3)
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for
≥24 hours
4)
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life
functions
5)
A congenital anomaly/birth defect.
6)
Important Medical Events (IME) that may not result in death, be life threatening, or require
hospitalization may be considered serious when, based upon medical judgment, they may jeopardize
the patient or subject and may require medical or surgical intervention to prevent one of the outcomes
listed in this definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6).
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via
CTEP-AERS within the timeframes detailed in the table below.
Hospitalization
Grade 1
Timeframes
Grade 2
Timeframes
Grade 3 Timeframes
Grade 4 & 5
Timeframes
Resulting in
Hospitalization
≥24 hrs
10 Calendar Days
24-Hour 5
Calendar
Days
Not resulting in
Hospitalization
≥24 hrs
Not required
10 Calendar Days
NOTE: Protocol specific exceptions to expedited reporting of serious adverse events are found in the
Specific Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR.
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 Late Phase 2 and Phase 3 Studies Utilizing an Agent under
a CTEP IND:
           Group-specific instructions
Submission of the on-line CTEP-AERS report plus any necessary
amendments generally completes the reporting requirements. In
addition, you may be asked to submit supporting clinical data to the
Operations Offices in order to complete the evaluation of the event.
If requested, the supporting data should be sent within 5 calendar
days by fax to 210-614-0006. Supporting clinical data submitted
should include:
x
Printed copy of the first page of the CTEP-AERS Report.
x
Copies of clinical sourced 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.
g.
Reporting Secondary Malignancy, including AML/ALL/MDS
           A secondary malignancy is a cancer caused by treatment for a previous
malignancy
(e.g.,
treatment
with
investigational
agent/intervention,
radiation or chemotherapy). A secondary malignancy is not considered a
metastasis of the initial neoplasm.
CTEP requires all secondary malignancies that occur following
treatment with an agent under an NCI IND to be reported via CTEP-
AERS. Three options are available to describe the event.
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/d
ocs/aeguidelines.pdf
           Any supporting documentation should be submitted to CTEP per NCI
guideline s for AE reporting located at:
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/d
ocs/aeguidelines.pdf


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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.
h.
Reporting Pregnancy, Fetal Death, and Death Neonatal
           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.
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.
           Pregnancy Loss Pregnancy loss is defined in CTCAE as “Death in utero.”
Pregnancy loss should be reported expeditiously as Grade 4 “Pregnancy
loss” under the Pregnancy, puerperium and perinatal conditions
SOC.
A Pregnancy loss should NOT be reported as a Grade 5 event under the
Pregnancy, puerperium and perinatal conditions SOC, as currently CTEP-
AERS recognizes this event as a patient death.
           Death Neonatal Death neonatal is defined in CTCAE as “Newborn death
occurring during the first 28 days after birth A neonatal death should be
reported expeditiously as Grade 4 “Death neonatal” under the General
disorders and administration SOC.
Neonatal death should NOT be reported as a Grade 5 event under the
General disorders and administration SOC as currently CTEP-AERS
recognizes this event as a patient death.
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.
Hills RK, Burnett AK. Applicability of a "Pick a Winner" trial design to acute myeloid leukemia.
Blood 118 (9):2389-94, 2011. PMID: 21734235.
2.
Thepot S, Itzykson R, Seegers V, et al. Azacitidine in untreated acute myeloid leukemia: a report
on 149 patients. Am J Hematol 89:410–416, 2013.
3.
Dombret H, Seymour JF, Butrym A, et al. International phase 3 study of azacitidine vs conventional
care regimens in older patients with newly diagnosed AML with >30% blasts. Blood 126(3):291-9,
2015.
4.
Personal communication: N. Daver, MDACC.
5.
Ozeki K1, Kiyoi H, Hirose Y, et al. Biologic and clinical significance of the FLT3 transcript level in
acute myeloid leukemia. Blood 103(5):1901-8, 2004. PMID: 14604973.
6.
Ravandi F, Arana Yi C, Cortes JE, et al. Final report of phase II study of sorafenib, cytarabine and
idarubicin for initial therapy in younger patients with acute myeloid leukemia. Leukemia 28(7):1543-
5, 2014. PMID: 24487412
7.
Röllig, C, Serve H, Hüttmann A, et al. Addition of sorafenib versus placebo to standard therapy in
patients aged 60 years or younger with newly diagnosed acute myeloid leukaemia (SORAML): a
multicentre, phase 2, randomised controlled trial. The Lancet Oncology 16(16): 1691-1699, 2015.
PMID: 26549589
8.
Cooper BW, Kindwall-Keller TL, Craig MD, et al. A phase I study of midostaurin and azacitidine in
relapsed and elderly AML patients. Clin Lymphoma Myeloma Leuk 15(7):428-432, 2015. PMID:
25776192
9.
Strati P, Kantarjian H, Ravandi F, et al. Phase I/II trial of the combination of midostaurin (PKC412)
and 5-azacytidine for patients with acute myeloid leukemia and myelodysplastic syndrome. Am J
Hematol 90(4):276-81, 2015. PMID: 25530214.
10.
Personal communication: Annie Im
11
Qin T, Youssef EM, Jelinek J, et al. Effect of Cytarabine and Decitabine in Combination in Human
Leukemic Cell Lines. Clin Cancer Res 13(14): 4225-32, 2007.
12
Avramis VI, Mecum RA, Nyce J, et al. Pharmacodynamic and DNA methylation studies of high-
dose 1-beta-D-arabinofuranosyl cytosine before and after in vivo 5-azacytidine treatment in
pediatric patients with refractory acute lymphocytic leukemia. Cancer Chemother  Pharmacol
24(4):203-10, 1989.
13
Borthakur G, Huang X, Kantarjian H, et al. Report of a Phase 1/3 Study of a Combination of
Azacitidine and Cytarabine in Acute Myelogenous Leukemia and High-Risk Myelodysplastic
Syndromes. Leuk Lymphoma 51(1): 73-8, 2010.
14
Butera J et al, ASCO Annual Meeting 2011 abstract 6537.
15
Scandura JM, Roboz GJ, Moh M, et al. Phase 1 Study of Epigenetic Priming with Decitabine Prior
to Standard Induction Chemotherapy for Patients with AML. Blood 118(6): 1472-80, 2011.
16.
Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization
classification of myeloid neoplasms and acute leukemia. Blood 127(20): 2391-2405, 2016.


Page 93
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17.
Pocock SJ, Simon R. Sequential treatment assignment with balancing for prognostic factors in the
controlled clinical trial. Biometrics (1):103-15, 1975.
18.
Dohner H, Estey E, Grimwade D, et al. Diagnosis and Management of AML in Adults: 2017 ELN
Recommendations from an International Expert Panel. Blood. Prepublished online November 28,
2016; doi: 10.1182/blood-2016-08-733196.
19.
Dombret H, Seymour JF, Butrym A, et al. International phase 3 study of azacitidine vs conventional
care regimens in older patients with newly diagnosed AML with >30% blasts. Blood 126(3):291-9.


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18.0
APPENDIX
18.1
Midostaurin Patient Drug Information Handout and Wallet Card
18.2
Drugs Known to be Metabolized by CYP450 Isoenzymes 2D6 and 3A4
18.3
Management
Algorithms
for
Immuno-Oncology
(I-O)
Therapy
for
Endocrinopathy,
Gastrointestinal, Hepatic, Neurological, Pulmonary, Renal and Skin Adverse Events for
Nivolumab (Arm B) Adverse Event Management
18.4
Drugs Known to be Metabolized by CYP450 Isoenzymes 2D6 and 3A4
18.5
Translational Medicine – Duplex Sequencing for Determining Measurable Residual Disease


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18.1
Midostaurin Patient Drug Information Handout and Wallet Card
Information for Patients, Their Caregivers and Non-Study Healthcare Team on Possible
Interactions with Other Drugs and Herbal Supplements
The patient
is enrolled on a clinical trial using the experimental
study drug, midostaurin. This clinical trial is sponsored by the National Cancer Institute. This form
is addressed to the patient, but includes important information for others who care for this patient.
These are the things that you as a healthcare provider need to know:
Midostaurin may interact with certain specific enzymes in your liver and certain transport proteins
that help move drugs in and out of cells.
x
The enzymes in question are CYP 3A4/5, 1A2, 2C8, 2C9, 2C19, 2D6 and UGT1A1. Midostaurin
is a substrate for CYP3A4/5 and may be affected by other drugs that are moderate or strong
inhibitors or inducers of this enzyme. Midostaurin is an inhibitor of CYP 3A4/5, 1A2, 2C9 and
an inducer of CYP 1A2, 2B6, 2C8, 2C9, 2C19, 3A4/5 and UGT1A1 and may affect the
clearance of other drugs that are sensitive substrates for these enzyme pathways.
x
The proteins in question are P-gp, OATP1B1, OATP1B3, MATE1, MATE2K, BCRP and MRP2.
Midostaurin is an inhibitor of P-gp, OATP1B1, OATP1B3, MATE1, MATE2K, BCRP and an
inducer of MRP2. Midostaurin has the potential to affect transport of other drugs that are moved
in and out of cells by these transporters.
To the patient: Take this paper with you to your medical appointments and keep the attached
information card in your wallet.
Midostaurin may interact with other drugs which can cause side effects. For this reason, it is very
important to tell your study doctors of any medicines you are taking before you enroll onto this
clinical trial. It is also very important to tell your doctors if you stop taking any regular medicines,
or if you start taking a new medicine while you take part in this study. When you talk about your
current medications with your doctors, include medicine you buy without a prescription (over-the-
counter remedy), or any herbal supplements such as St. John’s Wort. It is helpful to bring your
medication bottles or an updated medication list with you.
Many health care providers can write prescriptions. You must tell all of your health care providers
(doctors, physician assistants, nurse practitioners, pharmacists) you are taking part in a clinical
trial.
These are the things that you and they need to know:
Midostaurin must be used very carefully with other medicines that use certain liver enzymes or
transport proteins to be effective or to be cleared from your system. Before you enroll onto the
clinical trial, your study doctor will work with your regular health care providers to review any
medicines and herbal supplements that are considered “strong inducers/inhibitors of CYP3A4/5.”
Midostaurin inhibits CYP 3A4/5, 1A2, 2C9, P-glycoprotein (P-gp), OATP1B1, OATP1B3, MATE1,
MATE2K and BCRP and induces CYP 1A2, 2B6, 2C8, 2C9, 2C19, 3A4/5, UGT1A1 and MRP2.
These characteristics may change how other medicine works in your body.
x
Please be very careful! Over-the-counter drugs (including herbal supplements) may contain
ingredients that could interact with your study drug. Speak to your doctors or pharmacist to
determine if there could be any side effects.
x
Avoid ingesting grapefruit juice, grapefruit and Seville oranges while taking midostaurin.
x
Your regular health care provider should check a frequently updated medical reference or call
your study doctor before prescribing any new medicine or discontinuing any medicine. Your
study doctor’s name is
and he or she can be
contacted at
.


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March 2017
STUDY DRUG INFORMATION WALLET CARD
You are enrolled on a clinical trial using the experimental
study drug midostaurin. This clinical trial is sponsored by
the NCI. Midostaurin may interact with drugs that are
processed by your liver, or use certain transport proteins in
your body.  Because of this, it is very important to:
¾ Tell your doctors if you stop taking any medicines or if you
start taking any new medicines.
¾ Tell all of your health care providers (doctors, physician
assistants, nurse practitioners, or pharmacists) that you are
taking part in a clinical trial.
¾ Avoid ingesting grapefruit, grapefruit juice and Seville
oranges.
¾ Check with your doctor or pharmacist whenever you need
to use an over-the-counter medicine or herbal supplement.
Midostaurin interacts with CYP 3A4/5, 1A2, 2B6, 2C8, 2C9,
2C19, UGT1A1, P-gp, MRP2, OATP1B1, OATP1B3, MATE1,
MATE2K and
BCRP and must be used very carefully with other medicines
that interact with these enzymes and transporters.
¾ Before you enroll onto the clinical trial, your study doctor
will work with your regular health care providers to review
any medicines and herbal supplements that are considered
“strong inducers/inhibitors of CYP3A4/5.” Midostaurin
inhibits CYP 3A4/5, 1A2, 2C9, P-gp, OATP1B1, OATP1B3,
MATE1, MATE2K and BCRP and induces CYP 1A2, 2B6, 2C8,
2C9, 2C19, 3A4/5, UGT1A1 and MRP2. It may change how
other medicine works in your body.
¾ Before prescribing new medicines, your regular health care
providers should go to a frequently-updated medical
reference for a list of drugs to avoid, or contact your study
doctor.
¾ Your study doctor’s name is
can be contacted
.


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18.2
Drugs Known to be Metabolized by CYP450 Isoenzymes 2D6 and 3A4
Because the lists of these agents are constantly changing, it is important to regularly consult a
frequently-updated list such as http://medicine.iupui.edu/clinpharm/ddis/; medical reference texts
such as the Physicians’ Desk Reference may also provide this information.
CYP2D6 Substrates
Amitriptyline (hydroxylation)
Amphetamine
Betaxolol
Bisoprolol
Brofaromine
Buturolol
Bupropion
Captopril
Carvedilol
Cevimeline
Chlorpheniramine
Chlorpromazine
Cinnarizine
Clomipramine (hydroxylation)
Clozapine (minor pathway)
Codeine (hydroxylation, o-demelhylation)
Cyclobenzaprine (hydroxylation)
Cyclophosphamide
Debrisoquin
Delavirdine
Desipramine
Dexfenfluramine
Dextromethorphan (o-demethylation)
Dihydrocodeine
Diphenhydramine
Dolasetron
Donepezil
Doxepin
Encainide
Fenlluramine
Flecainide
Fluosetine (minor pathway)
Fluphenazine
Haiofantrine
Haioperidol (minor pathway)
Hydrocodone
Hydrocortisone
Hydroxyamphetamine
lmipramine (hydroxylation)
Labetalol
Loratadine
Maprotiline
m-Chlorophenylpiperazine (m-CPP)
Meperidine
Methadone
Methamphetamine
Metoclopramide
Metoprolol
Mexitetine
Mianserin
Mirtazapine (hydroxylation)
Molindone
Morphine
Nortriptyline (hydroxylation)
Olanzapine (minor, hydroxymethylation)
Ondansetron
Orphenadrine
Oxycodone
Papaverine
Paroxetine (minor pathway)
Penbutolol
Pentazocine
Perhexiline
Perphenazine
Phenformin
Pindolol
Promethazine
Propafenone
Propranolol
Quetiapine
Remoxipride
Risperidone
Ritonavir (minor)
Ropivacaine
Selegiline
Sertindole
Sertratine (minor pathway)
Sparteine
Tamoxifen
Thioridazine
Tiagabine
Timolol
Tolterodine
Tramadol
Trazodone
Trimipramine
Tropisetron
Venlafaxine (o-desmethylation)
Yohimbine


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CYP2D6 Inhibitors
Amiodarone
Celecoxib
Chloroquine
Chlorpromazine
Cimelidine
Citalopram
Clomipramine
Codeine
Deiavirdine
Desipramine
Dextropropoxyphene
Diitiazem
Doxorubicin
Entacapone (high dose)
Fluoxetine
Fluphenazine
Fluvoxamine
Haloperidol
Labetalol
Lobeline
Lomustine
Methadone
Mibefradil
Moclobemide
Nortluoxeline
Paroxetine
Perphenazine
Propafenone
Quinacrine
Quinidine
Ranitidine
Risperidone (weak)
Ritonavir
Sertindole
Sertraline (weak)
Thioridazine
Vaiprolc acid
Venlafaxine (weak)
Vinblastine
Vincristine
Vinorelbine
Yohimbine
CYP3A3/4 Substrates
Acetaminophen
Aifentanil
Alosetron
Alprazolam
Amiodarone
Amitriptyline (minor)
Amlodipine
Anastrozole
Androsterone
Antipyrine
Astemizole
Atorvastatin
Benzphetamine
Bepridil
Bexarotene
Bromazepam
Bromocriptine
Budesonide
Bupropion (minor)
Buspirone
Busutfan
Caffeine
Cannabinoids
Carbamazepine
Cevimeline
Cerivastatin
Chlorpromazine
Cimetidine
Cisapride
Citałopram
Ketoconazole
Lansoprazole (minor)
Letrozole
Levobupivicaine
Lidocaine
Loratadine
Losartan
Lovastatin
Methadone
Mibefradil
Miconazole
Midazolam
Mifepristone
Mirtazapine (N-demethylation)
Montelukast
Navelbine
Nefazodone
Nelfinavir
Nevirapine
Nicardipine
Nifedipine
Niludipine
Nimodipine
Nisoldipine
Nitrendipine
Omeprazole (sulfonation)
Ondansetron
Oral contraceptives
Orphenadrine
Paclitaxel


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Clarithromycin
Clindamycin
Clomipramine
Clonazepam
Clozapine
Cocaine
Codeine (demethylation)
Cortisol
Cortisone
Cyclobenzaprine (demethylation)
Cyclophosphamide
Cyclosporine
Dapsone
Dehydroepiandrostendione
Delavirdine
Desmethyldiazepam
Dexamethasone
Dextromethorphan (minor, N-demethylation)
Diazepam (minor; hydroxylation, N-
demethylation)
Digitoxin
Diltiazem
Disopyramide
Docetaxel
Dolasetron
Donepezil
Doxorubicin
Doxycycline
Dronabinol
Enalapril
Erylhromycin
Estradiol
Ethinyl estradiol
Ethosuximide
Etoposide
Exemestene
Dofetilide (minor)
Felodipine
Fentanyl
Fexotenadine
Finaxteride
Fluoxetine
Flutabmide
Glyburide
Granisetron
Halofantrine
Hydrocortixone
Hydroxyarginine
lfosfamide
lmipramine
lndinavir
lsradipine
ltraconazole
Pantoprazole
Pimozide
Pioglitazone
Pravastatin
Prednisone
Progesterone
Proguanil
Propafenone
Quercetin
Quetiapine
Quinidine
Quinine
Repaglinide
Retinoic acid
Rifampin
Risperidone
Ritonavir
Salmeterol
Saquinavir
Sertindole
Sertraline
Sibutramine
Sildenafil citrate
Simvastatin
Sirolimus
Sufentanil
Tacrolimus
Tamoxifen
Temazepam
Teniposide
Terfenadine
Testosterone
Tetrahydrocannabinol
Theophylline
Tiagabine
Tolterodine
Toremifene
Trazodone
Tretinoin
Triazolam
Troglitazone
Troleandomycin
Venlafaxine (N-demethylation)
Verapamil
Vinblastine
Vincristine
Warfarin (R-warfarin)
Yohimbine
Zaleplon (minor pathway)
Zatoestron
Zileuton
Ziprasidone
Zolpidem
Zonisamide


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CYP3A3/4 Inducers
Carbamazepine
Dexamethasone
Ethosuximide
Glucocorticoids
Griseofulvin
Nafcillin
Nelfinavir
Nevirapine
Oxcarbazepine
Phenobarbital
Phenylbutazone
Phenytoin
Primidone
Progesterone
Rifabutin
Rifampin
Rofecoxib (mild)
St John’s wort
Sulfadimidine
Sulfinpyrazone
Troglitazone
CYP3A3/4 Inhibitors
Amiodarone
Anastrozole
Azithromycin
Cannabinoids
Cimetidine
Clarithromycin
Clotrimazole
Cyclosporine
Danazol
Delavirdine
Dexamethasone
Diethyldithiocarbamate
Diltiazem Dirithromycin
Disulfiram
Entacapone (high dose)
Erythromycin
Ethinyl estradiol
Fluconazole (weak)
Fluoxetine
Fluvoxamine
Gestodene
Grapefruit juice
lndinavir
lsoniazid
ltraconazole
Ketoconazole
Metronidazole
Mibefradil
Miconazole (moderate)
Nefazodone
Nelfinavir
Nevirapine
Norfloxacin
Norfluoxetine
Omeprazole (weak)
Oxiconazole
Paroxetine (weak)
Propoxyphene
Quinidine
Quinine
Quinupristin and dalfopristin
Ranitidine
Ritonavir
Saquinavir
Sertindole
Sertraline
Troglitazone
Troleandomycin
Valproic acid (weak)
Verapamil
Zafirlukast
Zileuton
(Adapted from Cytochrome P-450 Enzymes and Drug metabolism. In : Lacy CF, Armstrong LL,
Goldman MP, Lance LL eds. Drug Information Handbook 8th ed. Hudson, OH; LexiComp Inc. 2000:
1364-1371)


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18.3
Management
Algorithms
for
Immuno-Oncology
(I-O)
Therapy
for
Endocrinopathy,
Gastrointestinal, Hepatic, Neurological, Pulmonary, Renal and Skin Adverse Events for
Nivolumab (Arm B) Adverse Event Management
Note:
For the following algorithms, prednisone PO may be utilized in place of
methylprednisone IV.
Please see below.


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a.
Endocrinopathy Management Algorithm


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b.
GI Adverse Event Management Algorithm


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c.
Hepatic Adverse Event Management Algorithm


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d.
Neurological Adverse Event Management Algorithm


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e.
Pulmonary Adverse Event Management Algorithm


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f.
Renal Adverse Event Management Algorithm


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g.
Skin Adverse Event Management Algorithm


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18.4
Drugs Known to be Metabolized by CYP450 Isoenzymes 2D6 and 3A4
Because the lists of these agents are constantly changing, it is important to regularly
consult a frequently-updated list such as http://medicine.iupui.edu/clinpharm/ddis/; medical
reference texts such as the Physicians’ Desk Reference may also provide this information.
CYP2D6
SUBSTRATES
Amitriptyline (hydroxylation)
Amphetamine
Betaxolol
Bisoprolol
Brofaromine
Buturolol
Bupropion
Captopril
Carvedilol
Cevimeline
Chlorpheniramine
Chlorpromazine
Cinnarizine
Clomipramine (hydroxylation)
Clozapine (minor pathway)
Codeine (hydroxylation, o-demelhylation)
Cyclobenzaprine (hydroxylation)
Cyclophosphamide
Debrisoquin
Delavirdine
Desipramine
Dexfenfluramine
Dextromethorphan (o-demethylation)
Dihydrocodeine
Diphenhydramine
Dolasetron
Donepezil
Doxepin
Encainide
Fenlluramine
Flecainide
Fluosetine (minor pathway)
Fluphenazine
Haiofantrine
Haioperidol (minor pathway)
Hydrocodone
Hydrocortisone
Hydroxyamphetamine
lmipramine (hydroxylation)
Labetalol
Loratadine
Maprotiline
m-Chlorophenylpiperazine (m-CPP)
Meperidine
Methadone
Methamphetamine
Metoclopramide
Metoprolol
Mexitetine
Mianserin
Mirtazapine (hydroxylation)
Molindone
Morphine
Nortriptyline (hydroxylation)
Olanzapine (minor, hydroxymethylation)
Ondansetron
Orphenadrine
Oxycodone
Papaverine
Paroxetine (minor pathway)
Penbutolol
Pentazocine
Perhexiline
Perphenazine
Phenformin
Pindolol
Promethazine
Propafenone
Propranolol
Quetiapine
Remoxipride
Risperidone
Ritonavir (minor)
Ropivacaine
Selegiline
Sertindole
Sertratine (minor pathway)
Sparteine
Tamoxifen
Thioridazine
Tiagabine
Timolol
Tolterodine
Tramadol
Trazodone
Trimipramine
Tropisetron
Venlafaxine (o-desmethylation)
Yohimbine


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INHIBITORS
Amiodarone
Celecoxib
Chloroquine
Chlorpromazine
Cimelidine
Citalopram
Clomipramine
Codeine
Deiavirdine
Desipramine
Dextropropoxyphene
Diitiazem
Doxorubicin
Entacapone (high dose)
Fluoxetine
Fluphenazine
Fluvoxamine
Haloperidol
Labetalol
Lobeline
Lomustine
Methadone
Mibefradil
Moclobemide
Nortluoxeline
Paroxetine
Perphenazine
Propafenone
Quinacrine
Quinidine
Ranitidine
Risperidone (weak)
Ritonavir
Sertindole
Sertraline (weak)
Thioridazine
Vaiprolc acid
Venlafaxine (weak)
Vinblastine
Vincristine
Vinorelbine
Yohimbine
CYP3A3/4
Substrates
Acetaminophen
Aifentanil
Alosetron
Alprazolam
Amiodarone
Amitriptyline (minor)
Amlodipine
Anastrozole
Androsterone
Antipyrine
Astemizole
Atorvastatin
Benzphetamine
Bepridil
Bexarotene
Bromazepam
Bromocriptine
Budesonide
Bupropion (minor)
Buspirone
Busutfan
Caffeine
Cannabinoids
Carbamazepine
Cevimeline
Cerivastatin
Digitoxin
Diltiazem
Disopyramide
Docetaxel
Dolasetron
Chlorpromazine
Cimetidine
Cisapride
Citałopram
Clarithromycin
Clindamycin
Clomipramine
Clonazepam
Clozapine
Cocaine
Codeine (demethylation)
Cortisol
Cortisone
Cyclobenzaprine (demethylation)
Cyclophosphamide
Cyclosporine
Dapsone
Dehydroepiandrostendione
Delavirdine
Desmethyldiazepam
Dexamethasone
Dextromethorphan (minor, N-
demethylation)
Diazepam (minor; hydroxylation, N-
demethylation)
Nefazodone
Nelfinavir
Nevirapine
Nicardipine
Nifedipine


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Donepezil
Doxorubicin
Doxycycline
Dronabinol
Enalapril
Erylhromycin
Estradiol
Ethinyl estradiol
Ethosuximide
Etoposide
Exemestene
Dofetilide (minor)
Felodipine
Fentanyl
Fexotenadine
Finaxteride
Fluoxetine
Niludipine
Nimodipine
Nisoldipine
Nitrendipine
Omeprazole (sulfonation)
Ondansetron
Oral contraceptives
Orphenadrine
Paclitaxel
Pantoprazole
Pimozide
Pioglitazone
Pravastatin
Prednisone
Progesterone
Proguanil
Propafenone
FLUTAMIDE
Substrates
Glyburide
Granisetron
Halofantrine
Hydrocortixone
Hydroxyarginine
lfosfamide
lmipramine
lndinavir
lsradipine
ltraconazole
Ketoconazole
Lansoprazole (minor)
Letrozole
Levobupivicaine
Lidocaine
Loratadine
Losartan
Lovastatin
Methadone
Mibefradil
Miconazole
Midazolam
Mifepristone
Mirtazapine (N-demethylation)
Montelukast
Navelbine
Toremifene
Trazodone
Tretinoin
Triazolam
Troglitazone
Troleandomycin
Venlafaxine (N-demethylation)
Verapamil
Vinblastine
Quercetin
Quetiapine
Quinidine
Quinine
Repaglinide
Retinoic acid
Rifampin
Risperidone
Ritonavir
Salmeterol
Saquinavir
Sertindole
Sertraline
Sibutramine
Sildenafil citrate
Simvastatin
Sirolimus
Sufentanil
Tacrolimus
Tamoxifen
Temazepam
Teniposide
Terfenadine
Testosterone
Tetrahydrocannabinol
Theophylline
Tiagabine
Tolterodine
Vincristine
Warfarin (R-warfarin)
Yohimbine
Zaleplon (minor pathway)
Zatoestron
Zileuton
Ziprasidone


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Zolpidem
Zonisamide
INDUCERS
Carbamazepine
Dexamethasone
Ethosuximide
Glucocorticoids
Griseofulvin
Nafcillin
Nelfinavir
Nevirapine
Oxcarbazepine
Phenobarbital
Phenylbutazone
Phenytoin
Primidone
Progesterone
Rifabutin
Rifampin
Rofecoxib (mild)
St John’s wort
Sulfadimidine
Sulfinpyrazone
Troglitazone
INHIBITORS
Amiodarone
Anastrozole
Azithromycin
Cannabinoids
Cimetidine
Clarithromycin
Clotrimazole
Cyclosporine
Danazol
Delavirdine
Dexamethasone
Diethyldithiocarbamate
Diltiazem Dirithromycin
Disulfiram
Entacapone (high dose)
Erythromycin
Ethinyl estradiol
Fluconazole (weak)
Fluoxetine
Fluvoxamine
Gestodene
Grapefruit juice
lndinavir
lsoniazid
ltraconazole
Ketoconazole
Metronidazole
Mibefradil
Miconazole (moderate)
Nefazodone
Nelfinavir
Nevirapine
Norfloxacin
Norfluoxetine
Omeprazole (weak)
Oxiconazole
Paroxetine (weak)
Propoxyphene
Quinidine
Quinine
Quinupristin and dalfopristin
Ranitidine
Ritonavir
Saquinavir
Sertindole
Sertraline
Troglitazone
Troleandomycin
Valproic acid (weak)
Verapamil
Zafirlukast
Zileuton
(Adapted from Cytochrome P-450 Enzymes and Drug metabolism. In : Lacy CF, Armstrong LL,
Goldman MP, Lance LL eds. Drug Information Handbook 8th ed. Hudson, OH; LexiComp Inc. 2000:
1364-1371)


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18.5
Translational Medicine – Duplex Sequencing for Determining Measurable Residual Disease
a.
Objective
1.
To test duplex sequencing (DS) against flow cytometry in patients treated 
under S0106.
b.
Hypothesis
That ultrasensitive mutation detection by duplex sequencing (DS) will be better at 
predicting relapse than the conventional method of flow cytometry. Our goal is to finish 
this proposal with a locked down model of MRD prediction of relapse. This may in the
end include only one parameter (e.g., DS) or a combination of parameters (e.g., DS, 
flow, and clinical variables). This MRD metric will then be employed in the prospective 
myeloMATCH trials for validation (note, flow will still initially be the MRD endpoint until 
“beaten” by another metric prospectively).
c.
Background and Rationale
1.
Preliminary Data and Study Justification
Relapse is the primary obstacle to cure in acute and chronic leukemia. The 
detection of measurable residual disease (MRD) is a direct measure of disease 
burden (and thus, treatment efficacy), and is the strongest predictor of relapse. 
MRD guides treatments and is an established trial endpoint in chronic myeloid 
leukemia (CML). Recent collaborative efforts by the FNIH, NCI, FDA, 
academia, and industry have further demonstrated the importance in acute 
lymphoblastic leukemia (ALL). Our labs have played a major role is establishing 
MRD as a standard of care procedure, as a measurement of outcomes in 
clinical trials in CML) and ALL. MRD measurement in AML is associated with 
relapse, but it is technically more difficult to perform and standardize and has 
not yet been integrated into trial
design and outcome. There is an 
acknowledged need recognized by the U.S. Cooperative groups and CTEP that 
AML needs accurate and reproducible molecular methods to predict response 
and relapse. This project proposal specifically addresses that unmet need, and 
will develop, validate, and integrate molecular diagnostics into AML trials and 
therapy.
2.
Rationale to Test Duplex Sequencing (DS) Against Flow Cytometry in 
Patients
The need for more accurate MRD assessment is shown in Figure 1, which is 
from a recently published metaanalysis of MRD and outcomes in adult AML (1). 
The results show that a substantial number of patients with MRD positivity do 
not relapse, while a substantial number of those that are MRD negative do .


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Quantitative genetic testing of MRD may eventually 1) be used as an early 
indication of novel drug efficacy, 2) serve as a reliable early endpoint in phase 
2 clinical trials 3) guide targeted drug therapy, and 4) yield understanding of 
tumor response issues such as clonal competition, selection, and evolution. 
However, an improved measurement of MRD would be an important, if not 
essential, development to best harness the
predictive potential of MRD. 
The NCI is launching a precision medicine initiative in AML (“myeloMATCH”). 
The initiative will use rapid NGS to identify mutations and will preferentially 
enter patients onto trials where targeted agents exist to the detected mutation. 
These phase II trials will be use flow cytometry as a measure of MRD and will 
use the achievement of MRD as an endpoint. Further, there will be a set of trials 
based on “erasing” MRD. Thus, a more accurate measurement of MRD is 
needed to better predict long term outcomes (essentially, pulling the two curves 
in Figure 1 farther apart). 
MyeloMATCH has identified duplex sequencing DS as a highly sensitive NGS 
method that may supplant, or complement, MRD assessment by flow 
cytometry. This proposal intends to test DS against flow cytometry in patients 
from S016, where outcome results and flow cytometry measurements already 
exist. This will allow for a more efficient integration into prospective 
myeloMATCH trials, where DS can be compared in real time to flow cytometry. 
Note that initially flow cytometry will be the assay study of choice for MRD 
assessments until prospective comparisons are complete.
3.
Expected Distribution of Duplex Sequencing (DS) Against Flow Cytometry in 
Patients
We have just completed DS on 69 diagnostic and remission samples from 
S0106. Of 69, flow cytometry detected MRD in 10 pts, while 59 were MRD 
negative. DS detected more MRD, with MRD positive in 42 cases, and MRD 
negativity found in 27 cases (p<0.001).
4.
Cut-points Used
The optimal cutoffs for outcome prediction are not known for either flow 
cytometry or DS. From a practical standpoint, the limits of detection of flow 
cytometry is ~0.01%, and this can vary from patient to patient, both from 
disease and sample effects (many studies will define any MRD <0.1% as 


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negative). The detection limit for DS is ~0.001%, but again this limit is influence 
by sample input, quality, and perhaps even specific mutation (e.g., FLT3ITD v. 
NPM1). One of the goals of this proposal is to have enough samples with both 
flow and DS data to more precisely define cut-offs for the prospective 
myeloMATCH trial tests.
Note in the above distribution counts any MRD counted as positive.
d.
Experimental Design and Methods
1.
Description of Duplex Sequencing (DS)
Duplex Sequencing (DS) is an ultra-high accuracy NGS method with an error 
rate below one-in-ten-million (Schmmidt et al. Nature Methods 2015). It is 
highly effective for high-resolution MRD detection through digital tabulation of 
tens of millions of individual DNA molecules to assess the proportion carrying 
AML-associated mutations. The principal of DS is that sequencing libraries are 
made from both sides of the DNA molecule. Mutation calls are only made when 
there are changes to complementary base pairs (e.g. C and G) at the same 
base pair address. Thus, the limitation of conventional NGS created by random 
errors made in the process of library preparation is corrected by including 
second strand information. We have used this method to great success in 
detecting BCR-ABL kinase domain mutations in CML and Ph+ ALL (refs). 
Results shown from a spike in experiment of 9 AML mutation cell lines is 
shown below. DS has the benefit of fully objective MRD quantification using 
any standard Illumina sequencer and without the need for expert interpretation 
of results. We will use a standardized ~60,000 BP panel comprising a 
collection of genes and hotspots that are mutated in >95% of adult AMLs. We 
will use this panel to carry out low depth standard NGS in the time-of-diagnosis 
samples and very deep (20-40,000x) DS at the MRD time points and look for 
low frequency mutations in the latter that were found clonally in the former. 
This approach has the advantage of being fairly simple, quite sensitive.
2.
Analytic Performance of Duplex Sequencing (DS)
The TwinStrand Duplex Sequencing AML MRD assay consists of a panel 
designed to target 29 genes or gene regions that are recurrently mutated in 
AML patients. 90%-95% of adult AML patients carry a mutation in at least one 
panel gene, which makes the assay a powerful, near-universal tool to detect 
MRD in AML patients. The flexible nature of the assay’s targeted enrichment 
strategy makes it very easy to expand to a larger collection of genes for 
increased sensitivity and applicability, to add new therapeutically-relevant 
targets as they are discovered, and to eventually develop patient-specific 
assays for sub one-in-one million sensitivity. The first part of this document 
describes the scientific and technical approaches designed to address the 
seven individual Project Activities identified in the SOW as necessary to support 
the NCI’s MyeloMATCH Precision Medicine Initiative. The second part of the 
document explains the technical approach to accomplish the Example Project: 
Expansion of the AMLMRD panel by incorporating additional genes that are 
covered in the Oncomine Myeloid Research Assay.
3.
Analytical Validation of the AML MRD Assay
The development and analytical validation of the AML MRD assay was the 
main goal of Phase I of our NCI-funded AML SBIR grant (R44CA233381, PIs 
J. Salk, J. Radich, PO Greg Evans), which we successfully accomplished a 
year ago. The assay was exhaustively validated using a mutation standard 
built with DNA from cell lines with known AML mutations spiked into peripheral 


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blood DNA from a healthy young donor. The Mutant Allele Frequency (MAF) 
ranged from 10-2 to 10-5 (Fig. 1). The mutation standard was sequenced in 
triplicate to test precision in addition to sensitivity and specificity of the AML 
MRD assay. All mutations, including mutations with the lowest MAF, were 
consistently detected, demonstrating the sensitivity of the assay to detect 
mutations at frequencies of at least 1x10-5. The Duplex Sequencing MAF 
closely correlated with the expected MAF in the 3 replicates (r2 values of 0.98, 
0.96 and 0.95 for replicates, 1, 2, and 3, respectively), demonstrating high 
concordance between predicted and obtained MAF and precision 
(reproducibility) within the intended range of detection (Fig. 1). The specificity 
of the assay for a limit of detection (LOD) of 10-5 was 100%.
To further validate technical performance of the assay we spiked DNA from an 
AML patient, containing five previously characterized AML mutations, into 
peripheral blood DNA from a healthy young donor.
This experiment mimics the detection of a low frequency AML clone, simulating 
the real clinical scenario of MRD in AML patients with multiple mutations. 
Dilutions ranged from 1:100 to 1:10,000 to test our goal of detecting an AML 
clone with an LOD of 0.01% (1:10,000). Predicted and Duplex MAF were 
highly correlated (r2=0.92). Most of the mutations in the dilution series were 
detected for all genes, with all single mutations ≥ 0.01% detected (Fig. 2). The 
combined information from the 5 mutations enabled the robust detection of the 
AML clone across every dilution tested (100% sensitivity). None of the 
mutations were detectable in normal DNA (100% specificity), indicating low 
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e. 
Specimens, Acquisition of Specimens and Data Scoring Measures 
 
Frozen cells will be shipped the Radich Lab. The primary source of samples will be from 
bone marrow, but where there are concurrent bone marrow and peripheral blood 
samples, we will perform DS on both, as we wish to determine if peripheral blood in the 
future can be used to measure MRD rather than bone marrow (as is now the 
standard of care in CML). 
 
Mutations will be assessed as a continuous variable VAF. This will allow a direct 
comparison to the continuous variable of flow cytometry (e.g., a X-Y plot), as well as 
comparisons based on arbitrary categorical cutoffs. 
 
f. 
Statistical Design 
 
1. 
Clinical Endpoints 
 
The primary clinical endpoints are time to relapse (TTR), relapse-free survival 
(RFS), and overall survival (OS). TTR is measured from date of CR to date of 
relapse, with patients last known to be alive without relapse censored at date 
of last contact; death without relapse is considered a competing event. RFS is 
measured from date of CR to first of date of death or relapse, with patients last 
known to be alive without relapse censored at date of last contact. OS is 
measured from date of CR to date of death from any cause, with patient last 
known to be alive censored at date of last contact. 
 
MRD by flow is measured both quantitatively (percent of cells with MRD) and 
as a binary variable (no MRD observed versus any MRD observed). MRD by 
DS is measured as a sequence of binary variables (marker present/absent for 
all markers evaluated; marker at baseline still present at remission; new marker 
at remission; any marker observed at remission). 
 
2. 
Sample Size Estimate 
 
We request BM samples among 200 patients who achieved complete remission 
from S0106. 101 will be selected based on having flow data available (170 
patients from S0106 have flow data; 69 have already been analyzed; this 
project requests BM samples from the remaining 101). An additional 99 patients 
without flow data but with baseline and remission BM samples will be 
requested; those 99 patients will be selected randomly from all patients 
available. In addition, we will request blood samples from 100 patients who 
have flow data available. We will randomly select the 100 from among the 170 
with flow results; we will stratify the random selection to maintain the percent of 
patients who are Flow MRD positive and negative in the sub-sample and full 
sample. 
 
3. 
Statistical Justification for Sample Size Estimate 
 
BM samples: The S0106 trial has flow outcome data on 170. We have DS 
completed on 69 of these patients. We request an addition 101 samples to have 
paired DS and flow data on all 170 patients to maximize the precision in 
characterizing these paired samples and comparing flow and DS. We request 
BM from an additional 99 patients to improve the precision of hazard ratios for 
DS. 
 
Blood samples: We request blood samples from 100 patients with flow data 
available. All 100 will have DS from marrow available through this proposal and 


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prior work. 100 samples will allow us to compare and characterize differences 
in using blood versus marrow for DS evaluation and blood DS versus flow. 
 
4. 
Statistical Analysis Methodology 
 
McNemar’s test will be used to evaluate concordance of MRD measurements 
on paired samples (Flow versus BM DS; BM DS versus blood DS; Flow versus 
blood DS). 
 
Cox regression models will be used to evaluate associations with RFS and OS. 
Cause-specific Cox regression models and Fine and Gray subdistribution 
hazard models will be used to evaluate TTR. 
Hazard ratios and 95% confidence intervals and C-statistics will be reported. 
 
Event-rate assumptions for power calculation are based on the observed 
S0106 data and are detailed in the following section. 
 
5. 
Power Calculations for Statistical Tests 
For McNemar’s test to describe the power available we follow the methodology 
of Connor (Connor et al. 
Biometrics 1987). 
 
To compare flow versus BM DS MRD: with n=170 paired samples and using a 
two-sided test with alpha=0.05, we will have 90% power if the proportion Flow 
positive and DS negative is 3% and the proportion Flow negative and DS 
positive is 18%. 
 
To compare flow versus blood DS MRD: with n=100 paired samples and using 
a two-sided test with alpha=0.05, we will have 87% power if the proportion Flow 
positive and DS negative is 3% and the proportion Flow negative and DS 
positive is 24%. 
 
To compare BM DS MRD versus blood DS MRD: we are interested in 
characterizing the concordance. It is possible that there will not be any patients 
who are discordant with DS MRD negative in BM but positive in blood, in which 
case McNemar’s odds ratio and confidence interval may not be well-defined. In 
this case we will calculate the proportion of patients who are MRD positive by 
DS in both blood and marrow and calculate an exact binomial confidence 
interval. The width of the interval will depend on the proportion. With n=100, if 
the proportion is 0.50 the exact confidence interval will be (0.40, 0.60); if the 
proportion is 0.80 the exact confidence interval will be (0.71, 0.87); if the 
proportion is 0.90 the exact confidence interval will be (0.82, 0.95). 
 
Power for the Cox regression models is characterized by the number of events 
observed: among the 170 patients with flow data, there have been 74 deaths 
and 66 relapses; 23 patients died without prior relapse and 15 patients who 
have relapsed have not died. Therefore, there are 74 deaths for OS analyses, 
89 events (relapses and deaths) for RFS analyses, and 66 relapses for TTR 
analyses. 
 
In the cohort of patients with both flow and DS (n=170), when using an two-
sided alpha of 5%, this cohort will have approximately 90% to detect a hazard 
ratio of magnitude 2.0 for RFS, 2.15 for OS, and 2.2 for TTR. C-statistics will 
be calculated to descriptively characterize the predictive performance of in Han 
et al. (Statistics in Medicine, 2017). We believe these HRs (or HRs more 
extreme) to be achievable regression models but will not be formally tested in 
comparison per the issusuch tests detailed with DS in BM. (Patkar et al. 
Leukemia 2021) 


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With the additional 99 patients with BM DS data we expect similar event rates 
as with the n=170 with flow data and so with n=269 patients with BM DS data, 
we expect 117 deaths of OS analysis, 140 RFS events for RFS analyses, and 
104 relapses for TTR analyses. This sample size gives us additional power: 
when using a two-sided alpha of 5%, this cohort will have approximately 90% 
to detect a hazard ratio of magnitude 1.7 for RFS, 1.85 for OS, and 2.0 for TTR. 
In addition, with n=270, the confidence intervals will have greater precision 
(intervals will be more narrow; width will depend on magnitude of HR) and 
additional descriptive subset analyses can be feasible. In addition, with n=269 
more complicated multivariable models can be fit (since the number of 
covariates is limited by the number events; a rough rule-of-thumb is 1 covariate 
term for every 10-15 events). It will be important to characterize the role of DS 
MRD in multivariable models controlling for the important prognostic factors of 
age, performance status, and baseline cytogenetic risk category (4 levels: 
favorable, intermediate, unfavorable, unknown). 
 
With 100 patients with blood DS data, we expect similar events rates as in the 
n=170 with flow data; so with n=100 we expect 43 deaths for OS analyses, 52 
RFS events for RFS analyses, and 38 relapses for TTR analyses. When using 
an two-sided alpha of 5%, this cohort will have approximately 90% to detect a 
hazard ratio of magnitude 2.5 for RFS, 2.65 for OS, and 2.85 for TTR. 
 
 
 
 
 
 


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Informed Consent Model for S1612
Specimen Submission: FLT3 Screening
*NOTES FOR LOCAL INSTITUTION INFORMED CONSENT AUTHORS:
This model informed consent form has been reviewed by the DCTD/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 additions, 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 SWOG 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
SWOG Operations Office.
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 SWOG.
"SWOG" 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
SWOG. This includes consent forms for studies where all patients are registered
directly through the SWOG Data Operations Office, all intergroup studies for
which the registration is being credited to SWOG (whether the registration is
Readability Statistics:
Flesch Reading Ease
62.1 (targeted above 55)
Flesch-Kincaid Grade Level 8.9 (targeted below 8.5)


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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 SWOG.
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 about participating in research. The
consent form provides a summary of the study, the individual's rights as a study
participant, and documents their willingness to participate.  The consent form is,
however, only one piece of an ongoing exchange of information between the
investigator and study participant.  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
Suggestion for Local Investigators: An NCI pamphlet explaining clinical trials is
available for your patients.  The pamphlet is titled: "Taking Part in Cancer
Treatment Research Studies". 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.


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Informed Consent Model for S1612
Specimen Submission: FLT3 Screening
Study Title for Study Participants: Comparing New Treatment Options to
One of the Standard Treatment Options for Older Patients with Newly
Diagnosed Acute Myeloid Leukemia
Official Study Title for Internet Search on http://www.ClinicalTrials.gov:
S1612, A Randomized Phase II/III Trial of “Novel Therapeutics” versus
Azacitidine in Newly Diagnosed Patients with Acute Myeloid Leukemia
(AML) or High-Risk Myelodysplastic Syndrome (MDS), Age 60 or Older
What is the usual approach to my leukemia?
You are being asked to take part in this study because you have acute myeloid leukemia (AML)
or high-risk myelodysplastic syndrome (MDS). Also, you and/or your doctor did not think you
should get intensive chemotherapy. People who are not in a study are usually treated with
single-agent chemotherapy such as azacitidine or decitabine, or with combinations of more
intense therapies.  Your doctor should discuss with you what option he or she would recommend
if you were not in a clinical trial.  For participants who receive the usual approach for this cancer,
anywhere from 0 to 10 out of 100 are free of cancer at five years.
What are my other choices if I do not take part in this study?
If you decide not to take part in this study, you have other choices. For example:
x
you may choose to have the usual approach described above
x
you may choose to take part in a different study, if one is available
x
or you may choose not to be treated for cancer, but you may want to receive comfort
care to relieve symptoms.
Why is this study being done?
The purpose of this screening step is to allow researchers to learn if a certain blood and
bone marrow test (called a biomarker) can help predict how a person’s AML/MDS will
respond to study drugs.   All participants that are in the study will take part in the
biomarker study. For the biomarker test, researchers will take a little less than an extra
teaspoon of bone marrow and about 2 teaspoons of blood. These will be taken at the time
you have bone marrow and blood drawn to diagnose your AML/MDS. If you don’t have
enough bone marrow, then just the blood will be used. If you don’t have blood available
from your previous blood draws, you will be asked to have another blood draw for this
testing.  Researchers will look at the biomarker, called FLT3, before you begin the
treatment part of the study to make sure that participants with the biomarker take part in


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all of the study treatment groups. Later the researchers will use the information to see if
the level of the FLT3 biomarker predicts if certain treatments work better than others.
The use of this biomarker is investigational. This biomarker is not being used to assign you
to any specific treatment group.  We expect that about 500 participants will have this
biomarker test each year of this study.  We expect that a total of between 550 to 1,700
people will take part in the biomarker research, and between 500 to 1,556 people will take
part in the treatment portion of the study. The treatment portion of the study is designed
to let the researchers expand the study if the treatment seems to be working, or stop it if the
treatment doesn’t seem to be working.  Because of this, it is difficult to know exactly      
how many people might take part in the study overall.
What are the study groups?
The study has two steps: the initial screening step where we will test for the biomarker, and
the study treatment step which will be discussed in a separate consent form.
All participants will have the biomarker test.  You will have to meet additional requirements
before you can begin treatment on the study treatment step.  If you don’t meet the criteria to go
on to the study treatment, you will not be able to be treated on the study treatment step. Your
treatment at that point will be decided between you and your study doctor. If you do meet the
criteria to go on to the study treatment, you will receive a separate consent form that will explain
the study treatment.
The study chart below is meant to help you understand the study design. Start reading at the top
of the chart and read down, following the arrows.
You agree to have specimens submitted for FLT3 testing
Your specimens are submitted for FLT3 testing
FLT3 testing is performed on your specimen
You will receive another consent form that explains the treatment portion of the study.
If you agree to take part in the treatment study, you will be randomized to one of the study
treatment groups.
How long will I be in this study?
The FLT3 screening step will take approximately 2-3 days from the time your specimen is taken
at your doctor’s office and shipped to the laboratory for examination.
Specimen Submission: FLT3 Screening
Treatment Study Randomization


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What extra tests and procedures will I have if I take part in this study?
The exams, tests and procedures you will have on the treatment step are part of the usual
approach for your cancer.  The only required test/procedure as part of the screening step is the
biomarker test for FLT3.
Before you begin the study:
You will need to have the following extra test in order to be in the study:
*
Biomarker test for FLT3
An additional sample of bone marrow (less than one teaspoon) and of blood (about two
teaspoons) will be taken for the study at the time your bone marrow and blood are taken to
diagnose your disease (within about 6 weeks before you start treatment on the study). The blood
and bone marrow have to be sent to the lab within a day after they are collected, so if you had
blood and bone marrow drawn previously for diagnosis, you will be asked to have more blood
and bone marrow drawn for this testing. If you do not have enough bone marrow available, just
the blood will be taken. This sample is required in order for you to take part in this study because
the research on the sample is an important part of the study.
Common side effects of a bone marrow biopsy are a small amount of bleeding at the time of the
procedure, pain at the biopsy site, which can be treated with regular pain medications, and
bruising. Rarely, an infection can occur.  Common side effects of a blood draw are bruising,
pain, and/or bleeding at the site of the draw.
If there is any blood or bone marrow left after the mandatory testing, the researchers would like
to keep it and store it for biobanking. This is not required for you to take part in the study. This
will be discussed in the section on optional studies.
Your privacy is very important and the researchers will make every effort to protect it. Your test
results will be identified by a unique code and the list that links the code to your name will be
kept separate from your sample and health information in a secure database.  The results of the
biomarker test will not be given to you or your doctor.
Neither you nor your health care plan/insurance carrier will be billed for the collection of the
bone marrow or blood that will be used for this study.
What possible risks can I expect from taking part in this study?
If you choose to take part in the screening part of this study, there is a risk that:
x
As with all medical screening tests, there is a chance of a false positive or a false
negative result. A “false positive” refers to the identification of a biomarker that is
not present. A “false negative” is the failure to find a biomarker that indeed exists.
The tests have been designed to ensure that the possibility of incorrect results is low.


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Either a false positive or a false negative test will not affect your treatment
assignment.
x
If you have to have another blood draw to get more blood, you may have pain,
bruising, bleeding, or swelling at the site of the blood draw. If you have to have
another biopsy to get more bone marrow you may have pain, bruising, bleeding,
swelling, and/or infection at the site of the biopsy.
x
You may lose time at work or home and spend more time in the hospital or doctor’s
office than usual.
x
You may be asked sensitive or private questions which you normally do not discuss.
x
There is a risk someone could get access to the personal information in your medical
records or other information researchers have kept about you. Someone might be
able to trace this information back to you. The researchers believe the chance that
someone will identify you is very small, but the risk may change in the future as
people come up with new ways of tracing information. In some cases, this
information could be used to make it harder for you to get or keep a job. The
researchers believe the chance these things will happen is very small, but cannot
promise that they will not occur. “(For non-US participants, please verify existence of
such laws before including the following text.) There are laws against misuse of genetic
information, but they may not give full protection. The Genetic Information
Nondiscrimination Act of 2008, also referred to as GINA, was passed by Congress to
protect Americans from such discrimination. The new law prevents discrimination
from health insurers and employers. This law does not cover life insurance,
disability insurance and long-term care insurance.
x
There can also be a risk in finding out new genetic information about you. New
health information about inherited traits that might affect you or your blood
relatives could be found during a study.
Let your study doctor know of any questions you have about possible risks. You can ask
the study doctor questions about risks at any time.
What possible benefits can I expect from taking part in this study?
Your study treatment will not be based on the results of this biomarker test, so your treatment
will not be any better or worse depending on the results. This biomarker test is meant to help
ensure that people with the biomarker take part in all study treatment groups. This study will
help researchers learn things that will help people in the future.
Can I stop taking part in this study?
Yes. You can decide to stop at any time. If you decide to stop for any reason, it is important to let
the study doctor know as soon as possible so you can stop safely. If you stop, you can decide
whether or not to let the study doctor continue to provide your medical information to the
organization running the study.


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The study doctor will tell you about new information or changes in the study that may affect
your health or your willingness to continue in the study.
The study doctor may take you out of the study:
x
If your health changes and the study is no longer in your best interest
x
If new information becomes available
x
If you do not follow the study rules
x
If the study is stopped by the sponsor, Institutional Review Board (IRB) or Food and
Drug Administration (FDA).
What are my rights in this study?
Taking part in this study is your choice. No matter what decision you make, and even if
your decision changes, there will be no penalty to you. You will not lose medical care or any
legal rights.
For questions about your rights while in this study, call the
(insert name of center) Institutional Review Board at
(insert telephone
number). (Note to Local Investigator: Contact information for patient representatives or other
individuals at a local institution who are not on the IRB or research team but take calls
regarding clinical trial questions can also be listed here.)
What are the costs of taking part in this study?
There is no cost to you or your insurance associated with this biomarker screening. If you need
an extra biopsy to collect more tissue for this screening, the biopsy cost will be provided by the
study. However, if you take part in the treatment study, you and/or your health plan/insurance
company will need to pay for the costs of caring for your cancer while in this treatment study,
including the cost of tests, procedures, or medicines to manage any side effects, unless you are
told that certain tests are supplied at no charge. Before you decide to be in the study, you should
check with your health plan or insurance company to find out exactly what they will pay for.
Other costs will be addressed in more detail in the consent form for the treatment you are
offered.
You will not be paid for taking part in this study.
What happens if I am injured or hurt because I took part in this study?
If you are injured or hurt as a result of taking part in this study and need medical treatment,
please tell your study doctor. The study sponsors will not offer to pay for medical treatment for
injury. Your insurance company may not be willing to pay for study-related injury. If you have
no insurance, you would be responsible for any costs.
If you feel this injury was a result of medical error, you keep all your legal rights to receive
payment for this even though you are in a study.


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Who will see my medical information?
Your privacy is very important to us and the researchers will make every effort to protect it.
Your information may be given out if required by law. For example, certain states require
doctors to report to health boards if they find a disease like tuberculosis. However, the
researchers will do their best to make sure that any information that is released will not identify
you. Some of your health information, and/or information about your specimen, from this study
will be kept in a central database for research. Your name or contact information will not be put
in the database.
There are organizations that may inspect your records. These organizations are required to make
sure your information is kept private, unless required by law to provide information. Some of
these organizations are:
x
The study sponsor and any drug and device companies supporting the study
x
The Institutional Review Board, IRB, is a group of people who review the research with
the goal of protecting the people who take part in the study.
x
The Food and Drug Administration and the National Cancer Institute in the U.S., and
similar ones if other countries are involved in the study.
Where can I get more information?
You may visit the NCI Web site at http://cancer.gov/ for more information about studies or
general information about cancer. You may also call the NCI Cancer Information Service
to get the same information at: 1-800-4-CANCER (1-800-422-6237).
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as
required by U.S. Law. This Web site will not include information that can identify you. At
most, the Web site will include a summary of the results. You can search this Web site at
any time.
Who can answer my questions about this study?
You can talk to the study doctor about any questions or concerns you have about this study or to
report side effects or injuries. Contact the study doctor
(insert name of
study doctor[s]) at
(insert telephone number).
ADDITIONAL STUDIES SECTION:
This section is about optional studies you can choose to take part in
This part of the consent form is about optional studies that you can choose to take part in. You
will not get health benefits from any of these studies. The researchers leading this optional study
hope the results will help other people with cancer in the future.


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The results will not be added to your medical records and you or your study doctor will not know
the results.
You will not be billed for these optional studies. You can still take part in the main study even if
you say ‘no’ to any or all of these studies. If you sign up for but cannot complete any of the
studies for any reason, you can still take part in the main study.
Circle your choice of “yes” or “no” for each of the following studies.
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.
OPTIONAL SAMPLE COLLECTIONS FOR LABORATORY STUDIES AND/OR
BIOBANKING FOR POSSIBLE FUTURE STUDIES
Circle your choice of “yes” or “no” at the end of this section that explains this Optional Study.
Researchers are trying to learn more about cancer, diabetes, and other health problems. Much of
this research is done using samples from your bone marrow and/or blood. Through these studies,
researchers hope to find new ways to prevent, detect, treat, or cure health problems.
Some of these studies may be about genes. Genes carry information about features that are found
in you and in people who are related to you. Researchers are interested in the way that genes
affect how your body responds to treatment.
If you choose to take part, a sample of bone marrow and/or blood, taken at the same time
as other marrows are being drawn for regular cancer care, will be collected. The
researchers ask your permission to store and use your samples and related health
information (for example, your response to cancer treatment, results of study tests and
medicines you are given) for medical research. The research that may be done is unknown
at this time. Storing samples for future studies is called “biobanking”. The Biobank is
being run by SWOG and supported by the National Cancer Institute.
WHAT IS INVOLVED?
If you agree to take part, here is what will happen next:
1) Less than one teaspoon of additional bone marrow and about 2 teaspoons of
additional blood will be collected during your regular bone marrow and blood draws
before you start treatment, after about 2 months of treatment, and after about 4
months of treatment.  Blood is collected from a vein in your arm. Bone marrow is
collected during a procedure where a needle is inserted into the marrow of your hip,


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called a bone marrow biopsy. If you do not have bone marrow available, the
researchers will only collect a blood sample.
Your bone marrow and/or blood and some related health information may be stored
in the Biobank, along with samples and information from other people who take part.
The samples will be kept until they are used up. Information from your medical
record will be updated from time to time.
2) Qualified researchers can submit a request to use the materials stored in the Biobanks.
A science committee at the clinical trials organization, and/or the National Cancer
Institute, will review each request. There will also be an ethics review to ensure that
the request is necessary and proper. Researchers will not be given your name or any
other information that could directly identify you.
3) Neither you nor your study doctor will be notified when research will be conducted or
given reports or other information about any future research that is done using your
samples.
4) Some of your genetic and health information may be placed in central databases that
may be public, along with information from many other people. Information that
could directly identify you will not be included.
WHAT ARE THE POSSIBLE RISKS?
1) The most common risks related to a bone marrow biopsy are a small amount of
bleeding at the time of the procedure, pain at the biopsy site, which can be treated
with regular pain medications, and bruising. Rarely, an infection can occur.  The most
common risks related to drawing blood from your arm are brief pain and possibly a
bruise.
2) There is a risk that someone could get access to the personal information in your
medical records or other information researchers have stored about you.
3) There is a risk that someone could trace the information in a central database back to
you. Even without your name or other identifiers, your genetic information is unique
to you. The researchers believe the chance that someone will identify you is very
small, but the risk may change in the future as people come up with new ways of
tracing information.
4) In some cases, this information could be used to make it harder for you to get or keep
a job or insurance. (For non-US participants, please verify existence of such laws
before including the following text.) There are laws against the misuse of genetic
information, but they may not give full protection. There can also be a risk in
knowing genetic information. New health information about inherited traits that
might affect you or your blood relatives could be found during a study. The
researchers believe the chance these things will happen is very small, but cannot
promise that they will not occur.
HOW WILL INFORMATION ABOUT ME BE KEPT PRIVATE?
Your privacy is very important to the researchers and they will make every effort to protect it.
Here are just a few of the steps they will take:
1) When your sample(s) is sent to the researchers, no information identifying you (such
as your name) will be sent. Samples will be identified by a unique code only.


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2) The list that links the unique code to your name will be kept separate from your
sample and health information. Any Biobank and SWOG staff with access to the list
must sign an agreement to keep your identity confidential.
3) Researchers to whom SWOG sends your sample and information will not know who
you are. They must also sign an agreement that they will not try to find out who you
are.
4) Information that identifies you will not be given to anyone, unless required by law.
5) If research results are published, your name and other personal information will not
be used.
WHAT ARE THE POSSIBLE BENEFITS?
You will not benefit from taking part. The researchers, using the samples from you and others,
might make discoveries that could help people in the future.
ARE THERE ANY COSTS OR PAYMENTS?
There are no costs to you or your insurance. You will not be paid for taking part. If any of the
research leads to new tests, drugs, or other commercial products, you will not share in any
profits.
WHAT IF I CHANGE MY MIND?
If you decide you no longer want your samples to be used, you can call the study doctor,
, (insert name of study doctor for main trial) at
(insert telephone number of study doctor for main trial) who will
let the researchers know. Then, any sample that remains in the bank will no longer be used and
related health information will no longer be collected. Samples or related information that have
already been given to or used by researchers will not be returned.
WHAT IF I HAVE MORE QUESTIONS?
If you have questions about the use of your samples for research, contact the study doctor,
, (insert name of study doctor for main trial), at 
(insert telephone number of study doctor for main trial).
Please circle your answer to show whether or not you would like to take part in each option
SAMPLES FOR FUTURE RESEARCH STUDIES:
My samples and related information may be kept in a Biobank for use in future health
research.
YES
NO
This is the end of the section about optional studies.


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My Signature Agreeing to Take Part in the Screening Study
(Specimen Submission: FLT3 Screening)
I have read this consent form or had it read to me. I have discussed it with the study doctor and
my questions have been answered. I will be given a signed copy of this form. I agree to take part
in the main study and any additional studies where I circled ‘yes’.
Participant’s signature
Date of signature


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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 SWOG. Your doctor does not work for SWOG, but has agreed
to help collect specimens from many participants. 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 SWOG and request samples for their studies. SWOG reviews the way that these
studies will be done, and decides if any of the samples can be used. SWOG gets the specimen and
information about you from your hospital, and sends the specimen samples and some information about
you to the researcher. SWOG 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 SWOG. If more information is needed,
SWOG 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 to the researcher. The researcher will not know who you are.


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How could the records be used in ways that might be harmful to me?
If your confidential genetic information is discovered, you may suffer from genetic discrimination. Genetic
discrimination occurs if people are treated unfairly because of differences in their genes that increase their
chances of getting a certain disease. In the past, this could have resulted in the loss of health insurance or
employment. Because of this, The Genetic Information Nondiscrimination Act of 2008, also referred to as
GINA, was passed by Congress to protect Americans from such discrimination. The new law prevents
discrimination from health insurers and employers. This act was signed into federal law on May 21, 2008,
and went into effect May 2009. This law does not cover life insurance, disability insurance and long-term
care insurance.
While this study has safeguards in place to protect your confidential genetic information and to make it
extremely unlikely that your identity would be connected with any special studies that are performed on
your tissue, it is possible that this information could be discovered by someone who is unauthorized to have
access to it.
How am I protected?
SWOG is in charge of making sure that information about you is kept private. SWOG 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.
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).


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Informed Consent Model for S1612
Treatment Study
*NOTES FOR LOCAL INSTITUTION INFORMED CONSENT AUTHORS:
This model informed consent form has been reviewed by the DCTD/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 additions, 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 SWOG 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
SWOG Operations Office.
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 SWOG.
"SWOG" 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
SWOG. This includes consent forms for studies where all patients are registered
directly through the SWOG Data Operations Office, all intergroup studies for
which the registration is being credited to SWOG (whether the registration is
Readability Statistics:
Flesch Reading Ease
63.7
(targeted above 55)
Flesch-Kincaid Grade Level 8.7
(targeted below 8.5)


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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 SWOG.
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 about participating in research. The
consent form provides a summary of the study, the individual's rights as a study
participant, and documents their willingness to participate.  The consent form is,
however, only one piece of an ongoing exchange of information between the
investigator and study participant.  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
Suggestion for Local Investigators: An NCI pamphlet explaining clinical trials is
available for your patients.  The pamphlet is titled: "Taking Part in Cancer
Treatment Research Studies". 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.


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Informed Consent Model for S1612
Treatment Study
Study Title for Study Participants: Comparing New Treatment Options to
One of the Standard Treatment Options for Older Patients with Newly
Diagnosed Acute Myeloid Leukemia
Official Study Title for Internet Search on http://www.ClinicalTrials.gov:
S1612, A Randomized Phase II/III Trial of “Novel Therapeutics” versus
Azacitidine in Newly Diagnosed Patients with Acute Myeloid Leukemia
(AML) or High-Risk Myelodysplastic Syndrome (MDS), Age 60 or Older
What is the usual approach to my leukemia?
You are being asked to take part in this study because you have acute myeloid leukemia (AML)
or high-risk myelodysplastic syndrome (MDS). Also, you and/or your doctor did not think you
should get intensive chemotherapy. People who are not in a study are usually treated with
single-agent chemotherapy such as azacitidine or decitabine, or with combinations of more
intense therapies, that are approved by the FDA.  There is not currently an FDA-approved
medication for patients that have AML but who cannot tolerate intensive chemotherapy.  These
patients are usually treated with azacitidine or decitabine, or with palliative medications
(medications to help with symptoms but that do not treat cancer).  Your doctor should discuss
with you what option he or she would recommend if you were not in a clinical trial. For patients
who receive the usual approach for this cancer, anywhere from 0 to 10 out of 100 are free of
cancer at five years.
What are my other choices if I do not take part in this study?
If you decide not to take part in this study, you have other choices. For example:
x
you may choose to have the usual approach described above
x
you may choose to take part in a different study, if one is available
x
or you may choose not to be treated for cancer, but you may want to receive comfort
care to relieve symptoms.
Why is this study being done?
The purpose of this study is to compare any good and bad effects of using different new
treatment options to one of the current standard treatment options given for patients with
AML or MDS who cannot tolerate or do not want to get intensive chemotherapy. The
investigators will keep testing new treatments to see if they have any different effects on
patients and their cancer when compared to the standard. Each patient will only get one
type of treatment on the study.  This is described more below. If one of the new treatments
seems to help patients more than the current standard, the study will start to use that


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treatment as the new standard.  If any of the treatments is not as helpful for any reason, or
the bad effects are too severe, then that treatment will no longer be used in this study. The
investigators want to use this study to find better treatment options for AML or MDS
patients who do not get intensive chemotherapy.
At any time, the study will have one standard treatment group. The number of
experimental treatment groups being tested at any time might be from one to four. The
current standard treatment group and the experimental treatment groups that are
currently open are discussed below. Some of the drugs used on the study are FDA
approved to treat AML and/or MDS, and some are not. This is also discussed below.
There will be between about 500 and 1,556 people taking part in this study.
What are the study groups?
As discussed above, this study will have several treatment groups, but not all of them are going
to be open at the same time. You can only take part in one of the currently open groups. The
groups that are currently open are outlined below. Your doctor will decide whether you need to
be admitted to the hospital for any part or all of your treatment.
x
Group A will get the usual drug used for this type of cancer, azacitidine alone.
Azacitidine is a drug used for this type of cancer when a person cannot get intensive
chemotherapy safely. You will get the drug in cycles that are 28 days long. You will
get the drug either as a shot under the skin or by an IV in your vein. You will get
drug for 7 out of the first 12 days, and then have a break from the drug for the
remainder of the 28-day cycle.  Azacitidine has not been approved by the FDA to
treat AML or all forms of MDS.
x
Group B will get the usual drug used for this type of cancer, azacitidine just like
Group A.  Group B will also get a study drug called nivolumab. Nivolumab will be
given by an IV into your vein on Days 1 and 15 of each 28-day cycle. Nivolumab is
approved by the FDA to treat some types of cancers, but not AML or MDS.
x
Group C will get the usual drug used for this type of cancer, azacitidine, just like
Group A.  Group C will also get a study drug called midostaurin. Midostaurin will be
taken by mouth as capsules twice a day on Days 8-21 of each 28-day cycle.
Midostaurin has been approved for use by the FDA for patients with FLT3 + AML
(AML with a specific mutation in a gene called FLT3) when used in combination
with the drugs cytarabine and daunonibicin, but not in combination with azacitidine.
The cycles for all study groups will repeat until your disease gets worse or your or your doctor
decide that you should stop.
A computer will by chance assign you to one of these treatment groups in the study. This is
called randomization.  This is done by chance because no one knows if one study group is better
or worse than the others. Some study groups do not allow patients with certain physical


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conditions to participate.  If you have one of the conditions, you can still be in the study, but the
computer will not assign you to a study group that does not allow that condition.
Another way to find out what will happen to you during this study is to read the chart below.
Start reading at the top and read down, following the lines and arrows.
How long will I be in this study?
You will receive the study treatment for as long as you and your doctor think the treatment is
helping you. After you stop taking study treatment, your doctor will continue to watch you for
side effects and follow your condition for up to 5 years after you are registered to the study. At
minimum, you will have clinic visits every 3 months for the first year, every 6 months for the
second and third years, and then annually until 5 years after you are randomized to study
treatment.
What extra tests and procedures will I have if I take part in this study?
All of the exams, tests, and procedures you will have are part of the usual approach for your
cancer.
What possible risks can I expect from taking part in this study?
You agree to take part in the biomarker study (FLT3 screening)
FLT3 screening performed
You agree to take part in the
treatment study.
Randomize
(The computer will randomly put
you in a study group)
Group A:
Azacitidine
(usual approach
group)
Group B:
Azacitidine +
Nivolumab
(study group)
Group C:
Azacitidine +
Midostaurin
(study group)


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If you choose to take part in this study, there is a risk that the study drugs may not be as
good as the usual approach for your cancer or condition at shrinking or stabilizing your
cancer.
You may also have the following discomforts:
x
Spend more time in the hospital or doctor’s office
x
Be asked sensitive or private questions about things you normally do not discuss
x
May not be able to take part in future studies
The drugs used in this study may affect how different parts of your body work such as your
liver, kidneys, heart, and blood. Your study doctor will test your blood and will let you
know if changes occur that may affect your health.
There is also a risk that you could have side effects from the study drug(s)/study approach.
Here are important things to know about side effects:
x
The study doctors do not know who will or will not have side effects.
x
Some side effects may go away soon, some may last a long time, and some may never
go away.
x
Some side effects may make it hard for you to have children.
x
Some side effects may be mild. Other side effects may be very serious and may even
result in death.
You can ask your study doctor questions about side effects at any time. Here are
important ways to make side effects less of a problem:
x
If you notice or feel anything different, tell your study doctor.  He or she can check
to see if it is a side effect.
x
Your study doctor will work with you to treat your side effects.
x
Your study doctor may adjust the study drugs to try to reduce side effects.
The tables below show the most common and the most serious side effects doctors know
about. Keep in mind that there might be other side effects doctors do not yet know about. If
important new side effects are found, the study doctor will discuss these with you.


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STUDY GROUPS A, B, and C:
Possible side effects of azacitidine, the usual approach for this type of cancer:
Possible Side Effects of Azacitidine (Updated 1/22/18)
COMMON, SOME MAY BE SERIOUS
In 100 people receiving azacitidine, more than 20 and up to 100 may have:
x
Anemia which may require blood transfusion
x
Constipation, diarrhea, nausea, vomiting
x
Tiredness, fever
x
Swelling and redness at the site of the medication injection
x
Infection, especially when white blood cell count is low
x
Bruising, bleeding
x
Loss of appetite
OCCASIONAL, SOME MAY BE SERIOUS
In 100 people receiving azacitidine, from 4 to 20 may have:
x
Heart failure which may cause shortness of breath, swelling of ankles, and
tiredness
x
Fluid around heart
x
Abnormal heartbeat
x
Swelling and redness of the eye
x
Pain
x
Bleeding from multiple sites including the nose
x
Internal bleeding which may cause black tarry stool, blood in vomit, or
coughing up blood
x
Heartburn
x
Difficulty swallowing or sleeping
x
Sores in the mouth
x
Chills
x
Swelling of arms, legs
x
Weight loss
x
Muscle weakness
x
Dizziness, headache
x
Worry, confusion, depression
x
Shortness of breath, cough, postnasal drip
x
Hair loss, itching, rash
x
Increased sweating
x
Sores on the skin
x
Low blood pressure which may cause feeling faint
x
Pale skin


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RARE, AND SERIOUS
In 100 people receiving azacitidine, 3 or fewer may have:
x
Allergic reaction which may cause rash, low blood pressure, wheezing, shortness
of breath, swelling of the face or throat
x
Kidney damage which may cause swelling, may require dialysis
Reproductive risks: Men: You should not father a baby while in this study. The drugs used
in this study could be very damaging to an unborn baby. Check with the study doctor
about what types of pregnancy prevention to use while in this study.
STUDY GROUP B: -
In addition to side effects outlined above for azacitidine, people who are in Group B may
also experience the possible side effects of nivolumab listed below. Some side effects of
either drug might also be more frequent because of the drug combination.
Possible Side Effects of BMS-936558 (Nivolumab)
Special Precautions
Side effects of BMS-936558 (nivolumab) may happen any time during treatment or even
after your treatment has ended. Some of these problems may happen more often when
BMS-936558 is used in combination with ipilimumab. Call or see your healthcare provider
right away if you develop any problems listed below or the symptoms get worse.
COMMON, SOME MAY BE SERIOUS
In 100 people receiving BMS-936558 (nivolumab), more than 20 and up to 100 may have:
x
Tiredness


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OCCASIONAL, SOME MAY BE SERIOUS
In 100 people receiving BMS-936558 (nivolumab), from 4 to 20 may have:
x
Anemia which may require blood transfusion
x
Swelling and redness of the eye
x
Pain
x
Diarrhea, nausea
x
Dry mouth
x
Fever
x
Swelling and redness at the site of the medication injection
x
Bruising, bleeding
x
Pain or swelling of the joints
x
Loss of appetite
x
Reaction during or following drug infusion which may cause fever, chills, rash
BMS-936558 may cause your immune system to attack normal organs and cause side
effects in many parts of the body. These problems may include but are not limited to:
x
Lung problems (pneumonitis and pleural effusion). Symptoms may include: new
or worsening cough, chest pain, shortness of breath.
x
Intestinal problems (colitis) that can rarely lead to tears or holes in your
intestine.  Signs and symptoms of colitis may include: diarrhea or increase in bowel
movements, blood in your stools or dark, tarry, sticky stools, severe belly pain or
tenderness.
x
Skin: itching; rash, blisters including inside the mouth; loss of skin pigment
x
Liver problems (hepatitis) which can cause liver failure. Signs and symptoms of
hepatitis may include: yellowing of your skin or the whites of your eyes, severe
nausea or vomiting; drowsiness; pain in the right upper belly.
x
Hormone gland problems (especially the thyroid, pituitary and adrenal glands, and
pancreas). Signs and symptoms may include: headaches that will not go away or
unusual headaches, extreme tiredness or changes in mood or behavior decreased
sex drive; weight loss or weight gain; excessive thirst or urine; dizziness or fainting.


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RARE, AND SERIOUS
In 100 people receiving BMS-936558 (nivolumab), 3 or fewer may have:
x
Dry eyes
x
Sores in the mouth which may cause difficulty swallowing
BMS-936558 may cause your immune system to attack normal organs and cause side
effects in many parts of the body. These problems may include but are not limited to:
x
Visual disturbances which may cause double vision, blurred vision, or loss of
vision with a chance of blindness
x
A condition with high blood sugar which leads to tiredness, frequent
urination, excessive thirst, headache, nausea and vomiting, and can result in
coma
x
Kidney problems, including nephritis and kidney failure requiring dialysis.
Signs of kidney problems may include: decrease in the amount of urine,
blood in your urine, ankle swelling.
x
Heart problems including swelling and heart failure. Symptoms and signs of
heart problem may include: Shortness of breath, swelling of the ankle and
body.
x
Problem of the muscle, including swelling, which can cause muscle pain and
severe muscle weakness sometimes with dark urine
x
Swelling of the brain (meningitis/encephalitis), which may cause: headache,
stiff neck, confusion, sleepiness, seizures or injury to the brain which may
cause headache, seizure, blindness (also known as Reversible Posterior
Leukoencephalopathy Syndrome
x
Allergic reaction which may cause rash, low blood pressure, wheezing,
shortness of breath, swelling of the face or throat
x
Problem of the nerves that can cause paralysis. Signs and symptoms may
include: numbness, tingling of hands and feet; weakness of the arms, legs and
facial muscle movement.
x
Complications associated with stem cell transplant using donor stem cells
(allogeneic stem cell transplant). These complications are caused by attack of
donor cells on the host organs (inducing liver, skin and gut damage), and can
lead to death.  If you are considering an allogeneic stem transplant after
participating in this study, please tell your doctor that you have received
BMS-936558 therapy, since the risk and severity of transplant-associated
complications may be increased.
Additional Reproductive Risks for Group B: Men receiving nivolumab and who are
sexually active with WOCBP must continue contraception for a period of 31 weeks after
the last dose of nivolumab.


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STUDY GROUP C:
In addition to side effects outlined above for azacitidine, people who are in Group C may
also experience the possible side effects of midostaurin listed below. Some side effects of
either drug might also be more frequent because of the drug combination.
Possible Side Effects of Midostaurin
COMMON, SOME MAY BE SERIOUS
In 100 people receiving midostaurin, more than 20 and up to 100 may have:
x Diarrhea, nausea, vomiting
Additional Reproductive Risks for Group C: Sexually-active men must use a condom
while receiving midostaurin and for five (5) months after the last dose. Vasectomized men
must also use a condom to avoid delivering drug in the seminal fluid.
Let your study doctor know of any questions you have about possible side effects. You can
ask the study doctor questions about side effects at any time.
What possible benefits can I expect from taking part in this study?
It is not possible to know at this time if the study drugs are better than the usual approach so this
study may or may not help you. This study will help researchers learn things that will help
people in the future.
Can I stop taking part in this study?
Yes. You can decide to stop at any time. If you decide to stop for any reason, it is important to let
the study doctor know as soon as possible so you can stop safely. If you stop, you can decide
whether or not to let the study doctor continue to provide your medical information to the
organization running the study.
OCCASIONAL, SOME MAY BE SERIOUS (updated 11/16/21)
In 100 people receiving midostaurin, from 4 to 20 may have:
x Anemia, which may require blood transfusion
x Infection, especially when white blood cell count is low
x Pain
x Constipation
x Swelling of arms, legs
x Tiredness, fever
x Bruising, bleeding
x Headache
x Shortness of breath
x Itching


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The study doctor will tell you about new information or changes in the study that may affect
your health or your willingness to continue in the study.
The study doctor may take you out of the study:
x
If your health changes and the study is no longer in your best interest
x
If new information becomes available
x
If you do not follow the study rules
x
If the study is stopped by the sponsor, IRB or FDA.
What are my rights in this study?
Taking part in this study is your choice. No matter what decision you make, and even if
your decision changes, there will be no penalty to you. You will not lose medical care or any
legal rights.
For questions about your rights while in this study, call the
(insert name of center) Institutional Review Board at
(insert telephone
number). (Note to Local Investigator: Contact information for patient representatives or other
individuals at a local institution who are not on the IRB or research team but take calls
regarding clinical trial questions can also be listed here.)
What are the costs of taking part in this study?
Nivolumab and midostaurin will be supplied at no charge while you take part in the study. The
costs of getting nivolumab and midostaurin ready and giving them to you is not paid by the study
sponsor so you or your insurance company may have to pay for this. It is possible that the drugs
may not continue to be supplied while you are on the study. Although this is not likely, if it
occurs, your study doctor will talk to you about your options.
Azacitidine is commercially available and will not be supplied. You and/or your health
plan/insurance company will need to pay for all of the other costs of treating your cancer while
in this study, including the cost of tests, procedures, or medicines to manage any side effects,
unless you are told that certain tests are supplied at no charge. Before you decide to be in the
study, you should check with your health plan or insurance company to find out exactly what
they will pay for.
You will not be paid for taking part in this study.
What happens if I am injured or hurt because I took part in this study?
If you are injured or hurt as a result of taking part in this study and need medical treatment,
please tell your study doctor. The study sponsors will not offer to pay for medical treatment for
injury. Your insurance company may not be willing to pay for study-related injury. If you have
no insurance, you would be responsible for any costs.


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If you feel this injury was a result of medical error, you keep all your legal rights to receive
payment for this even though you are in a study.
Who will see my medical information?
Your privacy is very important to us and the researchers will make every effort to protect it.
Your information may be given out if required by law. For example, certain states require
doctors to report to health boards if they find a disease like tuberculosis. However, the
researchers will do their best to make sure that any information that is released will not identify
you. Some of your health information, and/or information about your specimen, from this study
will be kept in a central database for research. Your name or contact information will not be put
in the database.
There are organizations that may inspect your records. These organizations are required to make
sure your information is kept private, unless required by law to provide information. Some of
these organizations are:
x
The study sponsor, SWOG, and any drug company supporting the study
x
The Institutional Review Board, IRB, is a group of people who review the research with
the goal of protecting the people who take part in the study.
x
The Food and Drug Administration and the National Cancer Institute in the U.S., and
similar ones if other countries are involved in the study.
Where can I get more information?
You may visit the NCI Web site at http://cancer.gov/ for more information about studies or
general information about cancer. You may also call the NCI Cancer Information Service
to get the same information at: 1-800-4-CANCER (1-800-422-6237).
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as
required by U.S. Law. This Web site will not include information that can identify you. At
most, the Web site will include a summary of the results. You can search this Web site at
any time.
Who can answer my questions about this study?
You can talk to the study doctor about any questions or concerns you have about this study or to
report side effects or injuries. Contact the study doctor
(insert name of
study doctor[s]) at
(insert telephone number).
My Signature Agreeing to Take Part in the Main Study
I have read this consent form or had it read to me. I have discussed it with the study doctor and
my questions have been answered. I will be given a signed copy of this form. I agree to take part
in the main study.
Participant’s signature
Date of signature