Conditions: Acute Leukemia of Ambiguous Lineage Acute Myeloid Leukemia Myeloid Neoplasm
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 50
Healthy volunteers: no

Brief summary:
This randomized pilot trial studies how well higher or lower dose cladribine, cytarabine, and mitoxantrone work in treating medically less fit patients with newly diagnosed acute myeloid leukemia or myeloid neoplasm. Drugs used in chemotherapy, such as cladribine, cytarabine, and mitoxantrone, 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. It is not yet known whether giving cladribine, cytarabine, and mitoxantrone at higher or lower dose may work better in treating patients with newly diagnosed acute myeloid leukemia.

Detailed description:
PRIMARY OBJECTIVES:

I. To evaluate the feasibility of randomizing medically less fit adults with newly diagnosed acute myeloid leukemia (AML) or analogous myeloid neoplasms to either intensive or non-intensive induction and post remission chemotherapy.

EXPLORATORY OBJECTIVES:

I. To evaluate the attitude of patients and physicians toward randomization and explore reasons for treatment preference.

II. To evaluate whether the ability to assess fitness for intensive chemotherapy can be improved by an augmented treatment-related mortality (TRM) score that includes additional (co-morbidity) factors, and to compare the ability of physicians and the prediction algorithm(s) to assess the likelihood of early death.

III. To compare, within the limits of a pilot study, response, duration of response, and survival between patients receiving intensive and those receiving non-intensive chemotherapy.

IV. To describe the impact of treatment intensity on quality of life of patients undergoing chemotherapy for newly diagnosed AML.

V. To describe the impact of treatment intensity on medical resource utilization and care cost of patients undergoing chemotherapy for newly diagnosed AML.

OUTLINE: Patients agreeable to randomization are randomized to 1 of 2 treatment arms. Patients not agreeable to randomization receive treatment based on their preference.

ARM I (HIGHER-DOSE):

INDUCTION: Patients receive granulocyte colony-stimulating factor (G-CSF) subcutaneously (SC) on days 0-5, higher dose cladribine intravenously (IV) over 2 hours on days 1-5, higher dose cytarabine IV over 2 hours on days 1-5, and higher dose mitoxantrone IV over 60 minutes on days 1-3. Treatment repeats every 6 weeks for up to 4 courses in the absence of disease progression or unacceptable toxicity.

CONSOLIDATION: Patients who achieve complete response (CR)/CR with incomplete count recovery (CRi) with up to 2 courses of Induction receive G-CSF, cladribine, and cytarabine as in Induction. Courses repeat every 6 weeks for up to 4 courses in the absence of disease progression or unacceptable toxicity.

ARM II (LOWER-DOSE):

INDUCTION: Patients receive G-CSF SC on days 0-5, lower dose cladribine IV over 2 hours on days 1-5, lower dose cytarabine IV over 1 hour on days 1-5, and lower dose mitoxantrone IV over 60 minutes on days 1-3. Treatment repeats every 6 weeks for up to 12 courses in the absence of disease progression or unacceptable toxicity.

CONSOLIDATION: Patients who achieve complete response (CR)/CR with incomplete count recovery (CRi) with up to 6 courses of Induction receive G-CSF, cladribine, and cytarabine as in Induction. Courses repeat every 6 weeks for up to 12 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up periodically for 5 years.

Arms:
arm 1: INDUCTION: Patients receive G-CSF SC on days 0-5, higher dose cladribine IV over 2 hours on days 1-5, higher dose cytarabine IV over 2 hours on days 1-5, and higher dose mitoxantrone IV over 60 minutes on days 1-3. Treatment repeats every 6 weeks for up to 4 courses in the absence of disease progression or unacceptable toxicity.

CONSOLIDATION: Patients who achieve CR/CRi with up to 2 courses of Induction receive G-CSF, cladribine, and cytarabine as in Induction. Courses repeat every 6 weeks for up to 4 courses in the absence of disease progression or unacceptable toxicity. arm 2: INDUCTION: Patients receive G-CSF SC on days 0-5, lower dose cladribine IV over 2 hours on days 1-5, lower dose cytarabine IV over 1 hour on days 1-5, and lower dose mitoxantrone IV over 60 minutes on days 1-3. Treatment repeats every 6 weeks for up to 12 courses in the absence of disease progression or unacceptable toxicity.

CONSOLIDATION: Patients who achieve CR/CRi with up to 6 courses of Induction receive G-CSF, cladribine, and cytarabine as in Induction. Courses repeat every 6 weeks for up to 12 courses in the absence of disease progression or unacceptable toxicity.

Interventions: intervention 1: Cladribine intervention 2: Cytarabine intervention 3: Granulocyte Colony-Stimulating Factor intervention 4: Mitoxantrone Hydrochloride intervention 5: Quality-of-Life Assessment intervention 6: Questionnaire Administration
Intervention descriptions: intervention 1: Given IV intervention 2: Given IV intervention 3: Given SC intervention 4: Given IV intervention 5: Ancillary studies intervention 6: Ancillary studies

Protocol document:
Prot_SAP_000.pdf: 
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FRED HUTCHINSON CANCER RESEARCH CENTER 
UNIVERSITY OF WASHINGTON SCHOOL OF MEDICINE 
Current version: 7/20/2021 
Previous version: 3/9/2020 
Impact of Treatment Intensity on Survival, Quality of Life, and Resource 
Utilization in Medically Less Fit Adults with Acute Myeloid Leukemia and 
Analogous Myeloid Neoplasms: A Randomized Pilot Study 
Principal Investigator: 
•
Anna B. Halpern, MD, Assistant Professor, FHCRC; Assistant Professor, UW (206-606-
1978) 
Sub-Investigators at FHCRC/UW: 
•
Roland B. Walter, MD PhD MS, Professor, FHCRC; Professor, UW (206-667-3599)
•
Mary-Beth Percival, MD, MS; Associate Professor, FHCRC; Associate Professor, UW
(206-606-1320) 
•
Paul Hendrie, MD, PhD; Associate Medical Director, SCCA; Clinical Professor, UW
(206-606-1000) 
Biostatistician: 
•
Megan Othus, PhD, Professor, FHCRC (206-667-5749)
Study Coordinator FHCRC: 
•
Anna B. Halpern, MD, Assistant Professor, FHCRC; Assistant Professor, UW (206-606-
1978) 
Emergency Phone (24 hours): Call the paging operator at the University of Washington 
Medical Center at 206-598-6190, and ask for the Fellow on call for Hematology/Oncology. 
IRO REC'D JUL 26 2021
FHCRC IRB Approval  
07/30/2021 
Document Released Date


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OVERVIEW OF TREATMENT PLAN AND DOSING SCHEME 
 
 
 
 


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TABLE OF CONTENTS 
1.0 
BACKGROUND AND RATIONALE ........................................................................................................... 4 
2.0 
OBJECTIVES ................................................................................................................................................ 7 
3.0 
PATIENT ELIGIBILITY ............................................................................................................................... 7 
4.0 
EVALUATION AND COUNSELING OF PATIENT .................................................................................... 8 
5.0 
SUBJECT REGISTRATION ......................................................................................................................... 9 
6.0 
TREATMENT PLAN .................................................................................................................................... 9 
7.0 
INFORMATION ON STUDY DRUGS ....................................................................................................... 14 
8.0 
EVALUATION AND END POINT DEFINITIONS .................................................................................... 19 
9.0 
TOXICITY MONITORING ........................................................................................................................ 20 
10.0 
SUBJECT DISCONTINUATION OF ACTIVE TREATMENT................................................................... 20 
11.0 
ADVERSE EVENTS ................................................................................................................................... 21 
12.0 
DATA AND SAFETY MONITORING PLAN ............................................................................................ 23 
13.0 
DATA MANAGEMENT/CONFIDENTIALITY ......................................................................................... 23 
14.0 
STATISTICAL CONSIDERATIONS .......................................................................................................... 24 
15.0 
INVESTIGATOR OBLIGATIONS ............................................................................................................. 27 
16.0 
ADMINISTRATIVE AND REGULATORY CONSIDERATIONS ............................................................. 27 
17.0 
STOPPING THE STUDY ............................................................................................................................ 28 
18.0 
REFERENCES ............................................................................................................................................ 29 
19.0 
APPENDICESError! Bookmark not defined. 
           APPENDIX A: Treatment-Related Mortality Score 
 
 
 
 
 
          31  
           APPENDIX B: Dose Modification Table 
 
 
 
 
 
                        32 
           APPENDIX C: EORTC QLQ-C30 Questionnaire 
 
 
 
 
 
          33 
           APPENDIX D: Patient Preference for Treatment Assignment Survey  
 
        
 
          35 
           APPENDIX E:  Physician Preference for Treatment Assignment Survey  
 
 
          36 
           APPENDIX F: Fax Cover Sheet for Patient Consent/HIPAA Form       
 
 
 
          38 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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1.0 
BACKGROUND AND RATIONALE 
 
In 2016, an estimated 19,950 individuals will develop AML in the U.S.1 With current 5-year 
relative survival rates of 55-60% for patients <45 years of age but only ∼5% for adults >age 65 
(the median age at diagnosis),2 many patients will ultimately die from either treatment-related 
toxicities or therapeutic resistance.3-5 The need for improved therapeutic approaches is therefore 
unquestioned. This is particularly true for individuals presenting with medical co-morbidities that 
may limit their ability to tolerate intensive treatments; such patients are generally, but not 
invariably, older. Many of these subjects never receive any AML-directed therapy.6,7 Among 
those who do, the optimal treatment strategy is unknown but typically revolves around the choice 
of non-intensive therapy (e.g. azacitidine/decitabine or low-dose cytarabine) or intensive therapy 
(e.g. “7+3”).8 
U.S. and European population-based registry data support the use of intensive chemotherapy 
rather than low-intensity therapy (or no therapy) in most AML patients up to age 80.6,9 Likewise, 
a recent retrospective analysis of 1,079 adults who received chemotherapy at 5 U.S. institutions 
from 2008-2012 suggested that, after adjustment for age, co-morbidity index, and 
cytogenetic/molecular risk, intensive therapy leads to better long-term survival even in older 
patients (age 70-79 years) with significant co-morbidities without increase in early mortality.10 
However, these observations must be interpreted cautiously since information on exact regimens 
is not available and differences in supportive care and selection bias may confound the apparent 
benefit of intensive therapy. This possibility highlights the need for a randomized clinical trial to 
define the optimal treatment intensity for medically less fit AML patients with varying co-
morbidity burden.  
One barrier to improving care for medically less fit adults with AML has been the lack of 
explicit definition of “less fit”. In the AZA-001 trial, which randomized older adults with newly 
diagnosed AML with >30% blasts to either azacitidine or “conventional care regimens” (CCRs), 
i.e. best supportive care (BSC), low-dose cytarabine, or “7+3”, the investigators determined 
which protocol-designated CCR was most appropriate for each patient on the basis of age, 
performance status, and institutional practice before randomization.11 Survival with azacitidine 
was best in those (presumably the most fit) in whom the alternative was “7+3”, and worst in 
those (presumably the least fit) in whom the alternative was BSC. This suggests that physicians 
are adept at distinguishing fit from less fit individuals. However, it seems doubtful that they are 
as adept as a quantitative model. To develop such a model, we recently analyzed data from 3,365 
adults with newly diagnosed AML given intensive chemotherapy in SWOG trials or at M.D. 
Anderson Cancer Center (MDA) and found that the weekly risk of death falls sharply once 4 
weeks elapse from start of intensive induction chemotherapy. This observation suggested that 
patients who die during this time comprise a qualitatively distinct group and allowed an empiric 
definition of treatment-related mortality (TRM) as deaths occurring within these 4 weeks.12 We 
then used areas under the receiver operating characteristic curve (AUC) to quantify the ability of 
individual covariates to predict TRM in 2,238 patients treated at MDA between 1995 and 2008. 
Performance status (PS) and age were the most important single covariates in predicting TRM 
(AUC of 0.75 and 0.65 for models with PS or age alone, respectively). However, a “simplified” 
multicomponent model, which was validated by bootstrapping and comprised the 7 most relevant 
individual covariates (PS, age, platelet count, serum albumin, type of AML [secondary vs. de 
novo], white blood cell count [WBC], peripheral blood blast percentage, and serum creatinine) 


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led to a model with an AUC of 0.82, demonstrating an advantage of multicomponent predictive 
models over the use of single factors to identify the subset of patients at high risk of TRM.12 
Importantly, removal of age from this model had only a minimal effect on the AUC, suggesting 
that age is largely a surrogate for the other covariates contained in the model. 
The TRM score, computationally derived from the “simplified” TRM model, is now in routine 
use at Fred Hutch, where research protocols now primarily assign patients based on predicted 
likelihood of TRM (e.g. NCT01342887, NCT01567059, NCT01607645, NCT01729845, 
NCT01804101, NCT02044796, NCT02121418, NCT02728050). Because the early death rates 
following intensive chemotherapy in adults with AML have declined substantially over the last 2 
decades,13,14 we very recently re-examined the value of the “simplified” TRM model to predict 
early deaths in patients treated at Fred Hutch.15 Among 285 patients with newly diagnosed AML 
treated with intensive induction chemotherapy from 2008-2014, 17 (6.0%) died within 28 days, 
with the AUC of the TRM score being 0.76,15 indicating the continued value of multicomponent 
modeling to predict early deaths after AML therapy. So far, the comparative abilities of a model 
such as the one that underlies the TRM score and “physician intuition” (“I know it when I see 
it”) to predict TRM are uncertain. Moreover, an AUC of 0.75-0.80 approximately intermediate 
between certainty (AUC=1.0) and a coin flip (AUC=0.5). Therefore, although the TRM score 
will be the principal eligibility criterion for the pilot randomized trial, an important part of this 
application will be examining (a) whether incorporation of other covariates (e.g. HCT-CI, ELN 
risk group) will improve the ability to forecast TRM and (b) the concordance between our 
models and simple physician judgment. While we have developed online means to rapidly 
compute TRM scores (https://cstaging.fhcrc-research.org/TRM/Default.aspx), it is perhaps naïve 
to expect widespread use barring a quantitative demonstration of the value of predictive models. 
Recognizing the current limitations in our knowledge regarding treatment approach to adults 
with AML who are medically less fit, the goal of our research, is to conduct a controlled clinical 
trial to improve outcomes in these patients. Because of the possibility of significant selection 
bias in non-randomized assessments, the preferred trial is based on a randomized assignment to 
higher-intensity vs. lower-intensity chemotherapy. However, such a trial may prove impractical. 
Therefore, this pilot study will explicitly test the feasibility of randomization in this situation, 
and explore reasons why patients and/or physicians might be reluctant to randomization in this 
situation. For this purpose, we will use preference surveys to examine patient and physician 
attitudes towards medical decision-making and treatment allocation. In addition to focusing on 
feasibility and estimates of anti-leukemia activity (e.g. response rates) and survival, we will also 
assess complementary dimensions of treatment benefit, in particular quality of life (QOL) as well 
as resource utilization and care cost. 
Contemporary clinical trials often utilize DNA methyltransferase inhibitors (e.g. azacitidine or 
decitabine) or low doses of cytarabine as non-intensive therapy, whereas multi-agent 
chemotherapy, most typically in the classic 7+3 combination between cytarabine and an 
anthracycline as intensive therapy. However, treatment outcomes with standard therapeutics in 
medically less fit individuals with AML are relatively poor. This is exemplified by the AZA-001 
trial, in which median overall survival times of approximately 6-7 months for low-dose 
cytarabine and 10-12 months for azacitine or 7+3 were estimated. This observation highlights the 
need for better therapies. In a recent phase 1/2 trial in medically fit adults with newly diagnosed 
AML, we found that combination therapy with G-CSF, cladribine, high-dose cytarabine, and 
escalated doses of mitoxantrone (G-CLAM) is well tolerated and appears to produce higher rates 


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of CR, CR without MRD, and possibly longer survival than 7+3, after accounting for prognostic 
covariates. Given these data, G-CLAM will be used as intensive therapy in our pilot trial 
(“higher-dose G-CLAM”). As comparator non-intensive therapy, we will use G-CLAM with 
reduced doses of cladribine, cytarabine, and mitoxantrone (“lower-dose G-CLAM”). Rather than 
selecting different classes for the non-intensive and intensive treatment arm in our trial – which 
may have different modes of action and therefore confound the question of treatment intensity – 
we purposefully chose G-CLAM as backbone for both arms. 
Development of G-CLAM as highly active, intensive chemotherapy for newly diagnosed AML 
Since 2012, we have used G-CLAM extensively in adults with newly diagnosed AML and high-
grade MDS, primarily as part of a large, ongoing institutional phase 1/2 trial (FHCRC #2734.00). 
Our interest in this regimen stems from data indicating improved anti-leukemic activity with 
regimens containing cladribine, high-dose cytarabine, and escalated doses of mitoxantrone 
compared to standard 7+3 chemotherapy. Data from this trial, which was presented at the 2016 
annual meeting of the American Society of Hematology, have established the safety of a G-
CLAM regimen with escalated doses of mitoxantrone, which will form the basis for the 
backbone used in this proposal. Specifically, the phase 1 portion on 33 patients established the 
highest dose tested (mitoxantrone at 18 mg/m2/day) as the maximally tolerated dose. A total of 
62 patients, including 6 treated in phase 1, received G-CLAM at MTD. Patient characteristics 
were as follows: median age 58 (21-81) years, median TRM score 2.85 (0.06-6.73), with AML 
(n=52) or high-risk MDS (n=10). Cytogenetics were favorable in 6, intermediate in 44, and 
adverse in 12 (MRC criteria); 11 patients had NPM1 and 6 had FLT3 mutations. Fifty-two 
patients (83.9%, 95% confidence interval: 72.3-92.0%) achieved a CR (n=48 [77.4%: 65.0-
87.1%]), or CRp/i (n=4 [6.5%: 1.8-15.7%]) with 1-2 cycles of therapy. Only 3 patients required 
2 cycles to best response. Among the 48 CR patients, 43 (89.6%) were negative for measurable 
residual disease (MRDneg) by flow cytometry. Four patients had morphologic leukemia free state, 
1 patient with myeloid sarcoma had a partial remission, 4 had resistant disease, and 1 died from 
indeterminate cause. One patient died within 28 days of treatment initiation (septic shock). 
Median times to an absolute neutrophil count ≥500/μL and a platelet count of ≥50,000/μL were 
26 and 23 days. Besides infections and neutropenic fever, maculopapular rash, and hypoxia 
(fluid overload/infection-related) were the most common grade ≥3 adverse events. In addition to 
the phase 1/2 MTD cohort, there were 15 patients treated in an expansion cohort and 3 eligible 
patients treated off protocol with mitoxantrone at 18 mg/m2. For these 80 patients combined 
treated at MTD, the CR and CR/CRp/i rates were 76.3% and 81.2%. After multivariable 
adjustment, compared to 300 patients treated with 7+3 on the SWOG S0106 trial, G-CLAM with 
mitoxantrone 18mg/ m2 was associated with an increased probability of CR (odds ratio [OR]= 
3.08, p=.02), CR/CRp/i (OR=2.96, p=.03), a trend towards improved MRDneg CR (OR= 3.70, 
p=.06), and a trend towards improved overall survival ([OS]; hazard ratio=0.34, p=.07). For the 
entire study cohort, the 6 and 12-month relapse-free survival were 73% (64-83%) and 62% (42-
74%) and the 6 and 12-month OS were 89% (82- 96%) and 77% (67-88%). Together, our study 
found G-CLAM with mitoxantrone up to 18 mg/m2/day to be well tolerated and to have potent 
anti-leukemia activity.  
 
In this pilot study, patients meeting the in/exclusion criteria and primary oncologists are asked 
whether or not they would agree to participate in the randomized treatment assignment. Patients 
agreeable to randomization will be assigned in a 1:1 ratio to the higher-intensity arm and given 
G-CLAM or the lower-intensity arm that is built on G-CLAM but utilizes lower doses of 


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cladribine, cytarabine, and mitoxantrone. For the other patients, the reasons to decline 
randomization will be recorded, and patients will be allowed to receive the treatment intensity of 
their choosing. We will then follow these patient for a variety of disease specific outcomes—
remission rates, overall survival—as well as examine patient and physician attitudes towards 
medical decision-making and treatment allocation, assess QOL, and examine resource utilization 
and care cost. 
 
 
2.0 
OBJECTIVES 
 
2.1  
Primary Objective 
2.1.1 To evaluate the feasibility of randomizing medically less fit adults with newly 
diagnosed AML or analogous myeloid neoplasms to either intensive or non-
intensive induction and post remission chemotherapy.  
 
2.2  
Exploratory Objectives 
2.2.1    To evaluate the attitude of patients and physicians toward randomization and 
explore reasons for treatment preference. 
2.2.2 To evaluate whether the ability to assess fitness for intensive chemotherapy can 
be improved by an augmented treatment-related mortality (TRM) score that 
includes additional (co-morbidity) factors, and to compare the ability of 
physicians and the prediction algorithm(s) to assess the likelihood of early death. 
2.2.3 To compare, within the limits of a pilot study, response, duration of response, and 
survival between patients receiving intensive and those receiving non-intensive 
chemotherapy. 
2.2.4 To describe the impact of treatment intensity on quality of life of patients 
undergoing chemotherapy for newly diagnosed AML. 
2.2.5  To describe the impact of treatment intensity on medical resource utilization and 
care cost of patients undergoing chemotherapy for newly diagnosed AML. 
 
 
3.0 
PATIENT ELIGIBILITY 
 
3.1  
Inclusion Criteria 
3.1.1 Age ≥18 years 
3.1.2 Diagnosis of untreated “high-grade” myeloid neoplasm (≥10% myeloid blasts by 
morphology in bone marrow and/or peripheral blood) or AML other than acute 
promyelocytic leukemia (APL) with t(15;17)(q22;q12) or variants according to 
the 2016 WHO classification.16 Patients with acute leukemias of ambiguous 
lineage are eligible. Outside diagnostic material is acceptable as long as peripheral 
blood and/or bone marrow slides are reviewed at the study institution and 
cytogenetic/molecular information is available. 


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3.1.3 Treatment-related mortality (TRM) score ≥13.1 as calculated with simplified 
model (see APPENDIX A). 12 
3.1.4 The use of hydroxyurea before enrollment is permitted; hydroxyurea should be 
discontinued prior to start of study treatment. Patients with symptoms/signs of 
leukostasis, WBC >100,000/μL, or acute symptoms felt related to their high-grade 
myeloid neoplasm can be treated with leukapheresis or may receive up to 1 dose of 
cytarabine (up to 500 mg/m2) anytime prior to study day 1. 
3.1.5  Patients may have received treatment (e.g. azacitidine/decitabine, lenalidomide, 
growth factors) for antecedent low-grade myeloid neoplasm. 
 
 
3.1.6 Left ventricular ejection fraction (LVEF) ≥45%, assessed within 3 months prior to 
registration, e.g. by MUGA scan or echocardiography, or other appropriate 
diagnostic modality.  
 
 
3.1.7 Women of childbearing potential and men must agree to use adequate 
contraception beginning at the signing of the consent until at least 4 weeks after 
the last dose of study drug.   
3.1.8    Ability to understand and the willingness to sign a written informed consent 
document 
3.2  
Exclusion Criteria   
3.2.1 Myeloid blast crisis of chronic myeloid leukemia (CML), unless patient is not 
considered candidate for tyrosine kinase inhibitor treatment. 
3.2.2 Concomitant illness associated with a likely survival of <1 year. 
3.2.3 Active systemic fungal, bacterial, viral, or other infection, unless disease is under 
treatment with anti-microbials and/or controlled or stable. Patients with fever 
thought to be likely secondary to leukemia are eligible.  Known hypersensitivity 
to any study drug. 
3.2.4 Known hypersensitivity to any study drug used in this trial. 
 
3.2.5     Pregnancy or lactation. 
   3.2.6     Concurrent treatment with any other anti-leukemia agent. 
 
 
4.0 
EVALUATION AND COUNSELING OF PATIENT 
 
The patient will be completely evaluated with a history, physical examination, diagnostic testing 
if necessary, and review of outside slides and records if available. The protocol will be discussed 
thoroughly with the patient and family (if present), with description of all known risks to the 
patient. Alternative forms of treatment will be presented as objectively as possible, and the risks 
and hazards of the study explained to the patient. Consent will be obtained using forms approved 
by the local Institutional Review Board (IRB). 
 
 
 


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5.0 
SUBJECT REGISTRATION 
 
To register, the attending physician involved in the care of the potential study participant must 
contact the Study Coordinator, and a copy of the signed consent form, a signed HIPAA 
authorization must be available and faxed to the study team (Fax Cover Sheet in APPENDIX E; 
FAX: +1-206-667-6519). To complete the registration process, the PI, Fred Hutch/UW Study 
Coordinator or designee will assign a patient study number, register the patient on the study, and 
enter the patient into the Clinical Trials Management System (CTMS), OnCore. A complete, 
signed, study consent and HIPAA consent are required for registration.  
 
 
6.0 
TREATMENT PLAN 
 
This study is a single-center, open-label randomized pilot study of lower-dose vs higher-dose G-
CLAM for medically less fit adults with newly diagnosed AML or analogous myeloid neoplasms 
at the Fred Hutchinson Cancer Research Center/University of Washington/Seattle Cancer Care 
Alliance.  
 
Study Overview 
In this pilot study, patients meeting the inclusion/exclusion criteria and their primary oncologists 
are asked whether or not they would agree to participate in the randomized treatment assignment 
(APPENDIX D). Patients agreeable to randomization will be assigned in a 1:1 ratio to the 
higher-dose G-CLAM arm or the lower-dose G-CLAM arm that utilizes lower doses of 
cladribine, cytarabine, and mitoxantrone. For those who wish to not be randomized, the reasons 
to decline randomization will be recorded, and patients will be allowed to receive the treatment 
intensity of their choosing. Patients will receive higher-dose or lower-dose G-CLAM as follows: 
 
 
After study enrollment, patients will receive a first cycle of G-CLAM on one of the designated 
treatment arms. Post-induction bone marrows will be reassessed upon blood count recovery or 
between day Days +28 to +35 after start of chemotherapy, whichever occurs first. If a response 
other than a measurable (“minimal”) residual disease-negative (MRDneg) CR is achieved, the 
patient will receive re-induction with G-CLAM at the same dosing. Patients who achieve a 
morphologic CR or CR with incomplete count recovery (CRi) with up to 2 courses of higher-
dose G-CLAM or up to 6 courses of lower-dose G-CLAM can receive consolidation therapy 
with G-CLA (i.e. mitoxantrone omitted; up to 4 cycles with high-dose G-CLA and up to 12 
cycles of low-dose G-CLA). 


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6.1  
Baseline/Pre-Treatment Assessment 
 
 
The following procedures should be obtained at baseline before initiation of study 
therapy to establish trial eligibility and allow patient characterization and disease 
prognostication. Results of tests and/or procedures conducted as per standard of care may be 
used to determine study eligibility if conducted within an appropriate window prior to screening. 
Outside testing and previously collected clinical data may be used if within the appropriate time 
frame. 
6.1.1 History and physical examination (assessed within 14 days prior to study day 0). 
6.1.2 Bone marrow examination (or peripheral blood assessment if ≥10% blasts are 
present) with morphologic and flow cytometric assessment. Routine cytogenetic 
analysis and molecular testing should be obtained. A bone marrow biopsy should 
be obtained if spicules are absent from the aspirate sample (aspirate and biopsy to 
be assessed within 2 months prior to study day 0).  
6.1.2 Complete blood counts with differential blood count and platelet count (assessed 
within 14 days prior to study day 0). 
6.1.3 Metabolic panel, including bilirubin, albumin, and creatinine (assessed within 14 
days prior to study day 0). 
6.1.4 MUGA scan or echocardiography, or other appropriate diagnostic modality, to 
assess left ventricular ejection fraction (LVEF; assessed within 3 months prior to 
study day 0). 
 
6.2 
Pre-Treatment 
 
 
At the discretion of the treating physician for clinical management only, allopurinol 300 
mg PO daily (or equivalent dose adjusted for renal function) may be considered in all patients 
without known allergies to allopurinol to reduce the risk of tumor lysis. Higher doses of 
allopurinol are permitted if patients develop tumor lysis syndrome. Patients may receive 
rasburicase, a recombinant uric acid oxidase, for the prevention and/or treatment of tumor lysis 
syndrome at the discretion of the treating physician if clinically indicated. All patients should be 
adequately hydrated and receive anti-emetics as necessary. 
 
6.3 
Administration of G-CSF, Cladribine, and Cytarabine Mitoxantrone on the Higher-
Dose Arm: INDUCTION 
 
 
6.3.1 For induction: The doses of the elements of G-CLAM chemotherapy will be as 
follows G-CSF 300 or 480 µcg/ (based on weight <76 kg vs. ≥76kg) daily 
subcutaneously daily on Days 0-5, Cladribine 5 mg/m2 IV daily over 2 hours on 
Days 1-5, Cytarabine 2,000 mg/m2 IV daily over 2 hours on Days 1-5, and 
Mitoxantrone 18 mg/m2 IV daily over 60 minutes on Days 1-3. 
 
 
6.3.2 The doses of all medications are calculated using the patient’s actual weight. 
 
 
6.3.3 Days 0 and 1 G-CSF may be omitted at physician discretion for WBC 
>20,000/µL, signs/symptoms of leukostasis, or acute symptoms felt related to 
their high-grade myeloid neoplasm. 
 
 
6.3.4 All treatment is given as intent-to-treat; missed doses will not be made up. 


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6.3.5 No investigational or commercial agents or therapies other than those described 
herein may be administered with the intent to treat the patient's malignancy.  
6.3.6 If the patient has significant organ-specific dysfunction at baseline (e.g. 
abnormal liver or kidney function), dose reduction can be considered as 
described in section 6.8 at the physician discretion in conjunction with the 
oncology pharmacist.  
 
Outline Treatment Schedule: Higher Dose G-CLAM 
Day 
Treatment 
0 
G-CSF 300/480 µcg  
1 
G-CSF, Cladribine 5 mg/m2, Cytarabine 2,000 mg/m2, 
Mitoxantrone 18 mg/m2 
2 
G-CSF, Cladribine 5 mg/m2, Cytarabine 2,000 mg/m2, 
Mitoxantrone 18 mg/m2 
3 
G-CSF, Cladribine 5 mg/m2, Cytarabine 2,000 mg/m2, 
Mitoxantrone 18 mg/m2 
4 
G-CSF, Cladribine 5 mg/m2, Cytarabine 2,000 mg/m2 
5 
G-CSF, Cladribine 5 mg/m2, Cytarabine 2,000 mg/m2 
28-35 OR blood 
count recovery 
Bone marrow assessment 
 
6.4 
Administration of G-CSF, Cladribine, and Cytarabine Mitoxantrone on the Lower-
Dose Arm: INDUCTION 
 
 
6.4.1 For induction: The doses of the elements of G-CLAM chemotherapy will be as 
follows G-CSF 300 or 480 µcg/ (based on weight <76 kg vs. ≥76kg) daily 
subcutaneously daily on Days 0-5, Cladribine 2 mg/m2 IV daily over 2 hours on 
Days 1-5, Cytarabine 100 mg/m2 IV daily over 1 hour on Days 1-5, and 
Mitoxantrone 6 mg/m2 IV daily over 60 minutes on Days 1-3. 
 
 
6.4.2 The doses of all medications are calculated using the patient’s actual weight. 
 
 
6.4.3 Days 0 and 1 G-CSF may be omitted at physician discretion for WBC 
>20,000/µL, signs/symptoms of leukostasis or acute symptoms felt related to their 
high-grade myeloid neoplasm. 
 
 
6.4.4 All treatment is given as intent-to-treat; missed doses will not be made up. 
6.4.5 No investigational or commercial agents or therapies other than those described 
herein may be administered with the intent to treat the patient's malignancy.  
 
Outline Treatment Schedule: Low-Dose G-CLAM 
Day 
Treatment 
0 
G-CSF 300/480 µcg  
1 
G-CSF, Cladribine 2 mg/m2, Cytarabine 100 mg/m2, 
Mitoxantrone 6 mg/m2 
2 
G-CSF, Cladribine 2 mg/m2, Cytarabine 100 mg/m2, 
Mitoxantrone 6 mg/m2 
3 
G-CSF, Cladribine 2 mg/m2, Cytarabine 100 mg/m2, 
Mitoxantrone 6 mg/m2 


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4 
G-CSF, Cladribine 2 mg/m2, Cytarabine 100 mg/m2 
5 
G-CSF, Cladribine 2 mg/m2, Cytarabine 100 mg/m2 
28-35 OR blood 
count recovery 
Bone marrow assessment 
 
6.5  
Assessment for Response after First Induction Course 
 
 
A bone marrow aspirate should be obtained upon blood count recovery (i.e. ANC 
>1,000/µL and platelet count >100,000/µL) or between Days +28 to +35 after start of G-CLAM 
chemotherapy, whichever occurs first; a bone marrow biopsy need only be obtained during this 
procedure if spicules are absent from the aspirate sample.  
6.5.1 Patients achieving an MRDneg CR: Patients are eligible to receive consolidation 
therapy with G-CLA (dosing as per section 6.6): up to 4 cycles on the high-dose 
arm and up to 12 cycles on the low-dose arm 
6.5.2 Patients achieving a MRDpos CR or CRi: Patients are eligible for a second cycle 
of induction therapy using the same dosing guidelines as cycle 1 or may proceed 
to consolidation therapy with G-CLA as per 6.6, per discretion of treating 
attending.  
6.5.3 Patients with persistent disease: Patients with persistent disease (≥5% blasts) are 
eligible for a second course of induction chemotherapy at the same dosing used in 
cycle 1 provided all non-hematologic toxicities have resolved to Grade <2. If they 
are not in CR or CRi after the 2nd induction course, they will be removed from the 
study. 
6.5.4 Patients with persistent aplasia without evidence of disease after Day +49: 
patients will be removed from protocol. 
 
6.6 
Consolidation Therapy 
 
 
After achievement of a CR/CRi (irrespective of MRD) with 1-2 courses of G-CLAM 
therapy, patients are eligible for post-remission therapy with G-CLA. 
 
 
6.6.1 The treatment is identical to the induction course but without mitoxantrone (i.e. 
G-CSF, cladribine, and cytarabine, or “G-CLA” at same dose level as induction). 
If a patient had excessive toxicities (grade >3 non-hematologic toxicity excluding 
neutropenic fever and infections) during induction, a dose reduction can be 
considered as described in sections 6.8 and 6.9, as well as APPENDIX B. 
 
 
6.6.2 Post-remission courses should start within 6 weeks of achieving CR/CRi once 
patients have recovered to ≤Grade 2 toxicities from the previous course of 
therapy. 
 
 
6.6.3 Patients on the higher-dose arm can receive up to 4 courses of consolidation 
therapy.  
 
 
6.6.4    Patients on the lower-dose arm can receive up to 12 cycles of consolidation 
therapy. 
 
 
 
6.6.5 Patients can proceed to transplantation barring contraindications and if a suitable 
donor is available. 
 


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6.7  
Monitoring during/after Induction and Consolidation Therapy 
For patient monitoring, the following studies and study intervals are suggested and will 
be performed at the physician’s discretion: 
6.7.1 Complete blood counts with differential blood count, including immature 
cells/blasts, and platelet count at least 2 times weekly until ANC >500/µL and 
then at least weekly until platelet count >100,000/µL. 
6.7.2 Metabolic panel, including bilirubin, ALT/AST, and creatinine at least weekly 
until ANC >1,000/µL and platelet count >100,000/µL. 
6.7.3 If patients develop signs or symptoms suggestive of cardiac dysfunction, LVEF 
should be assessed using the same method to evaluate baseline LVEF status 
(MUGA scan or echocardiography, or other appropriate diagnostic modality).   
 
6.8 
Dose Modifications of Chemotherapeutic Drugs for Induction or Subsequent 
Treatment Cycles for Higher-Dose Arm 
 
 
For patients who have organ dysfunction at baseline—defined as a serum creatinine > 2.0 
mg/dL or a bilirubin concentration is ≥3 x IULN-- or those who experienced ≥Grade 3 non-
hematologic toxicities excluding neutropenic fever and infections during the first induction, a 
dose reduction can be considered as follows (see also APPENDIX B]: 
6.8.1 If a patient develops Grade ≥3 non-hematologic toxicity other than Grade 3 
infections within 28 days from the last dose of G-CLAM, the next course of G-
CLAM will be given once toxicity is ≤ grade 2; doses for this course will be 
cladribine 4 mg/m2 days 1-5, cytarabine 1,500mg/m2 days 1-5, mitoxantrone 14 
mg/m2 days 1-3, and G-CSF dose unchanged. Assuming these doses are well-
tolerated the first course of G-CLA will be administered at these doses, omitting 
mitoxantrone. If Grade ≥3 non-hematologic toxicity occurs again, there will be a 
further reduction in doses of cladribine to 3 mg/m2 daily days 1-5 and cytarabine 
to 1,000mg/m2 daily days 1-5 for the first cycle of G-CLA. Doses for subsequent 
courses of G-CLA will be discussed with the Principal Investigator. 
 
6.8.2 Mitoxantrone: If the bilirubin concentration is ≥3 x IULN, consider a dose 
reduction of mitoxantrone by 25-50% in consultation with the Oncology 
Pharmacist 
 
6.8.3 Cladribine: If the serum creatinine exceeds 2.0 mg/dL and/or estimated creatinine 
clearance (calculated by Cockcroft-Gault) decreases to less than 50 mL/min 
during therapy, we will consider dose reduction in discussion with the Oncology 
Pharmacist. 
 
6.8.4 Cytarabine: If the serum creatinine exceeds 2.0 mg/dL and/or estimated creatinine 
clearance (calculated by Cockcroft-Gault) decreases significantly during therapy, 
we will consider dose reduction in discussion with the Oncology Pharmacist. 
 
6.9 
Dose Modifications of Chemotherapeutic Drugs for Subsequent Treatment Cycles 
for Low-Dose Arm 


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Given the doses of the chemotherapy in this arm are already low, there will be no further 
dose reduction for toxicity. Also, doses do not need to be adjusted based on liver or kidney 
function. Decisions whether to proceed with further cycles of chemotherapy if ≥ Grade 3 toxicity 
in cycle 1 will be made by the PI in conjunction with the treating physician.  
 
6.10  Supportive Therapy 
 
 
6.10.1 All patients will be adequately hydrated and receive appropriate anti-emetics 
based upon institutional guidelines. 
 
 
6.10.2 Additional growth factors may be used according to institutional practice 
guidelines or the preference of the attending physician.  
 
 
6.10.3 Antimicrobial prophylaxis should be used according to institutional practice 
guidelines. In case of neutropenic fever, standard diagnostic testing will be 
performed, and empiric antibiotic coverage will be utilized as per usual care and 
standard institutional practices. 
 
 
6.10.4 Transfusional support should be carried out according to institutional practice 
guidelines. 
 
6.11 
Treatment of CNS Disease 
 
 
Treatment of CNS disease is done according to institutional practice guidelines or the 
preference of the attending physician.  
 
6.12 
Recommended Follow-up Care 
 
 
After completion of protocol treatment, patients should be evaluated by treating 
physicians according to institutional and/or national guidelines or the discretion of the attending 
physician. These evaluations may include peripheral blood studies and/or bone marrow 
examinations, as clinically indicated. 
 
 
7.0 
INFORMATION ON STUDY DRUGS 
 
G-CSF, cladribine, cytarabine, and mitoxantrone will be obtained commercially. 
 
7.1  
Drug Information on G-CSF (Granulocyte colony-stimulating factor) 
7.1.1 Mechanism of Action: G-CSF is a growth factor that stimulates the production, 
maturation, and activation of neutrophils. Further, it promotes premature release 
of neutrophils from the bone marrow and enhances their phagocytic capacity.  
7.1.2  Pharmacokinetics: Peak G-CSF concentrations after sub-cutaneous dosing occur 
in 2 to 8 hours, though the onset of action is approximately 24 hours, with plateau 
concentrations in 3-5 days, and elimination over an 11-20 day period. G-CSF is 
cleared by systemic degradation. Notably, as G-CSF binds neutrophils, plasma 
levels are controlled in large part by the absolute neutrophil count.  
7.1.3  Adverse Effects (AEs): Common drug-related AEs (occurring in >10% of 
patients) include fever, petechiae, elevated uric acid, splenomegaly, bone pain, 
and epistaxis. Less common drug-related AEs (occurring in 1% -10% of patients) 


9759 
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include hyper- or hypotension, arrhythmias, headache, nausea, vomiting, 
leukocytosis, and transfusion reaction. Infrequent drug-related AEs (occurring in 
<1% of patients) include acute respiratory distress syndrome, allergic reactions, 
alopecia, alveolar hemorrhage, arthralgia, bone density decrease, capillary leak 
syndrome, cerebral hemorrhage, vasculitis, dyspnea, edema, erythema nodosum, 
hematuria, hemoptysis, hepatomegaly, hypersensitivity, injection site reaction, 
pericarditis, proteinuria, psoriasis exacerbation, pulmonary infiltrates, renal 
insufficiency, sickle cell crisis, splenic rupture, Sweet’s syndrome, tachycardia, 
and thrombophlebitis. 
7.1.4 Recommended dose adjustments for organ dysfunction: There is limited or no 
data examining the toxicity of G-CSF in patients with renal or liver dysfunction. 
Therefore, administration of G-CSF to patients with liver or kidney disease must 
be done with caution. 
 
7.2  
Drug Information on Cladribine (2-chloro-2’-deoxyadenosnie, 2-CdA) 
7.2.1 Mechanism of Action: Cladribine is a prodrug that is converted to an adenosine 
deaminase-resistant triphosphate derivative (2-CdATP). This molecule is then 
activated by deoxycytidine kinase to a 5’-triphosphate derivative (2-CdAMP), 
which is incorporated into DNA where it acts as a transcription regulator. In 
addition to its cytotoxic properties in dividing cells, cladribine induces death in 
quiescent cells of lymphoid origin through an unknown mechanism.  
7.2.2 Pharmacokinetics: Cladribine is renally excreted, with 18-35% as unchanged 
drug. It is able to penetrate the CSF, where it achieves 25% of plasma 
concentrations. It is 20% protein-bound. The half-life for elimination after a 2-
hour infusion is 6.7±2.5 hours in patients with normal renal function.   
7.2.3 Adverse Effects: Common adverse effects (occurring in >10% of patients) include 
fever, fatigue, headache, rash, nausea, anorexia, vomiting, myelosuppression 
(including grade 3/4 neutropenia/thrombocytopenia), injection site reaction, and 
infection. Less common adverse effects (occurring in 1 to 10% of patients) 
include edema, tachycardia, thrombosis, chills, dizziness, insomnia, malaise, 
diarrhea or constipation, weakness, myalgias and arthralgias, cough, dyspnea, 
epistaxis, and diaphoresis. Rare adverse effects (occurring in <1% of patients) 
include aplastic anemia, bacteremia, opportunistic infections, lymphocytopenia, 
altered mental status, hemolytic anemia, hypersensitivity, myelodysplastic 
syndrome, quadriparesis, and renal dysfunction/failure. 
7.2.4 Reconstitution: Cladribine is supplied as a sterile, preservative-free, isotonic 
solution containing 10 mg of cladribine (1 mg/mL) in 10 mL single-use vials. 
Cladribine should be passed through a sterile 0.22μm filter prior to introduction 
into the infusion bag containing 0.9% Sodium Chloride Injection, USP. 
7.2.5 Administration and Compatibility: The use of 5% dextrose is not recommended as 
a diluent because of increased degradation of cladribine. The infusion solution is 
stable for 24 hours at room temperature. 
7.2.6 Storage and Stability: Store refrigerated 2° to 8°C (36° to 46°F). Protect from 
light during storage. 


9759 
Page 16/38 
 
7.2.7 Recommended Dose Adjustments for Organ Dysfunction: Specific guidelines for 
cladribine dosing in patients with hepatic/renal dysfunction or hypoalbuminemia 
are not clearly defined. Because of the potential for compensatory elimination of 
cladribine in patients with hepatic and/or renal dysfunction, specific guidelines for 
dosing are difficult to define. Thus, when deciding whether to adjust cladribine 
doses for renal dysfunction, the risks for potential toxicities (e.g., 
myelosuppression, neurotoxicity) against the benefits and goals of treatment must 
be considered. 
 
7.3 
Drug Information on Cytarabine (Cytosine arabinoside) 
7.3.1  Mechanism of Action: Cytarabine is a synthetic pyrimidine analog, in which the 
sugar moiety (normally a ribose or deoxyribose) has been replaced with 
arabinose. Although its mechanism of action is not completely understood, the 
active form of cytarabine is probably incorporated into the DNA and interferes 
with DNA synthesis. As such, cytarabine has been found to primarily effect 
dividing cells, blocking their progression from G1 to S phase.  
7.3.2 Pharmacokinetics: Cytarabine is metabolized by deoxycytidine kinase and other 
kinases into its most active form (aracytidine triphosphate). Aracytidine 
triphosphate is converted to nontoxic uracil derivatives by pyrimidine nucleoside 
deaminases. This balance between the levels of kinases and deaminases is critical 
for regulating the sensitivity/resistance of cells to the drug. The plasma clearance 
of cytarabine is biphasic, with an initial rapid phase and more prolonged second 
clearance phase. The rapid clearance phase has a relatively short half-life (t1/2α = 
10 minutes), while the half- life of the second clearance phase is slightly longer 
(t1/2β = 1 – 3 hours). The nontoxic metabolites from the drug are excreted in the 
urine, and within 24 hours after the infusion, approximately 80% of these 
nontoxic metabolites can be recovered from the urine.  
7.3.3  Adverse Effects: The dose-limiting toxicity for cytarabine is myelosuppression. 
Adverse Events Associated with Standard Dose Cytarabine: Frequent AEs (not 
definitely quantified) include the following: myelosuppression (leucopenia, 
anemia, neutropenia, thrombocytopenia), pyrexia, rash, anorexia, diarrhea, 
nausea, vomiting, mucositis, anal inflammation or ulceration, hepatic dysfunction 
or increased liver enzymes, and local thrombophlebitis. Less frequent AEs (not 
definitely quantified) include chest pain, pericarditis, dyspnea dizziness, headache, 
neural toxicity, neuritis, alopecia, pruritis, skin freckling, skin ulceration, 
urticaria, abdominal pain, bowel necrosis, esophageal ulceration, esophagitis, 
pancreatitis, sore throat, urinary retention, jaundice/hyperbilirubinemia, local site 
cellulites, renal dysfunction, allergic edema or anaphylaxis, sepsis, and sudden 
respiratory distress syndrome. Infrequent AEs (not definitely quantified) include 
aseptic meningitis, cardiopulmonary arrest, cerebral dysfunction, cytarabine 
syndrome (bone pain, chest pain, conjunctivitis, fever, maculopapular rash, 
malaise, myalgia), exanthematous pustulosis, hyperuricemia, intestinal 
pneumonitis, increased lipase, paralysis with intrathecal and IV combination 
therapy, rhabdomyolysis, veno-occlusive disorder, and death. Adverse Events 
Associated with High Dose Cytarabine include cardiomegaly and 


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cardiomyopathy, coma, severe neurotoxicity, personality change, somnolence, 
total body alopecia, severe rash or skin desquamation, gastrointestinal ulceration, 
peritonitis, intestinal pneumatosis, necrotizing colitis, liver abscess or damage, 
peripheral neuropathy, corneal toxicity, hemorrhagic conjunctivitis, pulmonary 
edema, sudden respiratory distress syndrome, and sepsis.  
7.3.4 Reconstitution: Cytarabine should be reconstituted in sterile water and can be 
further diluted using either 5% dextrose or sodium chloride solutions into 
appropriate concentrations for infusion.  
7.3.5  Administration and Compatibility:  The diluted cytarabine solution should be 
inspected for particulate matter, discoloration, and haze prior to infusion.  If there 
is evidence of particulate matter, discoloration, or haze the solution should not be 
infused. Patients should be medicated with standard anti-emetic therapy. 
Cytarabine is not compatible (1) during Y-site administration with allopurinol, 
amphotericin B, ganciclovir; (2) in syringe with metoclopropamide; or (3) 
admixed with fluorouracil, heparin, insulin (regular), nafcillin, oxacillin, 
penicillin G. Cytarabine may have variable compatibility when admixed with 
gentamycin, hydrocortisone, and methylpredinsone. 
7.3.6 Storage and Stability: Vials of non-reconstituted cytarabine should be stored at 
room temperature 15°C - 30°C (59°F - 86°F). The diluted cytarabine solution may 
be stable for up to 48 hours if stored at room temperature.  
7.3.7 Drug-Drug Interaction: Reversible decreases in the plasma steady-state 
concentration for digoxin and cardiac glycosides may occur. Cytarabine may 
diminish the therapeutic effect of flucytosine. There is ex vivo data suggesting that 
cytarabine may reduce the effectiveness gentamycin for killing K. pneumoniae.  
7.3.8  Warnings and Precautions: Ex vivo and in vivo studies have found that cytarabine 
causes extensive chromosomal damage and potential malignant transformation.  
Although there have been some case reports describing cytarabine use in pregnant 
humans, these cases reports are few. Thus, cytarabine is considered Pregnancy 
Category D. Women should be advised not to become pregnant while receiving 
cytarabine, and men should be advised not to father a child while receiving 
cytarabine and for at least 3 months after completing the therapy. It is not known 
whether cytarabine or its metabolites are excreted in breast milk; thus, it is not 
recommended for lactating females who are breast-feeding. As with any highly 
immunosuppressive medication, cytarabine may diminish the effectiveness of 
dead and live vaccines and enhance the toxic/adverse effect of live vaccines. One 
should avoid use of live vaccines while receiving it. A small percentage of 
patients will have a hypersensitivity reaction to cytarabine, and these individuals 
should not receive the drug again. 
7.3.9  Recommended Dose Adjustments for Organ Dysfunction: Guidelines for 
adjusting cytarabine dose due to renal or liver dysfunction are not standardized, 
but many clinicians will adjust the dose based upon the function of these organs.   
 
7.4 
Drug Information on Mitoxantrone 


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7.4.1 Mechanism of Action: Mitoxantrone (dihydroxyanthracenedione) is an 
anthracenedione derivative that intercalates with DNA, resulting in inhibition of 
nucleic acid synthesis.  
7.4.2 Pharmacokinetics: Mitoxantrone is 78% bound to plasma proteins. A three-
compartment model was described after a single intravenous dose of 
mitoxantrone. The mean alpha half-life is 6 to 12 minutes, the mean beta half-life 
is 1.1 to 3.1 hours, and the mean terminal (gamma) or elimination half-life is 23 to 
215 hours (median 75 hours). Mitoxantrone has extensive distribution into body 
tissues and is metabolized in the liver to two main inactive metabolites 
(monocarboxylic acid derivative and dicarboxylic acid derivative). The major 
route of excretion for mitoxantrone appears to be biliary into the feces; 
approximately 11% of the dose is recovered in the urine within 5 days of drug 
administration, with 65% of this being unchanged drug. 
7.4.3 Adverse Effects: Common adverse effects (occurring in >10% of patients) include 
edema, fever, fatigue, headache, alopecia, nausea/vomiting, diarrhea, 
mucositis/stomatitis, myelosuppression, weakness, dyspnea, cough, and infection. 
Less common adverse effects (occurring in 1 to 10% of patients) include 
congestive heart failure, decreased left ventricular ejection fraction (LVEF), 
hypertension, chills, anxiety, cutaneous mycosis, hypcalcemia, hypokalemia, 
hyponatremia, menorrhagia, jaundice, myalgia, arthralgia, renal failure, 
proteinuria, rhinitis, diaphoresis, and infection.  
 
Mitoxantrone may cause cardiac toxicity with prolonged administration and doses 
exceeding 80 to 100 mg/m2; Appendix B provides an overview of the 
cardiotoxicity index of individual anthracyclines as well as mitoxantrone. When 
used after doxorubicin, cardiotoxicity is more frequent; an analysis by the 
Southwest Oncology Group revealed a risk of 6% at 134 mg/m2 prior doxorubicin 
and 60 mg/m2 mitoxantrone, rising to a 15% risk at 120 mg/m2 mitoxantrone. 
Cardiac events reported included arrhythmias, decreased left ventricular function, 
chronic heart failure, tachycardia, ECG changes, and, infrequently, myocardial 
infarction. Bradycardia has been rarely reported. Patients with prior treatment 
with anthracyclines, prior mediastinal radiotherapy, or with preexisting 
cardiovascular disease may have more frequent occurrences of cardiac toxicity. 
7.4.4 Reconstitution: Mitoxantrone must be diluted prior to use. The dose of 
mitoxantrone should be to at least 50 mL with either 0.9% Sodium Chloride 
Injection (USP) or 5% Dextrose Injection (USP). Mitoxantrone may be further 
diluted into Dextrose 5% in Water, Normal Saline or Dextrose 5% with Normal 
Saline and used immediately.  
7.4.5 Administration and Compatibility: Care in the administration of mitoxantrone will 
reduce the chance of extravasation. Mitoxantrone should be administered into the 
tubing of a freely running intravenous infusion of 0.9% Sodium Chloride 
Injection, USP or 5% Dextrose Injection, USP.  Care should be taken to avoid 
extravasation at the infusion site and to avoid contact of mitoxantrone with the 
skin, mucous membranes, or eyes. If any signs or symptoms of extravasation have 
occurred, including burning, pain, pruritis, erythema, swelling, blue discoloration, 


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or ulceration, the injection or infusion should be immediately terminated and 
restarted in another vein. 
 
Mitoxantrone should not be mixed in the same infusion as heparin since a 
precipitate may form. 
7.4.6 Storage and Stability: Mitoxantrone should be stored between 15°C - 25°C (59°F-77°F) 
 
8.0 
EVALUATION AND END POINT DEFINITIONS 
 
 
8.1 Treatment Response and Outcome 
Treatment response (e.g. morphologic/cytogenetic/molecular CR/CRi) or treatment 
failure (e.g. resistant disease, aplasia, morphological or molecular/cytogenetic relapse) as well as 
treatment outcome (e.g. overall survival, relapse-free survival, event-free survival, and remission 
duration) will be determine by peripheral blood count and bone marrow evaluation as per Section 
6.5 and categorized according to criteria recommended by International Working Groups.17,18 
Patients are routinely assessed for the presence of minimal residual disease (MRD) as detected 
by multi-parameter flow cytometry and cytogenetic assessment, as per institutional practice.  
 
8.2 Monitoring of Exploratory Endpoints 
 
8.2.1 Quality of life (QOL) assessment 
In order to measure QOL, we will use the European Organization for Research and 
Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30), a validated 30-
item instrument that includes 5 functional scales, 3 symptom scales, a global health scale, 
and 6 single items (APPENDIX C). Standardized scores for each scale range from 0 to 
100 (higher scores representing better domain-specific QOL),19 with a minimally 
clinically important difference of 10 points.20 We will request survey completion upon 
study enrollment as well as after each on-study treatment cycle.Given that patients do not 
always fill out questionnaires due to illness, time or other constraints, we will measure 
percentage of returned surveys as one of our feasibility outcomes.  
 
8.2.2 Evaluation of medical complications and use of medical resources 
Information on medical complications (e.g. need for intensive care unit (ICU)-level care, 
length of ICU stay, neutropenic fever, documented infections, bleeding, reasons for 
hospitalization, etc.) and use of medical resources (e.g. red blood cells and platelet 
transfusions; days of IV antimicrobial therapy, total hospital length of stay) will be 
collected from the medical records from the UWMC and SCCA as done previously.21,22 
 
8.2.3 Assessment of cost 
The costs associated with inpatient and outpatient management will be calculated using 
electronic billing information from the UWMC and SCCA. Costs will be converted from 
charges using departmental cost-to-charge ratios. We anticipate reporting descriptive 
information identifying major cost drivers and total/subset costs per phase of treatment 
(i.e. induction, outpatient management, and readmission), similar to our approach used 
previously.21,22 
 


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8.2.4 Examination of patient and physician attitudes towards medical decision-
making and treatment allocation 
8.2.4.1 
We will explore patient-reported factors influencing medical decision-
making though a Patient Preference Survey (APPENDIX D) distributed on study 
enrollment. This survey will include a question on whether they agree to be 
randomized or prefer to choose their treatment arm, and explores the reasons 
underlying this decision. As above, given that patients do not always fill out 
questionnaires, we will measure percentage of returned responses regarding reasons 
for treatment decision-making as one of our feasibility outcomes. Surveys not 
returned will not be considered a protocol deviation.  
8.2.4.1 
We will also explore physician preferences towards treatment-intensity 
randomization through a Physician Preference Survey (APPENDIX E) also 
distributed on study enrollment. This survey includes questions about whether the 
physician was agreeable to randomization (even if the patient was not) and explores 
reasons the physician might have not wanted to randomize the patient. As physicians 
are extremely busy, we will measure percentage of returned responses regarding 
reasons for treatment decision-making as one of our feasibility outcomes. Surveys not 
returned will not be considered a protocol deviation. 
 
8.3 Correlative Studies 
Due to the lack of translational science funding, there are no pre-planned correlative 
studies. However, study participants will be encouraged to provide biospecimens (i.e. peripheral 
blood and/or bone marrow specimens) to the Fred Hutch’s AML sample repository (FHCRC 
#1690.00; PI: Derek Stirewalt, MD). 
 
 
9.0 
TOXICITY MONITORING 
Both acute and chronic toxicities will be recorded and reported to the PI, and will be reviewed 
by the independent DMC at scheduled meetings. Monitoring for acute toxicity takes place during 
and following the administration of the medications. Subjects are observed for the development 
of an immediate localized allergic reaction or anaphylactic reaction during this time.  
 
Toxicity Criteria 
 
 
This study will use the CTCAE (NCI Common Terminology Criteria for Adverse Events) 
Version 5.0 for Toxicity and Adverse Event reporting. A copy of the CTCAE v5.0 can be 
downloaded from the CTEP home page (http://ctep.cancer.gov).  
 
 
10.0 SUBJECT DISCONTINUATION OF ACTIVE TREATMENT 
 
10.1  Criteria for Removal from Treatment 
All reasons for discontinuation of treatment must be documented:   
10.1.1 Completion of protocol treatment. 
10.1.2 Arrival to the transplant service for planned HCT. 


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10.1.3 Initiation of any leukemia-directed therapy other than protocol therapy 
10.1.4 Failure to achieve a CR or CRi after 2 courses of therapy with higher-dose G-
CLAM or 6 courses of therapy with lower-dose G-CLAM.  
10.1.5 Persistent aplasia (ANC <500/µL or platelets <50,000/ µL) without evidence of 
leukemia after Day +49. 
10.1.6 Relapse after achievement of CR/CRi during treatment. 
10.1.7 Adverse toxicities that prevent continuation with study treatment. 
       10.1.8 Withdrawal of consent; the patient may withdraw from the study at any time for 
any reason.  
 
10.2  Duration of Follow-up 
 
 
Patients will be followed after completion of study treatment to determine event free 
survival (EFS) and relapse-free survival ([RFS] (for patients achieving CR), as well as overall 
survival (for all patients) for a maximum of 5 years. Follow-up may include periodic (e.g. every 
3 months) review of medical records, and, if absolutely necessary, direct contact of the study 
participant. 
 
 
11.0 ADVERSE EVENTS 
 
11.1  Expedited Reporting Requirements 
In accordance with Fred Hutch/UW Cancer Consortium IRB policy, all adverse events 
(AEs; whether occurring on-site or off-site), which in the opinion of the principal investigator 
(PI) are (1) unexpected, and (2) related or possibly related to the research, and (3) serious or 
suggests that the research places research participants or others at a greater risk of physical or 
psychological harm than was previously known or recognized, will be submitted to the IRB 
within ten (10) calendar days of learning of the problem. Both the “Expedited Reporting Form 
for Unanticipated Problems or Noncompliance” and the “Adverse Event Reporting Form”, or 
equivalent forms, will be completed for this reporting.  
 
11.2 
Definitions: 
11.2.1 Adverse Event (AE): Any harm or untoward medical occurrence in a research 
participant administered a medical product, medical treatment or procedure even 
if it does not necessarily have a causal relationship with the product, treatment, or 
procedure. An adverse event can be any unfavorable and unintended sign 
(including an abnormal laboratory finding, for example), symptom, or disease 
temporally associated with the use of a medical product, medical treatment, or 
procedure whether or not considered to be related. Mechanisms of obtaining 
information on AE include monthly transcripts, assessment forms obtained after 
each clinic visit, and hospital progress and discharge notes.  
11.2.2 Related or Possibly Related AE: An AE is “related or possibly related to the 
research procedures” if in the opinion of the principal investigator, it was more 
likely than not caused by the research procedures. AEs that are solely caused by 


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an underlying disease, disorder or condition of the subject or by other 
circumstances unrelated to either the research or any underlying disease, disorder 
or condition of the subject are not “related or possibly related”. If there is any 
question whether or not an AE is related or possibly related, the AE should be 
reported. 
11.2.3 Serious AE (SAE): An adverse event that results in any of the following 
outcomes: 
• Death 
• Life-threatening adverse event (real risk of dying)  
• Prolongation of hospitalization* 
• Persistent or significant disability/incapacity/or change in psychosocial status 
• Congenital anomaly 
• Requirement of intervention to prevent permanent impairment of damage 
*Hospitalization itself will not be considered a serious adverse event if required 
for complications of AML or comorbid conditions. Hospitalization will be 
considered a SAE if it fulfills the criteria for a serious and unexpected adverse 
event as otherwise described. 
11.2.4 Unexpected AE: An unexpected adverse event is defined as an event that has a 
nature or severity, or frequency that is not consistent with the applicable 
investigator brochure, or the prior medical condition of the subject or other 
treatment given to the subject.  “Unexpected,” as used in this definition, refers to 
an adverse drug experience that has not been previously observed and reported in 
preclinical or clinical studies rather than an experience that has not been 
anticipated based on the pharmacological properties of the study drug. 
 
11.3 Grading Adverse Event Severity 
 
All AEs will be graded in severity according to the NCI Common Terminology Criteria 
for Adverse Events (CTCAE) Version 5.0 (http://ctep.cancer.gov). If a CTCAE criterion does 
not exist, the investigator should use the grade or adjectives: Grade 1 (mild), Grade 2 (moderate), 
Grade 3 (severe), Grade 4 (life-threatening), or Grade 5 (fatal) to describe the maximum intensity 
of the adverse event.  
 
11.4  Monitoring, Recordings, and Standard Reporting of Adverse Events 
Only grade ≥3 adverse events other than hematologic toxicities will be recorded, graded, 
and reported as appropriate per 11.1. AEs will be collected for the duration that the patient 
remains on protocol. If a subject decides to terminate the study early their medical record will 
continue to be followed for AEs for up to 4 weeks after the treatment was given or they start a 
new anti-leukemia therapy, whichever occurs first. AEs that do not meet the requirement for 
expedited reporting will be reported to the IRB as part of the annual renewal of the protocol. 
Myelosuppression and associated complications are expected events during leukemia therapy; 
therefore, myelosuppression and associated complications such as fever, infections, bleeding, 
and related hospitalizations will not be reported as individual AE but will be summarized in the 
annual report to the IRB.  
 


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11.5  Adverse Event Recording Period 
 
AEs will be monitored and recorded in the study database from the time of first exposure 
to the therapy in this study (i.e., the start of the first dosimetry infusion). AEs with an onset date 
prior to the first exposure to an investigational product will not be recorded, except in the case of 
clinically significant worsening of the AE during the specified AE monitoring time frame.  
 
 
12.0 DATA AND SAFETY MONITORING PLAN 
 
Institutional support of trial monitoring will be in accordance with the Fred Hutch/University of 
Washington Cancer Consortium Institutional Data and Safety Monitoring Plan.  Under the 
provisions of this plan, Fred Hutch Clinical Research Support (CRS) coordinates data and 
compliance monitoring conducted by consultants, contract research organizations, or Fred Hutch 
employees unaffiliated with the conduct of the study.  Independent monitoring visits occur at 
specified intervals determined by the assessed risk level of the study and the findings of previous 
visits per the institutional DSMP.  
 
In addition, protocols are reviewed at least annually and as needed by the Consortium Data and 
Safety Monitoring Committee (DSMC), Fred Hutch Scientific Review Committee (SRC) and the 
Fred Hutch /University of Washington Cancer Consortium Institutional Review Board 
(IRB).  The review committees evaluate accrual, adverse events, stopping rules, and adherence to 
the applicable data and safety monitoring plan for studies actively enrolling or treating 
subjects.  The IRB reviews the study progress and safety information to assess continued 
acceptability of the risk-benefit ratio for human subjects.  Approval of committees as applicable 
is necessary to continue the study. 
 
The trial will comply with the standard guidelines set forth by these regulatory committees and 
other institutional, state and federal guidelines. 
 
 
13.0 DATA MANAGEMENT/CONFIDENTIALITY 
 
Research data will be recorded in a study-specific, password protected database using a unique 
study ID for each patient to assure patient confidentiality. Data from source documents will be 
transcribed into this database. Source documents are documents where patient data are recorded 
and documented for the first time. They include, but are not limited to, hospital records, clinical 
and office charts, laboratory notes, memoranda, quality of life assessments, pharmacy dispensing 
records, recorded data from automated instruments, copies of transcriptions that are certified 
after verification as being accurate and complete, X-rays, patient files, and records kept at the 
pharmacy, laboratories, and medico-technical departments involved in the clinical trial. There 
will be no case reports forms (CRFs) used for this trial. 
 
The investigator will ensure that data collected conform to all established guidelines. Each 
subject is assigned a unique subject number to protect 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 


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documents. Patient research files will be maintained under control of the Principal Investigator 
and/or study team and kept in a locked office or file room within a secure building. Access to the 
study database will be restricted by electronic password protection and restricted access to 
computers (i.e., locked offices).  
 
 
14.0 STATISTICAL CONSIDERATIONS 
 
This is a pilot study of medically less fit adults with newly diagnosed AML or analogous 
myeloid neoplasm to evaluate the feasibility of randomized assignment to either lower-intensity 
or higher-intensity chemotherapy in a 1:1 fashion.  
14.1 Treatment allocation 
Treatment will be allocated based on patient preference. If agreeable to randomization, 
participants will be allocated to either lower-intensity G-CLAM or higher-intensity G-CLAM in 
a 1:1 ratio using a computer-generated random list of numbers. Randomization will occur in 
blocks of 4. Participants not agreeable to randomization will be allocated to lower-intensity G-
CLAM or higher-intensity G-CLAM as per subject’s preference.  
14.2 Sample Size and Power 
This study will enroll up to 50 subjects. 
14.3  Primary/Exploratory Endpoints/Hypotheses and Analytical Methods 
14.3.1 Primary endpoint 
The primary objective of this study is to evaluate the feasibility of randomizing patients 
to either intensive or non-intensive induction and post remission chemotherapy. We will consider 
randomization feasible (i.e. a subsequent, larger study would be designed as a randomized trial) 
if the true proportion of patients willing to be randomized is 60% or higher. With 50 patients in a 
feasibility study and accounting for the sample variation associated with 50 patients, we will 
consider randomization feasible if at least 52% of the patients agree to be randomized (i.e. 26 or 
more of 50 patients agree to be randomized). If the true proportion willing to be randomized is 
60%, the probability of observing 52% of more willing to be randomized is 90%. The probability 
of having 26 or more of the 50 patients agree to be randomized is only 6% if the true 
randomization agreement rate is 40%, and <1% if the true randomization agreement rate is 30% 
or lower, providing good operating characteristics not only to avoid a false negative result but 
also a false positive result. If one treatment arm closes prematurely (see section on monitoring 
below), we will conclude that randomization is not feasible, and the remaining patients will be 
treated on the remaining arm. Continuation of enrollment into that remaining arm will allow us 
to gain additional experience and provide more precise estimates of treatment efficacy and 
treatment-related toxicities. 
 
14.3.2 Exploratory endpoints 
This pilot study will use exploratory, descriptive, and observational methods to  
1) Evaluate the attitude of patients and physicians toward randomization and explore reasons 
for treatment preference 
2) Evaluate whether the ability to assess fitness for intensive chemotherapy can be improved 
by an augmented treatment-related mortality (TRM) score that includes additional (co-


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morbidity) factors, and to compare the ability of physicians of the prediction algorithm(s) and 
physician to assess the likelihood of early death 
3) Estimate differences between patients treated with lower-intensity G-CLAM and those 
treated with higher-intensity G-CLAM with regard to anti-leukemic efficacy (response, 
duration of response) and survival, QOL, and medical resource utilization as well as care cost 
 
Importantly, this trial is not powered to detect statistically significant differences between the 
study arms for these clinically important endpoints. Rather, the primary goal is to estimate 
outcomes with both treatment intensities to inform a subsequent larger study, should follow-
up investigation appear warranted. 
 
14.4 Monitoring for efficacy and early mortality     
This study will evaluate each regimen separately, and also compare regimens among patients 
who are randomized.  Details for both sets of analyses are provided below.   
Within-arm monitoring for efficacy and early mortality 
We will enroll patients in 2 stages in order to allow for early stopping for unacceptable 
differences in early mortality or inefficacy. Early mortality will be defined as death for any 
reason on or before day 28 after starting therapy. Inefficacy will be evaluated using MRDneg CR. 
 
We will use our ongoing clinical trial using a CPX-351 in medically less fit adults with AML or 
high-grade MDS will provide “historical” control data for both inefficacy and early mortality. In 
this trial (FHCRC #2642.00), which used essentially identically inclusion/exclusion criteria, we 
have so far treated 37 subjects at a CPX-351 dose of 32 units/m2. Among these, 8 patients 
achieved an MRDneg CR (22%). Ten patients (27%) died within 28 days of treatment initiation; 
at least 4 of these subjects experienced early disease progression as main cause of death, 
highlighting the balance between treatment efficacy and potential toxicity.  
 
In the first stage, 10 patients will be accrued to each arm, either in a randomized or non-
randomized fashion. Each arm will be evaluated separately for early death and inefficacy 
stopping rules. Accrual may temporarily be held while outcome data on these patients matures.. 
As some patients may choose to not be randomized, the 2 treatment arms may be evaluated at a 
different time point for early stopping.  
 
1) Lower-dose Arm: After 10 patients have been accrued to the lower-dose arm, we will 
evaluate for early death and inefficacy. 
Early death: If the number of early deaths is 5 or higher, accrual will stop with the 
conclusion that the arm is too toxic for further randomization. If the true early mortality 
rate is 30% or less, the probability of observing 5 or more early mortality events is 15%.  
Inefficacy: If there are 0 patients with MRDneg CR, accrual will stop with the conclusion 
that the arm is not efficacious enough for further randomization. If the true MRDneg CR 
rate is 22%, the probability of observing 0 MRDneg CRs in 10 patients is 8%.  
2) Higher-dose Arm: After 10 patients have been accrued to the higher dose arm, we will 
evaluate for early death and inefficacy. 


9759 
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Early death: If the number of early deaths is 5 or higher, accrual will stop with the 
conclusion that the arm is too toxic for further randomization. If the true early mortality 
rate is 30% or less, the probability of observing 5 or more early mortality events is 15%.  
Inefficacy: If there are 0 patients with MRDneg CR, accrual will stop with the conclusion 
that the arm is not efficacious enough for further randomization. If the true MRDneg CR 
rate is 22%, the probability of observing 0 MRDneg CRs in 10 patients is 8%.  
Between-arm monitoring for efficacy and early mortality 
After enrollment of at least 10 patients in each arm (at which point one arm may have more than 
10 patients accrued due to slower accrual in one arm), we will compare the two arms for relative 
mortality and efficacy. If, based on Fisher’s exact test, the early mortality rate is significantly 
higher in one arm at the alpha =10% level (this criterion will be met if, for example, both arms 
have accrued 10 patients one arm has 0 early mortality events and the other arm has 4), accrual 
will stop in that arm with the conclusion that the arm with the higher early mortality rate is too 
toxic for further randomization. In addition, if based on Fisher’s exact test, the MRDneg CR rate 
is significantly higher in one arm compared to the other at the alpha = 10% level (for example, 
this criterion will be met if both arms have accrued 10 patients and one arm has 2 MRDneg CRs 
and the other has 7), the accrual will stop in that arm with the conclusion that the arm with the 
lower MRDneg CR rate is not efficacious enough for further randomization. 
 
If accrual does not stop in both arms, up to a total of 50 patients will be accrued.  
14.5 Ethnic and Gender Distribution Chart 
All eligible patients will be included in this study without regard to gender or ethnicity. 
The incidence of AML is slightly higher in men, so it is expected that the distribution of these 
patients will reflect a slight male predominance of the disease as well as the general demographic 
distribution of AML patients seen at our institution. Up to 50 patients with newly diagnosed 
AML or analogous high-grade neoplasms will be enrolled in this study. 
 
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 
20 
28 
48 
Ethnic Category Total of All Subjects* 
21 
29 
50 
 
Racial Categories 
 
 
American Indian / Alaska Native 
0 
0 
0 
Asian 
1 
1 
2 


9759 
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Native Hawaiian or Other Pacific 
0 
0 
0 
Black or African American 
1 
1 
2 
White 
19 
27 
46 
More Than One Race 
0 
0 
0 
Racial Categories: Total of All 
21 
29 
50 
 
 
 
15.0 INVESTIGATOR OBLIGATIONS 
 
The PI is responsible for the conduct of the clinical trial at the site and is responsible for 
personally overseeing the treatment of all study subjects. The PI must assure that all study site 
personnel, including sub-Investigators and other study staff members, adhere to the study 
protocol and to all applicable regulations and guidelines regarding clinical trials both during and 
after study completion. 
 
All subjects are informed of the nature of the program, its possible hazards, and their right to 
withdraw at any time, and each subject signs a form indicating their consent to participate prior 
to receiving any study-related procedures. 
 
 
16.0 ADMINISTRATIVE AND REGULATORY CONSIDERATIONS 
 
16.1 Protocol Interpretation and Compliance 
The procedures defined in the protocol are carefully reviewed by the PI and his/her staff 
prior to the time of study initiation to ensure accurate representation and implementation. Protocol 
amendments, if any, are reviewed and implemented promptly following IRB/EC and relevant 
Competent Authorities approval.  
 
16.2 Ethical Considerations 
The Investigator agrees to conduct this study in accordance with applicable United States 
FDA clinical trial regulations and guidelines, the ICH (E6) GCP guidelines, the IRB/EC and 
local legal requirements and with the Declaration of Helsinki (1989). The Investigator will 
conduct all aspects of this study in accordance with all national, state, and local laws of the 
applicable regulatory agencies. 
 
16.3 Informed Consent 
The PI and qualified designees assume the responsibility of obtaining written Informed 
Consent for each subject or the subject’s legally authorized representative before any study-
specific procedures are performed. 
 
Subjects meeting the criteria set forth in the protocol will be offered the opportunity to 
participate in the study. To avoid introduction of bias, the Investigator must exercise no 
selectivity with regard to offering eligible subjects the opportunity to participate in the study. 
Subjects or parents/legal guardians of all candidate subjects will receive a comprehensive 
explanation of the proposed treatment, including the nature of the therapy, alternative therapies 


9759 
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available, any known previously experienced adverse reactions, the investigational status of the 
study drug, and other factors that are part of obtaining a proper Informed Consent. Subjects will 
be given the opportunity to ask questions concerning the study, and adequate time to consider 
their decision to or not to participate. Informed Consent will be documented by the use of a 
written Consent Form that includes all the elements required by FDA regulations and ICH 
guidelines. The form is to be signed and dated by the subject or subject's legally authorized 
representative and by the person who administers the consent process. A copy of the signed form 
will be given to the person who signed it, the original signed Consent Form will be filed with the 
subject’s medical records, and copy maintained with the subject’s study records. The date and 
time of time of the Informed Consent must be recorded in the source documents. If an 
amendment to the protocol changes the subject participation schedule in scope or activity, or 
increases the potential risk to the subject, the Informed Consent Form must be amended. Any 
amended Informed Consent must be reviewed by the Sponsor or designee and approved by the 
IRB/EC prior to use. The revised Informed Consent Form must be used to obtain re-consent from 
any subjects currently enrolled in the study if the subject is affected by the amendment, and must 
be used to document consent from any new subjects enrolled after the approval date of the 
amendment. 
 
16.4  Institutional Review Board/Ethics Committee 
The PI will assure that an appropriately constituted IRB/EC that complies with the 
requirements of 21 CFR Section 56 or written assurance of compliance with ICH (E6) guidelines 
will be responsible for the initial and continuing review and approval of the clinical study. 
Before initiation of the study, the PI or designee will forward copies of the protocol and Consent 
Form to be used for the study to the IRB/EC for its review and approval. The PI or designee will 
also assure that all changes in the research activity and all unanticipated problems involving risks 
to human subjects or others will be reported promptly to the IRB/EC, and that no changes will be 
made to the protocol without prior IRB/EC approval, except where necessary to eliminate 
apparent immediate hazards to human subjects. The Investigator or designee will be responsible 
for submitting periodic progress reports to the IRB/EC at intervals appropriate to the degree of 
subject risk involved in the study, but not less than once per year and at the completion or 
termination of the study. 
 
 
17.0 STOPPING THE STUDY 
 
The study will terminate as described in section 10.0. The Principal Investigator and the IRB 
reserve the right to terminate this study at any time.  
 


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18.0 REFERENCES 
 
1. 
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin. 2016;66(1):7-
30. 
2. 
Howlader N, Noone AM, Krapcho M, et al. SEER Cancer Statistics Review, 1975-2013, 
National Cancer Institute. Bethesda, MD, http://seer.cancer.gov/csr/1975_2013/, based on 
November 2015 SEER data submission, posted to the SEER web site, April 2016. 2016. 
3. 
Burnett A, Wetzler M, Löwenberg B. Therapeutic advances in acute myeloid leukemia. J 
Clin Oncol. 2011;29(5):487-494. 
4. 
Ferrara F, Schiffer CA. Acute myeloid leukaemia in adults. Lancet. 2013;381(9865):484-
495. 
5. 
Döhner H, Weisdorf DJ, Bloomfield CD. Acute myeloid leukemia. N Engl J Med. 
2015;373(12):1136-1152. 
6. 
Oran B, Weisdorf DJ. Survival for older patients with acute myeloid leukemia: a 
population-based study. Haematologica. 2012;97(12):1916-1924. 
7. 
Meyers J, Yu Y, Kaye JA, Davis KL. Medicare fee-for-service enrollees with primary 
acute myeloid leukemia: an analysis of treatment patterns, survival, and healthcare resource 
utilization and costs. Appl Health Econ Health Policy. 2013;11(3):275-286. 
8. 
Walter RB, Estey EH. Management of older or unfit patients with acute myeloid 
leukemia. Leukemia. 2015;29(4):770-775. 
9. 
Juliusson G, Antunovic P, Derolf Å, et al. Age and acute myeloid leukemia: real world 
data on decision to treat and outcomes from the Swedish Acute Leukemia Registry. Blood. 
2009;113(18):4179-4187. 
10. 
Sorror M, Storer B, Elsawy M, et al. Relative benefit for intensive versus non-intensive 
induction therapy for patients with newly diagnosed acute myeloid leukemia (AML) using a 
composite, age-comorbidity-cytogenetic, model [abstract]. Haematologica. 2016;101(S1):221-
222. 
11. 
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. 2015;126(3):291-299. 
12. 
Walter RB, Othus M, Borthakur G, et al. Prediction of early death after induction therapy 
for newly diagnosed acute myeloid leukemia with pretreatment risk scores: a novel paradigm for 
treatment assignment. J Clin Oncol. 2011;29(33):4417-4423. 
13. 
Othus M, Kantarjian H, Petersdorf S, et al. Declining rates of treatment-related mortality 
in patients with newly diagnosed AML given 'intense' induction regimens: a report from SWOG 
and MD Anderson. Leukemia. 2014;28(2):289-292. 


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14. 
Percival ME, Tao L, Medeiros BC, Clarke CA. Improvements in the early death rate 
among 9380 patients with acute myeloid leukemia after initial therapy: A SEER database 
analysis. Cancer. 2015;121(12):2004-2012. 
15. 
Godwin CD, Othus M, Powell MA, Buckley SA, Estey EH, Walter RB. Prediction of 
early death in adults with relapsed or refractory acute myeloid leukemia. Leuk Lymphoma. 
2016;57(10):2421-2424. 
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. 
2016;127(20):2391-2405. 
17. 
Cheson BD, Bennett JM, Kopecky KJ, et al. Revised recommendations of the 
International Working Group for Diagnosis, Standardization of Response Criteria, Treatment 
Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. J Clin 
Oncol. 2003;21(24):4642-4649. 
18. 
Döhner H, Estey EH, Amadori S, et al. Diagnosis and management of acute myeloid 
leukemia in adults: recommendations from an international expert panel, on behalf of the 
European LeukemiaNet. Blood. 2010;115(3):453-474. 
19. 
Aaronson NK, Ahmedzai S, Bergman B, et al. The European Organization for Research 
and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical 
trials in oncology. J Natl Cancer Inst. 1993;85(5):365-376. 
20. 
Osoba D, Rodrigues G, Myles J, Zee B, Pater J. Interpreting the significance of changes 
in health-related quality-of-life scores. J Clin Oncol. 1998;16(1):139-144. 
21. 
Walter RB, Lee SJ, Gardner KM, et al. Outpatient management following intensive 
induction chemotherapy for myelodysplastic syndromes and acute myeloid leukemia: a pilot 
study. Haematologica. 2011;96(6):914-917. 
22. 
Vaughn JE, Othus M, Powell MA, et al. Resource utilization and safety of outpatient 
management following intensive induction or salvage chemotherapy for acute myeloid leukemia 
or myelodysplastic syndrome: a nonrandomized clinical comparative analysis. JAMA Oncol. 
2015;1(8):1120-1127. 
23. 
Degner LF, Sloan JA. Decision making during serious illness: what role do patients really 
want to play? J Clin Epidemiol. 1992;45(9):941-950. 
 
 
 


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19.0 APPENDICES 
 
 
APPENDIX A: TREATMENT-RELATED MORTALITY (TRM) SCORE 
 
Calculation of Simplified Treatment-Related Mortality (TRM) Score 
 
Includes covariates: performance status (PS), age, platelet count, albumin, secondary AML, 
white blood cell count (WBC), peripheral blood blast percentage, and creatinine 
 
Score = 100/(1+e(-x)), with x = -4.08 + 0.89*PS + 0.03*age - 0.008*platelet count - 0.48*albumin 
+ 0.47*(have secondary AML) + 0.007*WBC - 0.007*(peripheral blood blast percentage) + 
0.34*creatinine 
 
 
Probability of TRM Above and Below Various Simplified TRM Score Cut-offs 
TRM Score 
Interval 
Patients below/ 
within/above TRM 
Score Interval (%) 
TRM Probability if 
below TRM Score 
Interval (%) 
TRM 
Probability if 
within TRM 
Score Interval 
(%) 
TRM 
Probability if 
above TRM 
Score Interval 
(%) 
0 – 1.9 
0/20/80 
- 
1 
12 
1.91 – 3.9 
20/20/60 
1 
2 
16 
3.91 – 6.9 
40/20/40 
1 
7 
20 
6.91 – 9.2 
60/10/30 
3 
7 
24 
9.21 – 13.1 
70/10/20 
4 
12 
31 
13.11 – 22.8 
80/10/10 
5 
20 
41 
22.81 – 100 
90/10/0 
6 
41 
- 
 
From: Walter RB, Othus M, Borthakur G, Ravandi F, Cortes JE, Pierce SA, Appelbaum FR, 
Kantarjian HM, Estey EH. Prediction of early death after induction therapy for newly diagnosed 
acute myeloid leukemia with pretreatment risk scores: a novel paradigm for treatment 
assignment. J Clin Oncol. 2011;29(33):4417-4424.  
 
 
 


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 APPENDIX B: DOSE MODFICATION TABLE 
 
For patients who experienced ≥Grade 3 non-hematologic toxicities excluding neutropenic fever 
and infections during the first induction, the following dose reduction can be considered for the 
next course  
 
High-Dose Arm 
 
Drug 
Dose Reduction #1 
Dose Reduction #2 
G-CSF 
No change 
No change 
Cladribine 
Cladribine 4 mg/m2 
Cladribine 3 mg/m2 
Cytarabine 
Cytarabine 1,500 mg/m2 
Cytarabine 1,000 mg/m2 
Mitoxantrone 
Mitoxantrone 14 mg/m2 
NA 
 
Low-Dose Arm 
 
No dose reductions required.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX C: EUROPEAN ORGANIZATION FOR RESEACH AND 
TREATMENT OF CANCER QLQ-C30 QUESTIONNAIRE 
 
 
 
 


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Aaronson, N.K., et al., The European Organization for Research and Treatment of Cancer QLQ-
C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl 
Cancer Inst, 1993. 85(5): p. 365-76. 
 
 


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APPENDIX D: PATIENT PREFERENCE FOR TREATMENT 
ASSIGNMENT SURVEY 
We would like to understand whether patients and their doctors are comfortable letting a “coin 
flip” decide whether lower- or higher-intensity chemotherapy is used. We also want to 
understand how you made this decision, and why. Please answer the following questions: 
 
 
1) Preference for treatment assignment  
After thinking about this study and discussing it with your doctor(s), how do you prefer to be 
treated? 
 
 
 
I am willing to let a coin flip (i.e. computer program) decide whether I receive lower- 
or higher intensity chemotherapy 
 
 
 
I would like to make the decision whether I receive lower- or higher-intensity 
chemotherapy myself 
 
           
 
 
My preference is to receive lower-intensity chemotherapy 
 
           
 
 
My preference is to receive higher-intensity chemotherapy 
 
 
2) How did you make this decision? 
 
 
 
I made the final decision about which treatment I would receive 
 
 
 
I made the final decision of my treatment after seriously considering my doctor's 
opinion 
 
 
 
My doctor and I decided together which treatment is best for me 
 
 
 
My doctor made the decision after seriously considering my opinion 
 
 
 
My doctor made the final decision about which treatment I would receive  
 
 
 
3) Which factors were most important for you in making this decision?  
 
 
 
 
 
 
 
Patient name/signature:  ________________________________ 
 
 Date: ____________  


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APPENDIX E: PHYSICIAN PREFERENCE FOR TREATMENT 
ASSIGNMENT SURVEY 
We are conducting a study to better understand whether patients and their doctors are 
comfortable letting a “coin flip” decide whether lower- or higher-intensity chemotherapy is used. 
We would like to ask you two questions about your preference for treatment assignment and 
which factors are important for making this decision. It should take about 5 minutes. There are 
no foreseeable risks to your participation. There is no payment for taking part in this research 
and your participation is voluntary. Choosing not to participate will not incur a loss of benefits to 
which you are otherwise entitled. You will not directly benefit from taking this survey, but we 
hope we can better understand how decisions about treatment intensity are made.  We will ask 
you to provide your name and we will link your responses to similar questions we are also asking 
the patient you are treating. However, your name will remain confidential and if results of this 
study are published we will not use your name.  If you have questions about this study, please 
contact Anna Halpern MD at 206-667-6233. If you have questions about your rights as a 
research participate, you can contact Karen Hansen, Director of the Institutional Review Office, 
Fred Hutchinson Cancer Research Center, at 206-667-4867. 
 
 
1) Preference for treatment assignment  
After thinking about this study and discussing it with the patient, how do you prefer for the 
patient to be treated. 
 
 
 
I am willing to randomize the patient to lower- or higher intensity chemotherapy and 
they agree 
 
 
 
I am willing to randomize the patient to lower- or higher intensity chemotherapy but 
the patient would prefer to choose treatment themselves and they chose: 
 
           
 
 
Lower-intensity chemotherapy 
 
           
 
 
Higher-intensity chemotherapy 
 
 
 
Neither I nor the patient want to proceed with randomization and the following 
person chose the treatment arm: 
 
 
 
 
 
Myself 
 
           
 
 
The patient 
 
2) Which factors were most important for you in making this decision?  
 
 
 
The patient did not want to be randomized (did not like the idea of a “coin flip”) 
 
 
 
The patient thought one treatment arm was better than another 
 
 
 
I thought one treatment arm was better than another 


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I thought the patient was too frail/unfit for the higher intensity treatment and that this  
 
 
arm would be too toxic 
 
 
 
I was concerned the lower intensity arm would not be efficacious enough 
 
 
 
Other, please explain:  
 
 
 
Physician name:  ________________________ 
 
 
 
Date: ______________ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX F: FAX COVER SHEET 
 
FAX COVER SHEET 
 
 
DATE:_____________
_ 
 
 
TO: Anna Halpern 
 
FAX (206) 667-6519 
 
RE: RESEARCH SUBJECT CONSENT/HIPAA FORM 
PROTOCOL 9759 
 
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-229, SEATTLE, WA 98109