Clinical trial NCT04562792
Conditions: Relapsed Pediatric ALL Relapsed Pediatric AML Refractory Acute Myeloid Leukemia Refractory Acute Lymphoblastic Leukemia
Sponsor: Children's Mercy Hospital Kansas City
Start date: 2020-05-08; Completion date: 2022-06-30
Enrollment: 1 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
In this pilot study, eligible pediatric patients will be treated with 5 consecutive days of low dose daunorubicin. All patients who receive low dose daunorubicin will be evaluated daily for potential toxicity during those 5 days. Once the patient has received 5 doses of daunorubicin, subsequent therapy will be at the discretion of the primary oncology team.

Detailed description:
Cancer remains the number one cause of non-accidental death in children with leukemia being the most common type of childhood cancer. Although cure rates for pediatric leukemia have greatly improved over the last few years, relapsed disease still carries a poor prognosis. Outcomes for children with multiply relapsed leukemia are dismal ranging from a remission rate of 25% in AML after 2 relapses falling to 17% after 3 or more relapses and 44% in ALL after 2 relapses and 27% after 3 or more relapses.

Leukemia stem cells that are resistant to chemotherapy primarily contribute to treatment failure and targeting these cells remains a challenge. Anthracyclines such as daunorubicin and doxorubicin have been the mainstays of childhood leukemia therapy for over 50 years. Prior investigations found that very low doses, significantly less than traditionally given, of doxorubicin and daunorubicin inhibit the interaction of Akt and beta catenin pathways which is known to drive the development of leukemia stem cells and chemoresistance. Mice models showed that treatment with these very low dose anthracyclines does not suppress the immune system but rather expands cancer targeting T cells while inhibiting populations known to help cancer cells evade the immune system. In addition, targeted treatment reduced immune checkpoint expression, a known cause of resistance, on leukemia stem cells, thus further sensitizing them to cytotoxic T cells. Standard doses of anthracyclines suppress hematopoiesis and in turn the immune system and thus do not permit the expression of these immunologic benefits.

Patients with relapsed and/or refractory acute lymphoblastic leukemia or acute myeloid leukemia, ages 1-21 years, will be approached to participate in this study. These patients must have pathologically confirmed ALL or AML, whose disease is refractory to two induction therapeutic attempts, or who are in 2nd or greater relapse, or who are in 1st relapse or refractory to a single therapeutic attempt but are unable to receive intensive therapy due to other comorbidities. Patients will receive daunorubicin at 6.75mg/m2 daily for 5 consecutive days for a total dose of 33.75mg/m2.

The primary objective of this study is to assess the feasibility and tolerability of low dose daunorubicin. Another objective of the study is to validate if T cell based immune responses against chemoresistant leukemia stem cells are stimulated at these lower doses of daunorubicin, in hopes to provide preliminary pediatric data for further research with the hypothesis being that targeted anthracycline treatment does in fact stimulate T cell based immune responses against chemoresistant leukemia stem cells. Samples will be analyzed by flow cytometry for stem cell and immune markers. The third primary objective is to identify pro vs anti-cancer cellular immune responses of targeted anthracycline treatment in these patients. The mechanism of low dose DNR treatment on activating immunogenic cell death (ICD) will be investigated by determining relative levels of damage-associated molecular patterns. The tumorigenic capacity of resistant populations such as LSCs expressing high levels of immune checkpoints will be tested. The secondary objective of this study is to evaluate the pharmacokinetic parameters of low dose daunorubicin in children with relapsed/refractory AML and ALL. Blood samples for evaluation of low dose daunorubicin pharmacokinetics (area under the time concentration curve, maximum concentration, elimination half-life, clearance) will be drawn prior to dosing and 5min, 20min, 40min, 1hr, 2hrs, 4hrs, 8hrs, and 24hrs only after the first day of dosing.

Once the patient has received 5 doses of daunorubicin, subsequent therapy will be at the discretion of the primary oncology team.

Arms: arm 1: Patients in this arm will receive daunorubicin 6.75mg/m2 daily for 5 consecutive days.
Interventions: intervention 1: Daunorubicin
Intervention descriptions: intervention 1: Eligible patients with relapsed and/or refractory acute leukemia will receive daunorubicin 6.75mg/m2 daily for 5 consecutive days.

Protocol documents:
Prot_001.pdf: 
SHORT TITLE:  Low Dose Dauno 
 
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PROTOCOL TITLE: 
A Pilot Study of Targeted Daunorubicin Dosing to Overcome Chemotherapeutic 
Resistance in Children with Relapsed or Refractory Acute Leukemia 
 
PRINCIPAL INVESTIGATOR: 
Name  Chandni Dargan 
Department  Hematology/Oncology 
Telephone Number 234-3265 
Email Address cdargan@cmh.edu 
VERSION NUMBER/DATE: 
Version 5 Date: 11/13/2020 
 
 
 


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Table of Contents 
1.0 
Study Summary ........................................................................................................ 3 
2.0 
Objectives ................................................................................................................ 4 
3.0 
Background .............................................................................................................. 4 
4.0 
Study Endpoints ....................................................................................................... 6 
5.0 
Study Intervention/Investigational Agent ............. Error! Bookmark not defined.6 
6.0 
Procedures Involved................................................................................................. 7 
7.0 
Data and Specimen Banking ................................ 7Error! Bookmark not defined. 
8.0 
Genetic Analysis Information .................................................................................. 7 
9.0 
Sharing of Results with Subjects ............................................................................. 7 
10.0 Study Timelines ....................................................................................................    8 
11.0 Inclusion and Exclusion Criteria .............................................................................. 8 
12.0 Vulnerable Populations ............................................................................................ 9 
13.0 Local Number of Subjects ....................................................................................... 9 
14.0 Screening and Recruitment Methods ..................................................................... 10 
15.0 Reimbursement, Payment and Tangible Property provided to subjects ......... Error! 
Bookmark not defined. 
16.0 Withdrawal of Subjects .......................................................................................... 10 
17.0 Risks to Subjects .................................................................................................... 11 
18.0 Potential Benefits to Subjects ................................................................................ 11 
19.0 Investigator Assessment of Risk/Benefits Ratio. ................................................... 11 
20.0 Data Management and Confidentiality .................................................................. 12 
21.0 Provisions to Monitor the Data to Ensure the Safety of Subjects .......................... 13 
22.0 Provisions to Protect the Privacy Interests of Subjects .......................................... 13 
23.0 Compensation for Research-Related Injury ........................................................... 14 
24.0 Economic Burden to Subjects ................................................................................ 14 
25.0 Permission/Assent/Consent Process ...................................................................... 14 
26.0 Process to Document Permission/Assent/Consent................................................. 14 
27.0 Setting .................................................................................................................... 15 
28.0 Resources Available............................................................................................... 15 
29.0 Multi-Site Research ............................................................................................... 15 
30.0 International Research ........................................................................................... 15 
 
 
 


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1.0 
Study Summary 
 
Study Title 
A Pilot Study of Targeted Daunorubicin Dosing to 
Overcome Chemotherapeutic Resistance in Children with 
Relapsed or Refractory Acute Leukemia 
Study Design
prospective, upfront window
Primary Objective 
1To assess the feasibility and tolerability of 
administration of low dose daunorubicin  
2 To observe if T-cell based immune responses 
against chemoresistant leukemia stem cells (LSC) are 
stimulated at lower doses of daunorubicin to provide 
preliminary data for further research. 
3 To identify the pro- vs. anti-cancer cellular immune 
response of targeted anthracycline treatment in patients with 
relapsed/refractory AML. 
Secondary 
Objective(s) 
To evaluate the pharmacokinetic parameters of low dose 
daunorubicin in children with relapsed/refractory AML and 
ALL as well as standard doses of daunorubicin in children 
with AML and ALL to assess for dose linearity relationship
Research 
Intervention(s)/ 
Investigational 
Agent(s) 
Daunorubicin at 6.75mg/m2/day given IV days 1-5 as an 
upfront window therapy  
 
IND/IDE #  
NA
Study Population 
ALL and AML refractory to two induction attempts, or 2nd or 
greater relapse, or in 1st relapse who are unable to receive 
standard intensive therapy 
PK analysis will also include first diagnosis ALL and AML 
who are receiving daunorubicin as standard of care
Sample Size 
10 to receive low dose dauno; 5 of whom will not have had a 
SCT   
12 additional patients for PK analysis
Study Duration for 
Individual 
Participants
5 days of treatment with 60 days of follow-up for patients 
receiving low dose daunorubicin 
Study Specific 
Abbreviations/ 
Definitions  
ALL – acute lymphoid leukemia; AML – acute myeloid 
leukemia, SCT – stem cell transplant; DNR daunorubicin  
 
 


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2.0 
Objectives 
2.1 Primary Objectives 
 
2.1.1 To assess the feasibility and tolerability of administration of low dose 
daunorubicin  
2.1.2 To observe if T-cell based immune responses against chemoresistant 
leukemia stem cells (LSC) are stimulated at lower doses of daunorubicin to provide 
preliminary data for further research. 
2.1.3 To identify the pro- vs. anti-cancer cellular immune response of targeted 
anthracycline treatment in patients with relapsed/refractory AML. 
 
2.2 Secondary Objective  
      
  
2.2.1 To evaluate the pharmacokinetic parameters of low dose daunorubicin in 
children with relapsed/refractory AML and ALL as well as standard doses of 
daunorubicin in children with AML and ALL to assess for dose linearity relationship. 
 
 
3.0 
Background 
3.1 Over the past 60 years there has been remarkable progress in our understanding 
of how to successfully use chemotherapy to treat children with cancer.  Despite this 
progress and resultant cure rate of approximately 80%, cancer remains the number one 
cause of non-accidental death in children.[1-2] Many of these deaths are due to relapsed 
disease with survival rates ranging from 15-50% while those experiencing early relapse 
(within 18 months of diagnosis) have a 5-year survival estimate of only 20%. [3-4] 
 
Leukemia is the most common type of childhood cancer.  Chemoresistant leukemia stem 
cells (LSCs) are responsible for cancer treatment failure, but targeting these cells remains 
a significant challenge. Recent data indicates that certain cancer therapies act, in part, by 
reactivating anti-cancer immunity whereas other therapies may be immunosuppressive.  
 
3.2   It is well established that the Wnt/β-catenin and PI3K/Akt pathways, which 
are frequently activated in human cancer, interact to drive LSC development and 
chemoresistance. [11-12]  Prior investigations by Dr. John Perry unexpectedly found that 
doxorubicin (DXR) and daunorubicin (DNR) inhibit the cooperative interaction of Akt and 
β-catenin at low doses [Fig.1]. These findings led to the repurposing of DXR as a targeted 
therapy to inhibit Akt:β-catenin interaction and specifically target chemoresistant LSCs in 
a mouse leukemia model. A pilot clinical trial (NCT02914977) applying these findings to 
relapsed/refractory adult leukemia patients has shown promising initial results [Fig.2]. [13 


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3.3 
Optimal delivery of chemotherapeutic agents remains a key focus in 
preventing disease relapse. Current clinical practice using broadly toxic agents is generally 
immunosuppressive.  Available preclinical data in murine models indicates that targeted 
DXR treatment expands cancer-targeting T-cells while inhibiting populations known to 
help cancer cells evade the immune system. Furthermore, targeted DXR treatment reduces 
immune checkpoint expression particularly on LSCs, potentially sensitizing LSCs to 
cytotoxic T-cells. These positive immunological “side” effects of targeted DXR treatment 
are negated or even reversed using the current clinical standard (high-dose) treatment in 
these models, which instead stimulates treatment-resistance mechanisms.  However, since 
preclinical cancer research typically involves testing human cancer cells grown in culture 
or in immunodeficient mice, a significant knowledge gap exists in that therapy-induced 
anti-tumor immunity is largely unexamined but potentially critical for successful treatment. 
 
Anthracyclines such as daunorubicin (DNR) and doxorubicin (DXR), have been the 
mainstays of childhood leukemia therapy both in upfront and relapse, for over 50 years. 
Targeted anthracycline therapy potentially reduces or eliminates minimal residual disease 
and chemoresistant LSCs in pediatric leukemia patients by inhibiting Akt:β-catenin 
interaction and/or reactivating anti-cancer immunosurveillance.  This is currently being 
investigated in de novo children with leukemia, both AML and ALL (MARS study 
13100340), and will be able to be compared to the baseline, days 8 and 29 results in this 
study.  
 
 
4.0 Study Endpoints 
If low dose daunorubicin is deemed feasible in this study, the next step would be to give 
traditional dose chemotherapy upfront in cycle 1, then await count recovery with minimal 
leukemia or minimal residual disease in end of induction bone marrow evaluation. This 
would be followed by low dose daunorubicin, waiting 14 days to repeat bone marrow 
evaluation to assess LSCs. Then move on with traditional cycle 2 chemo or a second low 
dose daunorubicin cycle. These would take place with a new protocol.  
 
 
5.0  Study Intervention/Investigational Agent 
DNR is an agent frequently used in the treatment of relapsed pediatric ALL and AML 
patients however it is not without long term side effects; primarily heart failure [8-10].  
Cardiotoxicity is directly correlated with the cumulative dose of anthracyclines received.  
Cells responsible for leukemia relapse in children may be eliminated by repurposing DNR, 
at a significantly lower dose, as a targeted therapy to reactivate anti-cancer immunity 
while avoiding broad toxicity, particularly cardiotoxicity, and the evolution of resistance. 
The standard dose given in de novo AML is 50mg/m2/day for 3 days and in de novo ALL 
is 25 mg/m2/dose once weekly for 4 weeks compared to the proposed dose of 
6.75mg/m2/dose for 5 consecutive days.  We will also measure the pharmacokinetics of 
low dose DNR in these patients to enable preliminary PK-PD analyses and because there 
are essentially no PK data for DNR at comparable doses. Pharmacokinetics of low dose 
daunorubicin will be analyzed along with pharmacokinetics of standard doses of 
daunorubicin to assess for potential dose linearity relationship. Following participation on 


SHORT TITLE:  Low Dose Dauno 
 
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this upfront window trial, patients who receive low dose daunorubicin can then proceed 
to other conventional or investigational therapies as clinically indicated 
 
6.0 Procedures Involved 
6.1   The proposed study is a prospective, upfront window, single-site investigation 
in study participants with relapsed/refractory ALL and AML.  The study will be comprised 
of 10 pediatric patients receiving low dose daunorubicin, 1-21 years of age. At least 5 of 
these patients will not have undergone hematopoietic stem cell transplant (SCT).  Once 5 
SCT patients have been enrolled, subsequent SCT patients will be excluded and the study 
will remain open until a total of 5 patients without a history of SCT have been enrolled if 
not already accomplished. An additional 12 patients will be enrolled to receive standard 
dose daunorubicin for PK evaluation.  Subjects will be identified through 
Hematology/Oncology at Children’s Mercy Hospital. Subjects who meet all inclusion 
criteria and whose parents, after provided study information, provide written consent and 
patient assent if age appropriate, will be eligible for study Provide a description of all 
research procedures being performed and when they are performed, including procedures 
being performed to monitor subjects for safety or minimize risks. 
6.2 All subjects receiving low dose daunorubicin will begin Induction therapy with 
daunorubicin within 5 days of signing consent. In this pilot study, patients will be treated 
with 5 consecutive days of low dose daunorubicin, 6.75mg/m2/dose given once daily IV 
over 10 minutes for one cycle.  Dexrazoxane will not be co-administered owing to the very 
low dose daunorubicin used in this trial. Subsequent therapy after day 8 is at the discretion 
of the primary referring oncologist.  During this study period, patients may be placed on 
hydroxyurea to aid in controlling hyperleukocytosis. Blood samples for evaluation of low 
dose daunorubicin pharmacokinetics (area under the time concentration curve, maximum 
concentration, elimination half-life, clearance) will be drawn prior to dosing and 5min, 
20min, 40min, 1hr, 2hrs, 4hrs, 8hrs, and 24 hrs after dosing. LSC samples will be obtained 
at baseline, end of day 5 daunorubicin infusion, on day 8, day 29, with subsequent bone 
marrow exams, and upon count recovery from this or subsequent chemotherapy defined as 
an APC > 500.  A CBC with differential will be obtained on the same day as the initial 
bone marrow aspirate which is considered standard of care as well as daily during the 
chemotherapy administration.  A CBC with differential will also be obtained on day 8 
which is typically standard of care. These samples will be obtained on days when other 
labs are already obtained and thus no additional visits or central line entries are required. 
PK analysis will also be performed in the additional 12 enrolled patients on standard 
dose daunorubicin with ALL and AML, 1-21 years of age, who are receiving daunorubicin 
as part of standard therapy. Blood samples for evaluation of standard doses of daunorubicin 
(0.67mg/kg/dose, 20mg/m2/dose, 25mg/m2/dose, 50mg/m2/dose) pharmacokinetics will 
be drawn at the same time points as those patients receiving low dose daunorubicin. Each 
blood draw for PK analysis will be 2-3ml unless patient weighs less than 8kg, in which 
case 1.5ml will be drawn to not exceed maximum allowed blood draw.  
 
7.0   Data and Specimen Banking: NA 
8.0   Genetic Analysis Information: N/A 
9.0   Sharing of Results with Subjects 


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All disease and treatment related lab results will be shared with the subject, as per 
the standard practice within Hematology/Oncology, and any other CMH providers 
directly involved in the subject’s care.  PK results will only be shared upon subject 
request due to the lack of clinical significance to the subject.   
10. Study Timelines 
 
Low dose DNR is designed in this study to be given for 5 days 
only.  At any time, the patient may withdraw from study.  The 
study therapy will be terminated if there are changes in the 
patient’s condition which renders the patient unacceptable for 
further treatment in the judgement of the investigator.  Patients 
who complete the 5 days of DNR, will be followed on study 
through collection of post-treatment disease assessments at 
count recovery not to exceed 60 days. The duration of an 
individual subject’s participation in the study. 
 
Patients receiving standard doses of daunorubicin will be 
enrolled in the study for 24 hours 
 
Once IRB approval is received, study personnel will begin 
identifying and enrolling patients with an expectation that 
enrollment will be completed within 24 months.  In parallel to 
recruitment, procurement and processing of patient samples as 
well as flow cytometry analysis of bone marrow and peripheral 
blood samples will occur. scRNA-seq genomic studies of the 
samples will begin in upon completion of patient enrollments. 
Data analysis will begin after the last enrolled patient has 
completed their treatment and 60 day follow-up period.  
 
Within 6-12 months, meeting abstract submissions, presentations, and  
publications (anticipated 2 to 3) will be developed from resultant data.    
 
11 Inclusion and Exclusion Criteria 
Inclusion Criteria for low dose daunorubicin 
 
Patients with pathologically confirmed ALL or AML, whose disease 
is refractory to two induction therapeutic attempts, or who are in 2nd 
or greater relapse, or who are in 1st relapse or refractory to a single 
therapeutic attempt but are unable to receive intensive therapy at the 
time of consent. 
 
All prior upfront therapies including bone marrow transplant are 
acceptable. Pulse steroids (of 5 days duration or less in the prior 
month) administered as part of a routine maintenance therapy are 
acceptable. 
 
Age 1 to 21 years of age, inclusive  
 
Established central catheter IV access 
 
                     Additional Inclusion Criteria for PK analysis of standard dose daunorubicin 


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 Patients with pathologically confirmed ALL or AML, including 
patients with Down Syndrome, who will receive daunorubicin as part of 
routine chemotherapy decided by the primary oncologist 
 Ages 1 to 21 years, inclusive 
Exclusion Criteria 
 
Females who are known to be pregnant or lactating 
 
Any Grade 3 or higher Cardiac Disorder per CTCAE version 5 
 
Patients with echocardiographic evidence of cardiomyopathy 
(shortening fraction <27% or ejection fraction <50%)   
 
Uncontrolled sepsis 
 
Absolute Blast Count >50 x10(3)/mcL at enrollment or on day 1 of 
study 
 
Direct hyperbilirubinemia >5mg/dL 
 
Grade 3 or higher anaphylaxis to daunorubicin 
 
Non-English speaking 
 
Patients, who in the opinion of the PI, are unable to tolerate any study-
specific procedures 
 
Patients who have received cyclosporine, tacrolimus or other agents 
to prevent or treat graft-vs-host disease post bone marrow transplant 
in the last 14 days     
 
Concurrent investigational drugs or other chemotherapeutic agents 
(excluding hydroxyurea), immunotherapies or biosimilars during the 
5 days of daunorubicin.  
 
Prior cumulative doses of anthracyclines will not be an exclusion 
regardless of the total cumulative dose previously received.   
 
Exclusion Criteria for PRK analysis of standard dose daunorubicin 
 
Patients who do not receive daunorubicin as part of their standard of 
care 
 
The following populations will be excluded:  
 
Adults unable to consent 
 
Prisoners 
 
Wards of the state 
 
12.0 Vulnerable Populations 
12.1 Potential subjects will consist of mostly children. The primary 
physician/advanced practice nurse will initially approach potential patients. If a 
family and subject are interested in the study.  The study will be further explained, 
and permission/assent/consent will be reviewed at this time, as will required 


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assessments for the study. Ample time and opportunity are provided to the child 
and family to ask about the details of the study, to consider other available 
options, and to decide whether to participate. We will be obtaining permission 
from at least one parent for study participation of minors. Assent will be obtained 
from all children at least 7 years of age and will be documented in the Child 
Permission/Assent form. Authorized personnel will document assent in the Child 
Permission/Assent form. The study will be directly explained to the minor in 
simpler terms that he/she will understand. The family will be given copies of the 
consent or permission/assent as well as contact information for the site PI.  
 
13.0 Local Number of Subjects 
The total number of subjects to be accrued to receive low dose 
daunorubicin: 10 who will have completed the prescribed 5 days of 
therapy.   
The total number of additional subjects accrued for PK analysis: 12 
 
14.0 Screening and Recruitment Methods 
14.1 Potential subjects will be recruited once determined they meet 
inclusion criteria. This may take place in Children’s Mercy Hospital 
Participants will be approached to provide informed consent or assent 
to enter the proposed study.  
14.2 Subjects will be patients of Children’s Mercy Hospital.  
14.3 Potential subjects will be identified by provider referral.  
 
 
15.0 Withdrawal of Subjects 
15.1 Patients can be taken off the study treatment at the discretion of the 
investigator for safety, behavioral or administrative reasons. The reason(s) for 
discontinuation will be documented and may include: 
 Patient is unable to comply with protocol requirements; 
 Patient experiences toxicity that makes continuation in the protocol 
unsafe; 
 Treating physician judges continuation on the study would not be in 
the patient’s best interest; 
 Patient becomes pregnant (pregnancy to be reported along same 
timelines as a serious adverse event); 
15.2 Patients who are removed from the study prior to the completion of 5 
days DNR due to disease progression or adverse events attributed to 
daunorubicin will continue to have their data reported from the time 
prior to study withdrawal. Patients removed from the study for any 


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other of the above reasons in addition to voluntarily withdrawing, will 
not have data reported. 
16.0 Risks to Subjects 
 
16.1 All people who receive cancer treatment are at risk of having side 
effects. In addition to killing tumor cells, cancer chemotherapy can 
damage normal tissue and produce side effects. Side effects are 
usually reversible when the medication is stopped but occasionally 
persist and cause serious complications. A person can die from these 
and other complications. People who do not undergo treatment will 
have side effects due to their disease.  
Common side effects of Daunorubicin include nausea, vomiting, hair 
loss, fatigue, red colored urine for 2 days after treatment, and loss of 
appetite. Drugs may be given to prevent or decrease nausea and 
vomiting. Hair loss is usually temporary but on very rare occasions, it 
may be permanent. Some chemotherapy may lead to sterility. There is 
also a possibility that a second cancer may develop years later as a 
result of chemotherapy.  
Daunorubicin is not an IND agent. It is FDA-approved and used in 
this protocol within an approved indication. This study does not 
involve any factors that would significantly increase the risk 
associated with daunorubicin. 
16.2 The risk involved in this study is Category 2 as highlighted below.  
16.3 No procedures will have risks that are currently unforeseeable.  
16.4 As the effect of Daunorubicin on an embryo or fetus is not fully 
understood, it will not be administered to any pregnant persons. 
16.5 There are no risks to those who are not subjects. 
 
17.0 Potential Benefits to Subjects 
Daunorubicin is an agent frequently used in the treatment of relapsed pediatric ALL and 
AML. Daunorubicin is a cytotoxic anthracycline chemotherapy isolated from the culture 
of Streptomyces. It acts through inhibition of topoisomerase II and DNA intercalation 
leading to cell death. It is commonly used at high doses in the treatment of both AML and 
ALL.  
 
18.0 Investigator Assessment of Risk/Benefits Ratio: (IRB makes the 
final determination)  
 
 
Select as applicable:
Pediatric Risk Category:


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Category 1 
Research not involving greater than minimal risk 
(45 CFR §46.404 and 21 CFR §50.51)  
X
Category 2
Research involving greater than minimal risk but 
presenting the prospect of direct benefit to the 
individual 
subjects. (45 CFR §46.405 and 21 CFR §50.52) 
Category 3
Research involving greater than minimal risk and no 
prospect of direct benefit to individual subjects, but 
likely to yield generalizable knowledge about the 
subject's disorder or condition.  
(45 CFR §46.406 and 21 CFR §50.53)
Category 4
Research not otherwise approvable which presents 
an opportunity to understand, prevent, or alleviate a 
serious problem affecting the health or welfare of 
children. (45 CFR §46.407 and 21 CFR §50.54) 
Select if applicable:
Adult Risk Category:
Not Greater than Minimal Risk
x
Greater than Minimal Risk
 
19.0 Data Management and Confidentiality 
19.1 The sample size for this study was determined based on number of 
relapsed leukemia patients in recent years as well as in coordination 
with a Children’s Mercy statistician.  
19.2 Each patient will be assigned a study number.  No other subject identifiers 
will be used on data forms. Subject data will be stored in a confidential database 
that does not contain patient protected information or identifiers.  A separate list 
linking the study numbers to the patients will be maintained electronically in a 
password-protected sector of the CMH server.  Only CMH research personnel 
will have access to this data. All personal information (e.g., PHI) will be kept 
confidential.   
 
19.3 Certificate of Confidentiality – NA 
 
19.4  Stored samples will be labeled with the IRB protocol number and the 
patient’s assigned study number only.  This will be clearly stated in the consent 
form.  If a participant withdraws prior to completing the study; the specimens and 
the data collected from that individual will not be included in the final data 
analysis.  All data will be stored with numerical identification and files will be 
kept in locked offices and or password-protected encrypted electronic files.  
Personal identity will be protected in any publication.  Whether associated with 
the storage/retention of protected health information or the dissemination of study 
results, the CMH policies pertaining to HIPPA and the storage of research data 
will be followed. 
 
19.5 Records to be kept/Secure Storage of Data 
Each subject will be assigned a study number which will be used for data 
collection. No other subject identifiers will be used on data collection instruments. 
Per hospital policy, the subject’s permission/assent/consent document will be 
labeled with the subject’s name and medical record. The original will be 


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v5 13NOV2020 
maintained in the study chart and an electronic version will be scanned into the 
subject’s medical record. Data will be stored in a password protected database. 
Access will be limited to study personnel.  A separate list linking the study 
numbers to the patients will be maintained electronically in a password-protected 
sector of the CMH server.  Only CMH research personnel will have access to this 
data.  Samples will be labeled with the IRB protocol number and the patient’s 
assigned study number only.  This will be clearly stated in the consent form.  
 
20.0 Provisions to Monitor the Data to Ensure the Safety of Subjects 
 
Feasibility will be determined based on multiple observations. Feasibility failure 
due to progressive leukemia is defined as a rise in ABC of >10,000/day on two 
consecutive days that continues to increase >10,000/day after starting hydroxyurea. 
Low dose daunorubicin will also be deemed not feasible if there is evidence of 
progression of extramedullary leukemia, or if the patient experiences 
uncontrollable nausea and/or vomiting. Low dose daunorubicin will be reported as 
not feasible as upfront treatment if more than 3 patients are unable to complete all 
5 doses of the drug. If the patient is hospitalized for any reason except the 
aforementioned, low dose daunorubicin will still be considered feasible. 
Complications leading to interruption in ability to dose daunorubicin consecutively 
such as need for surgery not attributable to daunorubicin will not be a marker of 
feasibility.  
 
The DSMB of the University of Kansas Cancer Center will be responsible for 
monitoring patient safety for this trial. Their monitoring will include review for 
progress and safety, review of adverse events, and review of any other component 
of the study identified by the DSMB.  
 
21.0 Provisions to Protect the Privacy Interests of Subjects 
21.1 Confidentiality of all subjects participating in the trial and all of their 
medical information will be maintained. All CRFs and any 
identifying information will be kept in a secure location with access 
limited to the study staff directly participating in the trial. 
21.2 Subjects will be provided with study contact information for any 
questions or concerns that arise before, during and after the study. 
21.3 While confidentiality cannot be guaranteed, PHI will be protected to 
the greatest extent possible. There also may be some situations 
where laws require the release of PHI. If PHI is shared with an 
organization that is not required to comply with federal privacy laws, 
health information is no longer considered protected and may be 
used and shared freely by that organization. 
21.4 PHI to be accessed and/or recorded for this research study: 
name/initials, date of birth, date of death, dates of service, medical 
record number, telephone number, and hospital account number. 


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21.5 The research team will not be obtaining a HIPAA Waiver for this 
study. 
 
22.0 Compensation for Research-Related Injury 
22.1 In the case of illness or injury resulting from this study, treatment is 
available at Children’s Mercy Hospital, but will be provided at the 
usual charge. Payment for this treatment will not be provided by the 
sponsor of this research study. The hospital may not be able to bill 
insurance or other third party payers for this care. The Children’s 
Mercy Hospital does not have funds set aside to pay research 
participants if the research results in injury. Children’s Mercy 
Financial Counselors may be able to help families find funds to help 
cover the cost of medical services. If a subject experiences difficulty 
paying for services not covered by insurance, a Financial Counselor 
can be reached at 816-234-3567. 
 
23.0 Economic Burden to Subjects: NA - All research related activities are 
funded by the study.    
 
24.0 Permission/Assent/Consent Process 
Consent will be obtained in person within the HEM/ONC division. 
Permission/assent/consent will be obtained upon initial discussion with 
the patient. We will be following CM research policies on informed 
permission/assent/consent. 
If 
we 
need 
to 
obtain 
permission/assent/consent via telephone, we will be following CM 
research policy.   
 
Subjects who are not yet adults (infants, children, teenagers) 
 
All children 7 years and older will be assented.   
 
Child assent will be documented in the medical record.  If a 
child is unable to assent, this too will be documented in the 
medical record 
 
Consent at 18 years of age, when minor subjects become adults. The 
child will be reconsented at the age of 18 if previously assented as a 
minor.    
 
25.0 Process to Document Permission/Assent/Consent 
25.1 We will follow CM Research Policy 10.04 Obtaining 
Permission/Assent/Consent  process. 


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26.0 Setting 
26.1 The research team will conduct research within the heme/onc 
division. 
26.2  Pharmacokinetic analysis will be performed at University of Kansas 
Medical Center  PACKAGING AND TRANSPORT OF SPECIMENS 
 Research Staff will complete a label which will have the assigned study number 
along with date and time of draw and location on study tubes.  The results will be 
analyzed by the PI of this protocol.  
 If study is obtained prior to 1:00, study tubes will be placed in marked transport 
container along with ice pack, wrapped in toweling, and taken to the Main Lab at 
CMH.  
o Research staff will notify CMH lab staff of delivery. 
 Staff will confirm delivery to University of Kansas Cancer Center  
between 3:30-4pm the same day.   
 CMH courier will transport samples to University of Kansas 
Cancer Center  security desk in the research building  
 University of Kansas Cancer Center security will alert cytometry 
staff to pick up samples 
 CMH Security will pick up new container and return it to the main 
lab at CMH. 
 Research Staff will pick up the container as soon as possible. 
 If study is obtained after 1:00pm, study tubes will be  refrigerated overnight. 
Tubes will be packed and taken to the lab prior to 1:00 the next day. 
27.0 Resources Available 
 
The goal accrual for this study is 22 subjects which will be 
feasible in the allotted time frame.  
 
As this research project is vital to fellowship graduation, a lot 
of time will be devoted to this research.  
 
Children’s Mercy Hospital is a free-standing children’s 
hospital with a hematology/oncology division that participates 
in many research projects.  
 
Research subjects have access to medical as well as 
psychological care within the heme/onc department. 
 
All persons assisting with the research are met with 
periodically to stay abreast of the protocol, procedures, etc.  
 
Dr. Alan Gamis and Dr. Susan Abdel-Rahman are providing 
mentorship. 
 
28.0 Multi-Site Research: NA 
29.0 International Research – N/A