Clinical trial NCT01812252
Conditions: Chronic Myelomonocytic Leukemia de Novo Myelodysplastic Syndrome Myelodysplastic Syndrome Secondary Myelodysplastic Syndrome
Keywords: myelodysplastic syndrome chronic myelomonocytic leukemia bone marrow transplant hypomethylating agent induction chemotherapy
Sponsor: Fred Hutchinson Cancer Center
Start date: 2013-08-19; Completion date: 2022-10-26
Enrollment: 50 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This randomized clinical trial studies different chemotherapies in treating patients with myelodysplastic syndrome before donor stem cell transplant. Giving chemotherapy before a donor stem cell transplant helps stop the growth of cancer cells in the bone marrow, including normal blood-forming cells (stem cells) and cancer cells, and may prevent the myelodysplastic syndrome from coming back after the transplant. When the healthy stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets.

Detailed description:
OUTLINE: Patients are randomized to 1 of 2 treatment arms.

Arm A: Patients receive decitabine or azacitidine intravenously (IV) or subcutaneously (SC) for 7 days. Treatment repeats every 28 days for 4 cycles of decitabine or 6 cycles of azacitidine in the absence of disease progression or unacceptable toxicity.

Arm B: Patients receive induction-like chemotherapy per standard of care or per experimental protocol. This study does not require a specific chemotherapy regimen for Arm B.

After completion of study treatment, patients are followed up for 18 months.

Arms: arm 1: Patients receive decitabine or azacitidine IV or SC per standard of care. Treatment repeats per standard of care, every 28 days for 4 cycles of decitabine or 6 cycles of azacitidine in the absence of disease progression or unacceptable toxicity. arm 2: Patients receive physician choice of standard of care or other experimental protocol using induction-like chemotherapy regimen. No one specific regimen is required. Several regimens are listed in the protocol for example only.
Interventions: intervention 1: Azacitidine (AZC) intervention 2: Decitabine intervention 3: Quality-of-Life Assessment
Intervention descriptions: intervention 1: Given IV or SC intervention 2: Given IV or SC intervention 3: Ancillary studies

Protocol documents:
Prot_SAP_000.pdf: 
 
 
Official Title: 
Initial cytoreductive therapy for myelodysplastic syndrome 
prior to allogeneic hematopoietic cell transplantation (the 
ICT-HCT Study). 
NCT Number: 
NCT01812252 
Document Type:  
Study Protocol and Statistical Analysis Plan 
Date of the 
Document: 
February 23, 2023 
 
 


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FRED HUTCHINSON CANCER RESEARCH CENTER
UNIVERSITY OF WASHINGTON SCHOOL OF MEDICINE
SEATTLE CHILDREN’S
Previous version:
01/18/2019
Current version:
05/28/2019
Title of Protocol:
Initial cytoreductive therapy for myelodysplastic syndrome prior to allogeneic hematopoietic
cell transplantation (the ICT-HCT Study).
Investigators List:
Investigator
Professional Title
Phone
Number
Bart Scott, MD, MS
Associate Member, FHCRC,
Associate Professor of Medicine, UW
(206) 667-
1990
Aaron Gerds, MD, MS
Assistant Professor Cleveland Clinic, OH
(216) 444-
6833
Joachim Deeg, MD
Member, FHCRC, Professor of Medicine, UW
(206) 667-
5985
Elihu Estey, MD
Member, FHCRC, Professor of Medicine, UW
(206) 288-
7176
Biostatistician:
Ted Gooley, PhD
Member, FHCRC
(206) 667-
6533
Research Staff:
Lisa Grimm
Study Coordinator, FHCRC
(206) 667-
2353
Emergency number (24 hours):
•
Seattle Cancer Care Alliance: (206) 598-6190
IRO REC'D 1/30/2023
FHCRC IRB Approval
FEB 23 2023
Document Released Date


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TABLE OF CONTENTS
1.0
INTRODUCTION
2.0
BACKGROUND
2.1
Study Disease
2.2
Clinical Data to Date
2.3
Study Agent
2.4
Risks/Benefits
3.0
STUDY OBJECTIVES
3.1
Primary Objectives
3.2
Secondary Objectives
4.0
STUDY DESIGN
4.1
Description of Study
4.2
Endpoints
5.0
SUBJECT SELECTION
5.1
Inclusion Criteria
5.2
Exclusion Criteria
6.0
SUBJECT REGISTRATION
7.0
TREATMENT PLAN
7.1
Agent Administration
7.2
Concomitant Medication and Supportive Care Guidelines
7.3
Duration of Therapy
7.4
Screening Assessments
7.5
Duration of Follow Up
7.6
Dosing Delays/Dose Modifications
7.7
Criteria for Removal/Withdrawal from Study
8.0
GUIDELINES FOR ADVERSE EVENT REPORTING
9.0
DATA AND SAFETY MONITORING PLAN
10.0
STUDY AGENT INFORMATION
11.0
ASSESSMENT OF EFFICACY
11.1
Efficacy Parameters
11.2
Method and Timing
11.3
Quality of Life Assessment
12.0
DATA MANAGEMENT/CONFIDENTIALITY
13.0
STATISTICAL CONSIDERATIONS
14.0
TERMINATION OF THE STUDY
REFERENCES
APPENDICES


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1.0 INTRODUCTION
While allogeneic hematopoietic cell transplantation (HCT) is currently the only curative treatment
modality for myelodysplastic syndrome (MDS), relapse remains a major cause of failure. Pre-HCT
cytoreductive therapy has been utilized with regularity to reduce post-HCT relapse. – at our institution
among 141 MDS patients transplanted over the past three years 130 (92%) received prior
chemotherapy (unpublished data) – however, the optimum modality, and the impact on post-HCT
outcome remain to be determined. Since MDS is primarily a disease of older age, often complicated
by comorbidities, a major concern with induction chemotherapy (IC) as used for acute myeloid
leukemia is treatment-related toxicity and mortality. Treatment-related toxicities are likely to affect
patients’ candidacy for and capacity to tolerate the subsequent HCT. Recently, many patients have
received pre-HCT cytoreduction with hypomethylating agents (azacitidine and decitabine), rendered
attractive by ease of administration and a low toxicity profile. Although there is a growing body of
retrospective literature, no randomized prospective trials comparing IC with hypomethylation have
been performed.
We are conducting a prospective trial randomizing patients with intermediate and high-risk MDS who
are HCT candidates to receive pre-HCT therapy with IC versus hypomethylation. The primary aim is to
prospectively assess the impact of IC versus hypomethylation as initial therapy on survival in the study
population. We will also assess transplant frequency, relapse, and quality of life. Results from this
study will provide controlled, prospective data on the impact of pre-HCT IC versus hypomethylating
therapy on transplantability and transplant outcome, thereby guiding clinical practice.
2.0BACKGROUND
2.1 Study Disease
MDS represents a group of clonal myeloid stem cell disorders with a heterogeneous spectrum of
presentation, ranging from an indolent course over several years to rapid progression to acute myeloid
leukemia (AML). MDS typically occurs without a preceding insult (de novo MDS) but can also occur
after chemotherapy or radiotherapy resulting in secondary MDS. The natural history of patients with
MDS is varied with a median survival ranging from 5.7 years for patients with low-risk IPSS
(International Prognostic Scoring System) scores, to 0.4 years for those with high-risk scores [1].
Although some conventional therapies have been shown to prolong survival, the only treatment
modality for MDS with demonstrated curative potential is allogeneic hematopoietic cell transplantation.
With a median age at the time diagnosis of 65 years, the care of patients with MDS is often
complicated by medical comorbidities, and treatment considerations revolve around a balance of the
benefit and tolerability of a given modality. Historically, transplantation had been reserved for the
young and fit with related donors as the intensive conditioning led to high rates of transplant-related
mortality. As a result of improved conditioning regimens, prevention of liver toxicity with ursodiol, and
improved microbial surveillance, prevention, and treatment with reduced complications from
cytomegalovirus and fungal infections HCT outcomes have improved over time [2]. Furthermore, the
development of reduced intensity conditioning (RIC) regimens has extended transplantation to
patients with increasing age and comorbidities. Currently, over 60% of patients undergoing HCT for
MDS are conditioned with a reduced intensity regimen.
Despite the curative potential of HCT, relapse remains the primary cause of failure after
transplantation [3-5]. The risk of relapse not only correlates with intrinsic disease properties such as
cytogenetics, but also with the total disease burden. Although there is less non-transplant-related
mortality with RIC regimens, there is an increase in relapse as compared to conventional high-dose
regimens [4,5]. This result is thought to be due to the fact that little disease reduction occurs with
reduced conditioning, placing more responsibility on the graft-versus-leukemia effect to clear the
disease. This conclusion is supported by the fact that patients with a higher disease burden prior to


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HCT, regardless of conditioning regimen, experience increased rates of relapse as compared to those
in remission [4,5].
2.2 Clinical Data to Date
The strategy of using chemotherapy prior to transplantation in an attempt to reduce disease burden,
therefore reducing the risk of relapse after HCT, has become commonplace. Nevertheless, in the
absence of randomized prospective trials the role of pre-HCT cytoreduction remains undefined. Prior
to 2004, the mainstay of cytoreduction was intensive chemotherapy regimens developed as induction
therapy for AML though retrospective studies of these regimens before HCT have not pointed to a
clear benefit [6-8]. Furthermore, intensive pre-HCT therapy may lead to lead to a worsening in
performance status impacting patients’ candidacy for and capacity to tolerate the subsequent HCT [9].
More recently, hypomethlyating agents (azacitidine and decitabine) have increasingly been used for
pre-HCT cytoreduction rendered attractive by their ease of administration and a low toxicity profile in
an attempt to better balance cytoreduction and treatment-related toxicity. In the absence of
prospective data, several groups have published the results of retrospective analyses noting the
feasibility of this approach [10-12]. We recently reported our experience in 68 patients who underwent
HCT for MDS who received either induction chemotherapy or azacitidine prior to HCT [13]. The 1-year
overall survival after transplant was 57% in the azacitidine group, and 36% in the group given
induction chemotherapy. Although the risk of post-HCT relapse and non-relapse mortality was lower in
the azacitidine group, none of the differences including overall survival were statistically significant
suggesting that at a minimum azacitidine did not confer worse outcomes when compared to induction
chemotherapy.
2.3 Study Agent
This study does not prescribe a specific study agent, but rather a treatment strategy with a particular
class of agents as the backbone of each treatment strategy. Therefore, a description of the study
agent, its make-up, chemical properties and any relevant physical properties is not applicable. If
patients are subsequently enrolled on an additional study for treatment after randomization on the
present study, please refer to the protocols of the other studies for information regarding the specific
agents of those studies. If patients are not enrolled on other studies, the agents administered as part
of the treatment plan will be at the discretion of the attending physician.
2.4 Risks/Benefits
There is a potential risk of increased toxicity and death with intensive chemotherapy over that of
hypomethylating agent-based therapy. However, this risk will be mitigated by selecting patients who
are deemed to have an adequate level of fitness to receive intensive chemotherapy. In the
prospective AZA 001 study [14], patients selected for and who received intensive chemotherapy had
comparable rates of early treatment-related mortality and grade 3/4 toxicity compared to those who
received azacitidine. Based on the available data, it is reasonable to conclude that cytoreduction prior
to transplant can improve the rates of post-HCT relapse, thereby improving the overall outcome for
patients with MDS. The knowledge gained from the present study will help identify the optimal pre-
HCT cytoreductive strategy.
3.0STUDY OBJECTIVES
3.1 Primary Objectives
The primary objective is to determine the effect of IC (intensive AML-like therapy), versus less
intensive hypomethylating agents (HMA) as initial therapy, on failure-free survival. We will test the
hypothesis that HMA will lead to failure-free survival that is at least as good as that with IC.


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3.2 Secondary Objectives
Determine if IC (intensive AML-like therapy) in comparison to HMA as initial therapy, will affect
transplantation frequency, and quality of life. Conduct exploratory analysis of post-HCT outcomes
(overall survival, and relapse).
4.0STUDY DESIGN
4.1 Description of Study
This study is a multi-center, open-label randomized study of intensive chemotherapy versus
hypomethylating agent-based therapy as the initial pre-transplant cytoreductive therapy in patients
with myelodysplastic syndrome.
Patients will be randomized to receive treatment with either hypomethylating agent therapy or
intensive chemotherapy; they will not receive both.
4.2 Endpoints
4.2.1 Primary Endpoint
18-month failure-free survival (failure defined as death or relapse)
4.2.2 Secondary Endpoints
1.
Frequency at which the patients undergo transplantation
2.
Impact on quality of life
3.
Post-transplant outcomes:
a.
Overall Survival
b.
Relapse
5.0SUBJECT SELECTION
5.1 Inclusion Criteria
5.1.1 Disease Criteria
1.
Diagnosis of de novo or secondary MDS, including chronic myelomonocytic leukemia, as
defined by the 2008 World Health Organization Classification System.
2.
Patients must have measurable disease requiring cytoreduction, defined as a bone marrow
myeloblast count ≥5% and < 20% on morphologic examination or by flow cytometry in cases
in which adequate morphologic examination is not possible.
5.1.2 Age Criteria
1.
Age ≥18 years
5.1.3 Organ Function, Performance Status and Other
General Criteria
1.
Patients must be considered to have an acceptable risk of early mortality with intensive
chemotherapy as determined by the attending physician at the time of the initial visit. Since


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the specific therapy within each arm will be determined after randomization, there is no
threshold of organ dysfunction or performance status for inclusion.
2.
Considered a potential transplant candidate. The attending/treating physician will determine
transplant candidacy at the time of consent.
3.
Capable of understanding the investigational nature, potential risks and benefits of the study,
and able to provide valid informed consent.
5.2 Exclusion Criteria
1.
A diagnosis of acute promyelocytic leukemia as defined by the 2008 World Health
Organization Classification System.
2.
Previous treatment for MDS or AML with intensive chemotherapy regimen (induction
chemotherapy) or hypomethylating agent.
3.
Have any other severe concurrent disease or have a history of serious organ dysfunction or
disease involving the heart, kidney, liver, or other organ system that may place the patient at
undue risk to undergo treatment.
4.
Patients with a systemic fungal, bacterial, viral, or other infection not controlled (defined as
exhibiting ongoing signs/symptoms related to the infection and without improvement, despite
appropriate antibiotics or other treatment).
5.
Females who are pregnant or breastfeeding.
6.
Fertile men and women unwilling to use contraceptive techniques during and for 12 months
following treatment.
7.
Any uncontrolled or significant concurrent disease, illness, or psychiatric disorder that would
compromise patient safety or compliance, interfere with consent, study participation, follow up,
or interpretation of study results.
8.
Clinical evidence suggestive of central nervous system (CNS) involvement with MDS unless a
lumbar puncture confirms the absence of leukemic blasts in the cerebrospinal fluid (CSF).
6.0 SUBJECT REGISTRATION
Complete and submit the FHCRC Research Subject Registration Form (see Appendix A) with the
signed informed consent to the FHCRC Research Coordinator, Fax (206) 667-2284.
After the eligible subjects have been registered, subjects will be randomized by the FHCRC Data
Management Office (DMO), Monday through Friday between 8:30 and 4pm PST/PDT. FHCRC
Research Coordinator will fax the randomization assignment back to the Study Coordinator at the
outside site.
7.0TREATMENT PLAN
Treatment Schema
This schema is a pictorial overview only; please see narrative sections of the protocol for specifics and
allowable deviations from time frames shown.


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Pre-treatment Determination of Eligibility and Randomization
Treatment Schema


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5.37.1 Agent Administration
For patients enrolled on subsequent treatment protocols, the treatment regimen, including treatment
agents, doses and method, timing and setting of administration (inpatient or outpatient) will be
determined by the specific treatment protocol.
For patients who are not enrolled on other treatment protocols, the treatment regimen, including
treatment agents, doses and method, timing and setting of administration (inpatient or outpatient) will
be determined by the attending physician.
Although not mandatory, a suggested treatment for patients in Arm A is azacitidine intravenous or
subcutaneous at 75 mg/m2/day for 7 days repeated every 28 (+/- 3) days [14]. For patients in Arm B,
the suggested treatment is the "7+3" regimen, which combine a seven-day continuous intravenous
infusion of cytarabine (100 or 200 mg/m2 per day) with a short infusion or bolus of an anthracycline
(idarubacin 10-12 mg/m2 or daunorubicin 40-90 mg/m2) given on days one through three [15,16]. (See
Appendix B)
7.2 Concomitant Medication and Supportive Care Guidelines
Supportive care measures (e.g. antibiotic prophylaxis and treatment, transfusion support) should be
carried out according to institutional practice guidelines or the preference of the attending physician.
7.3 Screening
Bone marrow biopsy or aspirate for morphology must be collected within 60 days prior to Day 1 of
treatment.
Within 30 days before Day 1 of treatment, perform these assessments
•
Complete medical history and physical examination,
•
CBC with differential
•
Serum Chemistry
•
Pregnancy test for women of childbearing potential
•
EORTC-QLQ-C30 questionnaire
7.4 Duration of Therapy (Treatment Phase)
Duration of study therapy will depend on response and donor availability. Please see Appendix C for
definitions of response criteria. For patients enrolled on concurrent treatment protocols, assessment of
response as dictated by the treatment protocol will take precedence over the following treatment
response evaluation and treatment duration guidelines.
The specific treatment agents and schedule will vary per patient within both study arms (please see
section 7.1 for details). These agents and schedules will be determined by treatment protocols,
institutional standards, or physician preference. Follow-up prior to each cycle of therapy will also be
determined by treatment protocols, institutional standards, or physician preference.
Patients randomized to either arm must receive at least one cycle of therapy. If at any point after the
administration of the first cycle of therapy a donor is available, the patient may proceed to HCT.
Patients may receive additional cycles of treatment to maintain response while waiting for donor
availability. However, continued therapy should not be used to delay available HCT. If patients
demonstrate disease progression at any point after the first cycle, they should discontinue the study
treatment.
For patients who are receiving decitibine-based therapy under Arm A, it is recommended that a bone
marrow biopsy or aspirate be obtained after 2 to 4 cycles to assess response. For patients who are
receiving azacitidine-based therapy under Arm A, it is recommended that a bone marrow biopsy or


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aspirate be obtained after 4 to 6 cycles to assess response. If at that point stable disease or better is
achieved and a donor is available, the patient may proceed to HCT. If the desired degree of response
or cytoreduction has not been met by 4 cycles of decitibine-based therapy, or 6 cycles of azacitidene-
based therapy patients should be offered alternative treatments.
For patients randomized to Arm B, response to therapy will be determined by bone marrow biopsy or
aspirate 28 (+/- 3) days after the start of therapy or at the time of count recovery. If a desired response
is achieved, the patient may proceed to HCT. If a less-than desired response is achieved with the first
cycle of intensive chemotherapy, it is recommended that the patient receive an additional cycle of
intensive therapy (re-induction). If after re-induction a partial remission or better is achieved, the
patient may proceed to HCT. However, if the patient has stable disease or disease progression, the
patient should be offered alternative treatment or proceed directly to transplant if possible. .
If at any point a patient no longer desires to undergo HCT, or is no longer considered an HCT
candidate, the patient will be withdrawn from the study. However, the patient may go on to receive the
assigned treatment off study protocol.
The number and timing of clinic visits or scheduled inpatient admissions will be determined by either
the primary treatment protocol or at the discretion of the attending physician.
Treatment phase evaluations are outlined in the study calendar (Appendix D). After initial treatment
and before transplant, complete the EORTC-QLQ-C30 and EORTC-QLQ-HDC29 questionnaires.
7.5Duration of Follow-Up
Study follow-up and evaluations are outlined in the study calendar (Appendix D). The total length of
follow-up will be 18 months from the start of treatment (day 1).
Assessments required within 30 days prior to HCT will be completed as per institutional protocols and
should include a physical exam, medical history, pregnancy test (women of childbearing potential),
CBC, serum chemistry, and bone marrow biopsy or aspirate for morphology.
At Day 100 post-HCT (+/- 14 days), EORTC-QLQ-C30 and EORTC-QLQ-HDC29 quality-of-life
measures will be collected.
7.6Dosing Delays/Dose Modifications
For patients who are enrolled on subsequent treatment protocols, the strategy for managing situations
that require dosing delays or modifications, e.g. if the subject’s marrow has not recovered to
acceptable levels for the next cycle of therapy will be determined by the subsequent treatment
protocol.
For patients who are not enrolled on other treatment protocols, the management of situations that
require dosing delays or modifications should be carried out according to institutional practice
guidelines or the preference of the attending physician.
7.7Criteria for Removal/Withdrawal
A patient must be discontinued from protocol-prescribed therapy under the following circumstances:
•
Consent withdrawal at the patient’s own request or at the request of their legally authorized
representative;
•
Any event that, in the judgment of the Investigator, poses an unacceptable safety risk to the
patient;
•
If, in the investigator’s opinion, continuation in the study would be detrimental to the patient’s
well-being;


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•
Significant deviation from inclusion/exclusion criteria, in the opinion of the investigator;
•
A positive pregnancy test at any time during the study;
•
An intercurrent illness that, in the judgment of the investigator, would affect assessments of
the clinical status to a significant degree and requires discontinuation of therapy, or
•
Completion of the study
Once the attending physician has met and discussed the decision with the patient and/or family
member, the Notice of Withdrawal from a Research Study form (see Appendix E) should be filled out.
Complete this form only when the patient has withdrawn consent.
•
It is the responsibility of the PI or his/her designee to complete the Notice of Withdrawal From
a Research Study Form and fax it to the FHCRC Research Coordinator at (206) 667-2284.
Study treatment is defined as “any activity involving a patient or donor described in a protocol that is
not part of their routine medical care”. Patients who withdraw from study treatment will be asked
permission to continue to collect and record survival data up to the protocol-described end of the
subject follow-up period.
Patients who are withdrawn from the protocol will not be replaced as this is intent to treat analysis.
8.0 Adverse Event Reporting
Adverse events will not be reported as all AEs and SAEs that occur are considered to be related to
treatment and would be considered “expected” side effects from standard of care treatment for either
study arm. If patients are enrolled on an additional treatment protocol where they will receive an
investigational drug, please refer to that protocol for a list of expected adverse events and event-
capture procedures.
Patients who are not enrolled on this protocol who are not enrolled on an additional protocol, will
receive standard therapies with FDA-approved medications. Please refer to the package insert of
those medications for a listing of specific expected adverse events.
Death will be reported at the annual continuing review if it occurs within the participant’s 18-month
study participation period.
After the completion of treatment, patients will be tracked for progression and survival during the
patient’s 18-month study participation.
Outside sites will be required to report all deaths to the coordinating center that occur during subjects’
18-month participation period. Outside sites will communicate deaths to the coordinating center by
email or fax. The coordinating center will maintain a death log for all protocol participants.
9.0 DATA AND SAFETY MONITORING PLAN
The principal investigator (PI) of the study will have primary responsibility for ensuring that the protocol
is conducted as approved by the FHCRC Scientific Review Committee and Institutional Review Board.
The PI will ensure that the monitoring plan is followed and that all data required for oversight of
monitoring are accurately reported to the FHCRC/UW Cancer Consortium Data and Safety Monitoring
Committee (DSMC).,. Once per month, the PI will personally review with the Research Nurse the
clinical status of all the enrolled patients.
Under the provisions of the DSMP, the Cancer Consortium Clinical Research Support (CRS) team
provides monitoring for quality process and compliance by qualified monitors unaffiliated with the


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conduct of the study. Monitoring visits occur at specified intervals determined by the FHCRC DSMC
assessed risk level of the study and the findings of the previous visit.
An annual review of the progress of the study with respect to the monitoring plan will be performed by
the DSMC. The DSMC reviews accrual, serious adverse events, stopping rules and adherence to the
protocol-specific data and safety-monitoring plan.
10.0 STUDY AGENT INFORMATION
Patients enrolled in this study may receive different treatments under each of the study arms. If
enrolled on a treatment protocol, please refer to that protocol for information regarding information
regarding obtaining, handling and accounting for the study agent and whether the study agent is
provided by the study.
If the patient is not enrolled on a treatment protocol, the agent will be obtained and handled through
the pharmacy where the patient is receiving care. The study agent will not be provided by the study.
11.0 ASSESSMENT OF EFFICACY
11.1 Efficacy Parameters
The primary outcome is 18-month failure-free survival (failure defined as death or relapse).
Relapse will be as defined by the International Working Group (IWG) response criteria in
myelodysplasia (Cheson, et. al., Blood 2006;108:419.). Please see Appendix B for a table defining the
response criteria for this study. Response criteria are determined by a morphologic count of the
myeloblast population on aspirate smear. If an aspirate cannot be obtained, myeloblast percentage
should be determined by morphologic and/or immunohistochemical staining of the bone marrow
biopsy or alternatively determined by flow cytometry of a decalcified bone marrow biopsy sample.
11.2 Method and Timing of disease burden assessment
The results of a bone marrow biopsy/ aspirate obtained for clinical purposes within 60 days of the start
of treatment will be used to establish a baseline prior to the start of treatment. For patients enrolled on
concurrent treatment protocols, timing of response assessment will be as outlined by the protocol and
will take precedence over the following treatment response assessment guidelines.
If at any point a patient is suspected to have disease progression, a bone marrow biopsy or aspirate
may be obtained for clinical purposes to document this progression. For patients who are receiving
decitibine-based therapy under Arm A, it is recommended that a bone marrow biopsy or aspirate be
obtained after 2 to 4 cycles to evaluate response. For patients who are receiving azacitidine-based
therapy under Arm A, it is recommended that a bone marrow biopsy or aspirate be obtained after 4 to
6 cycles to evaluate response.
For patients randomized to Arm B, response to therapy will be determined by bone marrow biopsy or
aspirate 28 (+/- 3) days after the start of therapy or at the time of count recovery.
A bone marrow biopsy/ aspirate will be obtained prior to HCT as per institutional protocol (standard
practice).


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11.3 Quality of Life Assessment
Quality of life will be assessed using the EORTC QLQ-C30 questionnaire and the QLQ-HDC29
module (Appendix G) at the following timepoints:
•
EORTC QLQ-C30 questionnaire at the time of screening
•
EORTC QLQ-C30 & QLQ-HDC29 at the completion of initial therapy prior to transplant
•
EORTC QLQ-C30 & QLQ-HDC29 at 100 (± 14) days after stem cell infusion (Day +100)
The QLQ-C30 is a validated and widely used questionnaire to assess quality of life in cancer patients.
The QLQ-HDC29 is treatment-specific quality of life questionnaire to QLQ-C30), that addresses
treatment-specific side effects as well as emotional, social, and family issues for patients treated with
high-dose regimens and HCT. The QLQ-HDC29 module is targeted to cover time during the treatment
and up to 6 months post-treatment.
The QLQ-C30 is composed of both multi-item scales and single-item measures. These include five
functional scales, three symptom scales, a global health status / quality-of-life scale, and six single
items. Each of the multi-item scales includes a different set of items - no item occurs in more than one
scale.
All of the scales and single-item measures range in score from 0 to 100. A high scale score represents
a higher response level.
When the Quality of Life questionnaires are scored, the principle for scoring these scales is the same
in all cases:
1.
Estimate the average of the items that contribute to the scale; this is the raw score.
2.
Use a linear transformation to standardize the raw score, so that scores range from 0 to 100; a
higher score represents a higher ("better") level of functioning, or a higher ("worse") level of
symptoms.
The QLQ-HDC29 module includes 29 items, consisting of 6 multi-item scales and 8 single-items. The
scoring algorithms are similar to the scoring for the EORTC QLQ-C30. For the multi-item scales and
single-item scales (except item 52) a high score is equivalent to worse or more symptoms/problems.
For Spiritual item 52, a higher score indicates positive experience or less problems.
12.0 DATA MANAGEMENT/CONFIDENTIALITY
Study data will be stored in a locked cabinet in a building with restricted key-card access. A password
protected data recording tool (e.g., excel spreadsheet) will be used to record disease progression,
relapse and death for all patients (See Appendix I). Each subject is assigned a unique patient number
to assure subject confidentiality. Subjects will not be referred to by this number, by name, or by any
other individual identifier in any publication or external presentation.
The licensed medical records department, affiliated with the institution where the subject receives
medical care, maintains all original inpatient and outpatient chart documents.
At FHCRC, local subject clinical records and transplant-related documents are scanned and stored in
a secure, electronic document management platform (OWL). OWL records are maintained by the
FHCRC data abstraction staff. Access is restricted to personnel authorized by the Division of Clinical
Research.


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13.0 STATISTICAL CONSIDERATIONS
Eligible patients will be randomized in a 1:1 fashion. The primary outcome will be analyzed on an
intention-to-treat basis. It is not possible to enroll enough patients to this trial to show a statistically
significant difference in overall survival between groups unless the assumed-true difference is
unrealistically large. Instead, we have set a benchmark for “success” to be that the observed 18-month
failure-free survival with hypomethylating agent-based treatment be at least as high as that in the
intensive chemotherapy group. With 30 patients per arm, if the assumed-true survival probabilities are
50% and 30%, respectively, then the probability of observing an 18-month failure-free survival in the
HMA group that is at least as high as that in the IC group is approximately 0.96. If the assumed-true
probabilities are 45% and 30%, the probability of observing a success is approximately 0.91. On the
other hand, if the 18-month failure-free survival in the HMA group and IC group is 50% and 60%,
respectively, then the probability of observing a rate in the HMA group that is at least as high as that in
the IC group is approximately 0.26.
The quality-of-life questionnaires will be scored. In addition to reporting the absolute scores, a
distribution-based interpretation will be conducted using the standardized response mean to analyze
changes in scores over time and differences between groups.
Projected Target Accrual
ETHNIC AND GENDER DISTRIBUTION CHART
TARGETED / PLANNED ENROLLMENT: Number of Subjects
Ethnic Category
Sex / Gender
Females
Males
Total
Hispanic or Latino
1
1
2
Not Hispanic or Latino
24
34
58
Ethnic Category Total of All Subjects*
25
35
60
Racial Categories
American Indian / Alaska Native
0
0
0
Asian
0
1
1
Native Hawaiian or Other Pacific Islander
0
0
0
Black or African American
1
1
2
White
24
33
57
Racial Categories: Total of All Subjects*
25
35
60
*The “Ethnic Category Total of All Subjects” must be equal to the “Racial Categories Total of All
Subjects.”
14.0
TERMINATION OF THE STUDY
The principal investigator may terminate the study at any time. The IRB and FDA also have the
authority to terminate the study should it be deemed necessary.


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REFERENCES
1.
Greenberg P, Cox C, LeBeau MM, et al. International scoring system for evaluating prognosis
in myelodysplastic syndromes [erratum appears in Blood 1998 Feb 1;91(3):1100]. Blood.
1997;89(6):2079-2088.
2.
Gooley TA, Chien JW, Pergam SA, et al. Reduced mortality after allogeneic hematopoietic-cell
transplantation. New England Journal of Medicine. 2010;363(22):2091-2101.
3.
Deeg HJ, Storer B, Slattery JT, et al. Conditioning with targeted busulfan and
cyclophosphamide for hemopoietic stem cell transplantation from related and unrelated
donors in patients with myelodysplastic syndrome. Blood. 2002;100(4):1201-1207.
4.
Lim Z, Brand R, Martino R, et al. Allogeneic hematopoietic stem-cell transplantation for
patients 50 years or older with myelodysplastic syndromes or secondary acute myeloid
leukemia. J Clin Oncol. Jan 20 2010;28(3):405-411.
5.
Warlick ED, Cioc A, DeFor T, Dolan M, Weisdorf D. Allogeneic stem cell transplantation for
adults with myelodysplastic syndromes: importance of pretransplant disease burden. Biology
of Blood and Marrow Transplantation. 2009;15(1):30-38.
6.
Nakai K, Kanda Y, Fukuhara S, et al. Value of chemotherapy before allogeneic hematopoietic
stem cell transplantation from an HLA-identical sibling donor for myelodysplastic syndrome.
Leukemia. Mar 2005;19(3):396-401.
7.
Scott BL, Storer B, Loken M, Storb R, Appelbaum FR, Deeg HJ. Pretransplantation induction
chemotherapy and posttransplantation relapse in patients with advanced myelodysplastic
syndrome. Biology of Blood and Marrow Transplantation. 2005;11:65-73.
8.
Yakoub-Agha I, de La Salmoniere P, Ribaud P, et al. Allogeneic bone marrow transplantation
for therapy-related myelodysplastic syndrome and acute myeloid leukemia: a long-term study
of 70 patients-report of the French society of bone marrow transplantation. J Clin Oncol. Mar
2000;18(5):963-971.
9.
Estey E, de Lima M, Tibes R, et al. Prospective feasibility analysis of reduced-intensity
conditioning (RIC) regimens for hematopoietic stem cell transplantation (HSCT) in elderly
patients with acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS).
Blood. Feb 15 2007;109(4):1395-1400.
10.
De Padua Silva L, de Lima M, Kantarjian H, et al. Feasibility of allo-SCT after hypomethylating
therapy with decitabine for myelodysplastic syndrome. Bone Marrow Transplant. Jun
2009;43(11):839-843.
11.
Field T, Perkins J, Huang Y, et al. 5-Azacitidine for myelodysplasia before allogeneic
hematopoietic cell transplantation. Bone Marrow Transplant. Feb 2010;45(2):255-260.
12.
Lubbert M, Bertz H, Ruter B, et al. Non-intensive treatment with low-dose 5-aza-2'-
deoxycytidine (DAC) prior to allogeneic blood SCT of older MDS/AML patients. Bone Marrow
Transplant. Nov 2009;44(9):585-588.
13.
Gerds AT, Gooley TA, Estey EH, Appelbaum FR, Deeg HJ, Scott BL. Pretransplantation
Therapy with Azacitidine vs Induction Chemotherapy and Posttransplantation Outcome in
Patients with MDS. Biol Blood Marrow Transplant. Aug 2012;18(8):1211-1218.
14.
Fenaux P, Mufti GJ, Hellstrom-Lindberg E, et al. Efficacy of azacitidine compared with that of
conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a
randomised, open-label, phase III study. Lancet Oncology. 2009;10(3):223-232.
15.
Lowenberg B, Ossenkoppele GJ, van Putten W, et al. High-dose daunorubicin in older
patients with acute myeloid leukemia. N Engl J Med. Sep 24 2009;361(13):1235-1248.
16.
Pautas C, Merabet F, Thomas X, et al. Randomized study of intensified anthracycline doses
for induction and recombinant interleukin-2 for maintenance in patients with acute myeloid
leukemia age 50 to 70 years: results of the ALFA-9801 study. J Clin Oncol. Feb 10
2010;28(5):808-814.


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APPENDIX A
Clinical Research Division
Research Subject Registration Form
Protocol Number: 2661
Research Subject Name:___________________________________
Date of Birth: ___ ___/___ ___/ ___ ___ ___ ___
Month
Day
Year
Ethnicity: (Choose one)
Hispanic or Latino (A person of Cuban, Mexican, Puerto Rican, South or Central
American, or other Spanish culture or origin, regardless of race. Term “Spanish Origin” can also
be used in addition to “Hispanic” or “Latino”
Not Hispanic or Latino
Refused to Report
Race: (check all that apply)
American Indian/Alaska Native (A person having origins in any of the original
peoples of North, Central, or South America, and who maintains tribal affiliations or community
attachment)
Asian (A person having origins in any of the original peoples of the Far East, Southeast,
Asia, or the Indian subcontinent including, for example, Cambodia, China, India Japan, Korea,
Malaysia, Pakistan, the Philippine Islands, Thailand and Vietnam)
Native Hawaiian/Pacific Islander (A person having origins in any of the
original peoples of Hawaii, Guam, Samoa or other Pacific Islands)
Black/African American (A person having origins in any of the black racial groups
of Africa.
White (A person having origins in any of the original peoples of Europe, the Middle East
or North Africa)
Unknown
Refused to Report
Gender:
Male
Female
Unknown
HIPAA Authorization: (check one)
Protocol covered under general HIPAA authorization
Protocol specific HIPAA authorization required for this protocol.
(Attach and submit with this form)
Name of person completing form (Please Print)
_______________________________________________________
Name
Phone Number
_____________________________________________________
Date Submitted
Time
ATTACH SIGNED CONSENT AND SEND TO DATA MANAGEMENT WITHIN 10 HOURS OF CONSENTING.


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Clinical Research Division
Research Subject Registration Fax
Coversheet
Date:
_____________________________
TO:
MDS Protocol 2661 Research Coordinator
FAX:
(206) 667-2284
RE:
RESEARCH SUBJECT REGISTRATION FORM
FROM:
___________________________________
FAX:
___________________________________
PHONE:
___________________________________
THE INFORMATION CONTAINED IN THIS TRANSMISSION IS INTENDED ONLY FOR THE ADDRESSEE OR THE ADDRESSEE’S
AUTHORIZED AGENT. THE FAX CONTAINS INFORMATION THAT MAY BE PRIVILEGED, CONFIDENTIAL AND EXEMPT FROM
DISCLOSURE. IF THE READER OF THE MESSAGE IS NOT THE INTENDED RECIPIENT OR RECIPIENT’S AUTHORIZED AGENT
THEN YOU ARE NOTIFIED THAT ANY DISSEMINATION, DISTRIBUTION OR COPYING OF THIS INFORMATION IS PROHIBITED.
IF YOU HAVE RECEIVED THIS INFORMATION IN ERROR, PLEASE NOTIFY THE SENDER BY TELEPHONE, AND RETURN THE
ORIGINAL AND ANY COPIES OF THE MESSAGE BY MAIL TO THE SENDER AT FRED HUTCHINSON CANCER RESEARCH
CENTER, 1100 FAIRVIEW AVE N. LF-210, SEATTLE, WA 98109


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APPENDIX B
Potential Regimens for Each of the Treatment Arms
This list is intended to serve as a guide while determining if a potential regimen is appropriate for
either Arm A or Arm B of this study. This list is not exhaustive as protocols over time may change, and
is again to serve as a guide. The principal investigator makes the final determination if a regimen is
appropriate for either arm prior to treatment.
Potential regimens for Arm A (HMA-based therapy):
•
Azacitidine 75 mg/m2/day IV/SQ Days 1-7 (J Clin Oncol. 2002 May 15;20(10):2429-40.)
•
Azacitidine 75 mg/m2/day IV/SQ Days 1-5 (J Clin Oncol. 2009 Apr 10;27(11):1850-6.)
•
Decitabine 15 mg/m2 q8H IV Days 1-3 (Cancer. 2006 Apr 15;106(8):1794-803.)
•
Decitabine 20 mg/m2/day Days 1-5 (Blood. 2007 Jan 1;109(1):52-7.)
•
Tosedostat 120 mg/day Days 1-21, Decitabine 20 mg/m2/day Days 1-5 (FHCRC 2566)
Potential regimens for Arm B (intensive chemotherapy):
•
Cytarabine 100-300 mg/m2/day CIVI Days 1-7, Daunorubicin 40-90 mg/m2/day IV Days 1-3
(Blood. 1987 May;69(5):1441-9., N Engl J Med. 2009 Sep 24;361(13):1249-59.)
•
Cytarabine 100-300 mg/m2/day CIVI Days 1-7, Idarubicin 10-12 mg/m2/day IV Days 1-3 (J Clin
Oncol. 2013 Jan 20;31(3):321-7.)
•
Fludarabine 30mg/m2/day IV Days 1-5, Cytarabine 2000 mg/m2/day IV Days 1-5, GCSF 400
mcg/m2/day IV Day 0 until ANC recovers (J Clin Oncol. 1994 Apr;12(4):671-8.)
•
Cytarabine 200 m g/m2/day CIVI Days 1-7, Daunorubicin 60 mg/m2/day Days 1-3, Cladribine 5
mg/m2/day Days 1-5 (J Clin Oncol. 2012 Jul 10;30(20):2441-8.)
•
Cytarabine 3 g/m2 q12h Day 1-4, Daunorubicin 60 mg/m2/day IV Days 1-3 (Blood. 1996 Oct
15;88(8):2841-51.).
•
PF-04449913 100-200 mg PO Days 1-18, Cytarabine 100 mg/m2/day CIVI Days 1-7,
Daunorubicin 60 mg/m2/day IV Days 1-3 (Arm C of FHCRC 2592)


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APPENDIX C
Response Criteria
Category
Response criteria (responses must last at least 4 wk)
Complete remission (CR)
Bone marrow: ≤5% myeloblasts with normal maturation of all
cell lines
Partial remission (PR)
All CR criteria if abnormal before treatment except:
- Bone marrow blasts decreased by ≤50% over pretreatment
but still > 5%
- Cellularity and morphology not relevant
Stable disease (SD)
Failure to achieve at least PR, but no evidence of progression
Disease Progression (DP)
For patients with:
- Less than 5% blasts: ≥50% increase in blasts to > 5% blasts
- 5%-10% blasts: ≥50% increase to > 10% blasts
- 10%-20% blasts: ≥50% increase to > 20% blasts
- 20%-30% blasts: ≥50% increase to > 30% blasts
Relapse after CR or PR
At least 1 of the following:
- Return to pretreatment bone marrow blast percentage
- Decrement of ≥50% from maximum remission/response
levels in granulocytes or platelets
- Reduction in Hgb concentration by ≥1.5 g/dL or transfusion
dependence
From: Cheson, BD, et al. Blood. 2006;108:419-425.


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APPENDIX D
Study Calendar
Screening
Phase
Treatment Phase**
Follow-up phase
Screening
Cycle 1
Cycle 2-
n***
After
Prior to HCT
100 Days
Post HCT
(+/- 14 days)
18 months
Post C1 D1
Procedure
within 30
days
Day 1
Day 1
Initial
Treatment∆
within 30 days
Physical Exam
X
X
Medical History
X
X
Pregnancy Test*
X
X
CBC
X
X
Serum Chemistries
X
X
Bone Marrow
Aspiration/ Biopsy
X±
X ∞
X
EORTC-QLQ-30
X
X
X
EORTC-QLQ-
HDC29
X
X
Treatment
X**
X**
Survival
X
Relapse
X
*women of childbearing potential
**per physician determination following
randomization
*** per treatment protocol and/or local institutional
policy
∆after initial treatment and before transplant
± must be collected within 60 days prior to Day 1
of treatment
∞recommended after 6 cycles of the HMA, if the
patient has not had a bone marrow procedure
since screening


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APPENDIX E
Notification of Withdrawal From a Research Study
This form must be completed and routed when a study participant notifies you of his/her
withdrawal from a Fred Hutchinson Cancer Research Center (FHCRC) Clinical Research
Division Protocol.
_______________________________
___________________
______________
Research Subject Name
Hospital No. (U-number)
UPN/Study No.
__2661_________________________
__Bart Scott, MD_____
______________
Protocol Number or Title
Principal Investigator
Current Attending
Person(s)
Responsibility
Initial person who receives
the participant’s notification
of withdrawal (e.g., Team
Nurse, Study Nurse or
Study Coordinator)
❑Complete Notification of Withdrawal From a Research Study form.
❑If appropriate, notify other members of participant’s care team.
❑Fax the completed form to FHCRC (667-2284).
Attending Physician
❑Acknowledge the notice from the participant or responsible adult on
behalf of a pediatric participant to withdraw from a research study if
appropriate.
❑Meet with participant/family member and discuss reasons for withdrawal
and the risks and benefits of withdrawing from the study if appropriate.
❑If a meeting occurs with the participant/family, document discussion with
participant/family in the participant’s medical record.
Primary Provider
❑Review medical orders and discontinue any upcoming research study-
related orders.
I ensure that the above providers and staff have been notified of their responsibilities.
Signature
Printed Name
Date
*****For FHCRC Data Management Use*****
Sent to PI on ______________(date)
Sent to Study Coordinator on ______________(date)
Sent to SCCA HIM (SCCA patients only) on ______________(date)


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APPENDIX F
Adverse Event Reporting Form was deleted in Protocol Amendment dated 17 February 2015


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APPENDIX G
EORTC QLQ-C30 and HDC29


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ENGLISH
During the past week:
Not at
A
Quite
Very
All
Little
a Bit
Much
17. Have you had diarrhea?
1
2
3
4
18. Were you tired?
1
2
3
4
19. Did pain interfere with your daily activities?
1
2
3
4
20. Have you had difficulty in concentrating on things,
like reading a newspaper or watching television?
1
2
3
4
21. Did you feel tense?
1
2
3
4
22. Did you worry?
1
2
3
4
23. Did you feel irritable?
1
2
3
4
24. Did you feel depressed?
1
2
3
4
25. Have you had difficulty remembering things?
1
2
3
4
26. Has your physical condition or medical treatment
interfered with your family life?
1
2
3
4
27. Has your physical condition or medical treatment
interfered with your social activities?
1
2
3
4
28. Has your physical condition or medical treatment
caused you financial difficulties?
1
2
3
4
For the following questions please circle the number between 1 and 7 that
best applies to you
29.
How would you rate your overall health during the past week?
1
2
3
4
5
6
7
Very poor
Excellent
30.
How would you rate your overall quality of life during the past week?
1
2
3
4
5
6
7
Very poor
Excellent
© Copyright 1995 EORTC Quality of Life Group. All rights reserved. Version 3.0


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ENGLISH
EORTC QLQ – HDC29
Patients sometimes report that they have the following symptoms or problems. Please indicate the extent
to which you have experienced these symptoms or problems during the past week. Please answer by
circling the number that best applies to you.
During the past week:
Not
A
Quite
Very
at all
little
a bit
much
31. Have you had soreness in your mouth?
1
2
3
4
32. Have you had a dry mouth?
1
2
3
4
33. Have you had trouble swallowing?
1
2
3
4
34. Did food and drink taste different from usual?
1
2
3
4
35. Have you had abdominal pains or cramps?
1
2
3
4
36. Have you had skin problems (e.g. itchy, dry)?
1
2
3
4
37. Have you been upset by how the treatment has affected your hair?
1
2
3
4
38. Have you worried about your weight being too low?
1
2
3
4
39. Have you had fevers or chills?
1
2
3
4
40. Did you urinate frequently?
1
2
3
4
41. Have you had aches or pain in your bones?
1
2
3
4
42. Have you found it difficult to finish things you started?
1
2
3
4
43. Did you worry about the results of examinations and tests?
1
2
3
4
Please, complete the following questions if you are currently still in hospital for your treatment. If not, please
go to question 48 on next page.
During the past week:
Not
A
Quite
Very
at all
little
a bit
much
44. Have you had trouble coping with the hospital stay?
1
2
3
4
45. Has the isolation in hospital troubled you?
1
2
3
4
46. Have you worried that the blood
(i.e. blood counts) may not recover?
1
2
3
4
47. How satisfied were you with the preparation for your treatment?
1
2
3
4
Please go on to the next page


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ENGLISH
© Copyright 1994 EORTC Quality of Life Group, version 1.0 All rights reserved
During the past four weeks:
Not
A
Quite
Very
at all
little
a bit
much
48. Have you felt isolated from those close to you (family, friends)?
1
2
3
4
49. Have you been concerned about disruption to your
family life because of your treatment?
1
2
3
4
50. How distressing, do you think, your illness or
treatment has been to those close to you?
1
2
3
4
51. Have you felt a need to keep your fears/
concerns from family or friends?
1
2
3
4
52. Has your experience helped you to distinguish between
important and non-important things in life?
1
2
3
4
53. Were you worried about your health in the future?
1
2
3
4
54. Have you felt physically less attractive
as a result of your illness or treatment?
1
2
3
4
Please mark the box, if the next question does not apply to you
55. Have you been concerned about your ability to have children?
1
2
3
4
Please, complete the following questions only if you have completed your hospital treatment and are
currently at home.
During the past four weeks:
Not
A
Quite
Very
at all
little
a bit
much
56. Did having to take your drugs regularly interfere with your daily life?
1
2
3
4
57. Have you been watching yourself closely for any new symptoms?
1
2
3
4
58. Have you felt less interest in sex?
1
2
3
4
59. Have you felt less sexual enjoyment?
1
2
3
4


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APPENDIX H
Data Collection (an excel spreadsheet will be used)
UPN
or
Study
ID
Date
consent
signed
Date
Screened
&
diagnosis
ARM
A or
B
Date
started &
regimen
SCRN
QLQ-30
Done
Y/N
Post
treatment/
pre
transplant
QLQ-30 &
C29
Date of
transplant
Post-
transplan
t QLQ-30
& C29
~ Day 100
(+/- 14
days)
Off
Study
Date
F/U
status


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APPENDIX
I deleted with 28 May 2019 revision