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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/ct2/show/NCT01861002




Registration number
NCT01861002
Ethics application status
Date submitted
21/05/2013
Date registered
23/05/2013
Date last updated
9/06/2021

Titles & IDs
Public title
A Phase I Study of 5-Azacytidine in Combination With Chemotherapy for Children With Relapsed or Refractory ALL or AML
Scientific title
A Phase I Study of 5-Azacytidine in Combination With Chemotherapy for Children With Relapsed or Refractory ALL or AML
Secondary ID [1] 0 0
T2011-002
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Lymphoblastic Leukemia, Acute, Childhood 0 0
Myelogenous Leukemia, Acute, Childhood 0 0
Condition category
Condition code
Cancer 0 0 0 0
Leukaemia - Acute leukaemia
Cancer 0 0 0 0
Leukaemia - Chronic leukaemia
Cancer 0 0 0 0
Children's - Leukaemia & Lymphoma
Cancer 0 0 0 0
Lymphoma (non Hodgkin's lymphoma) - High grade lymphoma
Cancer 0 0 0 0
Lymphoma (non Hodgkin's lymphoma) - Low grade lymphoma
Other 0 0 0 0
Research that is not of generic health relevance and not applicable to specific health categories listed above

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Azacytidine
Treatment: Drugs - Fludarabine
Treatment: Drugs - Cytarabine
Treatment: Drugs - Intrathecal (IT) Cytarabine
Treatment: Drugs - Intrathecal Methotrexate (IT MTX)

Experimental: AML Arm - Participants with Acute Myeloid Leukemia (AML)
Intervention:
Azacytidine (Dose Level 1 @ 75 mg/m2/day)
Fludarabine 30 mg/m2/dose
Cytarabine 2000 mg/m2/dose
Intrathecal (IT) Cytarabine

Experimental: ALL Arm - Patients with Acute Lymphocytic Leukemia
Intervention:
Azacytidine (Dose Level 1 @ 75 mg/m2/day)
Fludarabine 30 mg/m2/dose
Cytarabine 2000 mg/m2/dose
Intrathecal Methotrexate (IT MTX)


Treatment: Drugs: Azacytidine
Dose assigned at study entry (75 mg/m2/day). Given subcutaneously, once daily on days 1 to 5, for a total of 5 doses.

Treatment: Drugs: Fludarabine
30 mg/m2/dose, intravenous infusion over 30 minutes, once daily, on days 6 to 10, total 5 doses

Treatment: Drugs: Cytarabine
2000 mg/m2/dose intravenous infusion over 3 hours, starting 4 hours after the beginning of fludarabine, once daily, on days 6 to 10, total 5 doses.

Treatment: Drugs: Intrathecal (IT) Cytarabine
Intrathecally to AML patients on day 1 of course 1 and 2.
Omit on day 1 of course 1 if patient received IT therapy within 7 days prior to study enrollment
IT therapy may be given during the end of course 1 disease evaluation and repeated every 7 days
For patients with CNS disease, IT cytarabine can be given weekly until the CSF is clear. Two additional doses of IT cytarabine should be given weekly after the initial CSF clearing. It is permitted to change to intrathecal triple therapy (ITT) if persistent blasts are present in the CSF based on the treating physician's clinical judgment. Cytarabine dose defined by age:
30 mg for patients age 1-1.99
50 mg for patients age 2-2.99
70 mg for patients >3 years of age
ITT Dosing:
Age (yrs) - Dose Methotrexate (MTX), Hydrocortisone (HC), Cytarabine (ARAC):
- 1.99 MTX: 8 mg, HC: 15 mg, ARAC: 30 mg
- 2.99 MTX: 10 mg, HC: 25 mg, ARAC: 50 mg
3 - MTX: 12 mg, HC: 35 mg, ARAC: 70 mg

Treatment: Drugs: Intrathecal Methotrexate (IT MTX)
Intrathecally to patients with ALL on day 1 of course 1 and 2.
Omit IT MTX on Day 1 of course 1 if patient received IT therapy within 7 days prior to study enrollment
IT therapy may be given during the end of course 1 disease evaluation and repeated every 7 days
For patients with CNS 2 or 3 disease, IT MTX can be given weekly until the CSF is clear. Two additional doses of IT MTX should be given weekly after the initial clearing of the CSF. It is permitted to change to ITT if persistent blasts are present in the CSF. Methotrexate dose defined by age
8 mg for patients age 1-1.99
10 mg for patients age 2-2.99
12 mg for patients 3-8.99 years of age
15 mg for patients >9 years of age
Triple IT Therapy Dosing:
Age (yrs): Dose Methotrexate (MTX), Hydrocortisone (HC), Cytarabine (ARAC):
- 1.99 MTX: 8 mg, HC: 8 mg, ARAC: 16 mg
- 2.99 MTX: 10 mg, HC: 10 mg, ARAC: 20 mg
- 8.99 MTX: 12 mg, HC: 12 mg, ARAC: 24 mg
9 MTX: 15 mg, HC: 15 mg, ARAC: 30 mg
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Number of Participants Who Experienced a Dose Limiting Toxicity (DLT)
Timepoint [1] 0 0
From Day 1 to Day 42 (Cycle 1)
Secondary outcome [1] 0 0
Disease Response Rate After Treatment
Timepoint [1] 0 0
Between Days 36-42 of Courses 1 and 2

Eligibility
Key inclusion criteria
Patients must be = 1 and = 21 years of age.

Diagnosis

1. Patients with AML must have =5% blasts (by morphology) in the bone marrow.

2. Patients with ALL must have an M2 or M3 marrow (=5% blasts by morphology).

3. Patients may have disease in the central nervous system (CNS) or other sites of
extramedullary disease. No cranial irradiation is allowed during the protocol therapy.

4. Patients with secondary AML are eligible.

5. Patients with Down syndrome and DNA fragility syndromes (such as Fanconi anemia, Bloom
syndrome) are excluded.

Karnofsky > 50% for patients > 16 years of age and Lansky > 50% for patients = 16 years of
age.

Patients must have fully recovered from the acute toxic effects of all prior chemotherapy,
immunotherapy, or radiotherapy prior to entering this study.

Myelosuppressive chemotherapy - the eligibility criteria is different between phase I and
expansion phase

1. Phase I

- Any patient with AML in 1st or greater relapse, OR

- Any patient with ALL in 2nd or greater relapse, OR

- Patients with AML or ALL failed to go into remission after first or greater
relapse, OR

- Patients with AML or ALL failed to go into remission from original diagnosis
after two or more courses of induction attempts.

2. Expansion phase - will be restricted to AML patients only

3. Cytoreduction with hydroxyurea can be initiated and continued for up to 24 hours prior
to the start of azacytidine. It is recommended to use hydroxyurea in patients with
significant leukocytosis (WBC > 50,000/L) to control blast count before initiation of
systemic protocol therapy.

4. Patients who relapsed while they are receiving cytotoxic therapy (including AZA ,
decitabine, or vorinostat) At least 14 days must have elapsed since the completion of
the cytotoxic therapy.

Hematopoietic stem cell transplant: Patients who have experienced their relapse after a
stem cell transplant are eligible, provided they have no evidence of acute or chronic
Graft-versus-Host Disease (GVHD) and are at least 90 days post-transplant at the time of
enrollment.

Hematopoietic growth factors: It must have been at least 7 days since the completion of
therapy with filgrastim or other growth factors at the time of enrollment. It must have
been at least 14 days since the completion of therapy with pegfilgrastim (Neulasta®).

Biologic (anti-neoplastic agent): At least 7 days after the last dose of a biologic agent.
For agents that have known adverse events occurring beyond 7 days after administration,
this period must be extended beyond the time during which adverse events are known to
occur. The duration of this interval must be discussed with the study chair

Monoclonal antibodies: At least 3 half-lives of the antibody must have elapsed after the
last dose of monoclonal antibody. (i.e. Gemtuzumab = 36 days)

Immunotherapy: At least 42 days after the completion of any type of immunotherapy, e.g.
tumor vaccines.

Radiation Therapy (XRT): Craniospinal XRT is prohibited during protocol therapy. No washout
period is necessary for radiation given to non-CNS chloromas; = 90 days must have elapsed
if prior total body radiation or craniospinal radiation.

Renal and hepatic function

Patients must have adequate renal and hepatic functions as indicated by the following
laboratory values:

- Patient must have a calculated creatinine clearance or radioisotope glomerular
filtration rate (GFR) greater than or equal to 70ml/min/1.73m2 OR a normal serum
creatinine based on age/gender.

- Direct bilirubin < 1.5 x upper limit of normal (ULN) for age or normal, AND alanine
transaminase (ALT) < 5 x ULN for age.

Adequate Cardiac Function Defined as: Shortening fraction greater than or equal to 27% by
echocardiogram, OR ejection fraction greater than or equal to 50% by radionuclide angiogram
(MUGA).

Reproductive Function

- Female patients of childbearing potential must have a negative urine or serum
pregnancy test confirmed within 2 weeks prior to enrollment.

- Female patients with infants must agree not to breastfeed their infants while on this
study.

- Male and female patients of child-bearing potential must agree to use an effective
method of contraception approved by the investigator during the study and for a
minimum of 6 months after study treatment.

Patients and/or their parents or legal guardians must be capable of understanding the
investigational nature, potential risks and benefits of the study. All patients and/or
their parents or legal guardians must sign a written informed consent.
Minimum age
1 Year
Maximum age
21 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Patients will be excluded if they have a known allergy to any of the drugs used in the
study.

Patients will be excluded if they have a systemic fungal, bacterial, viral or other
infection that is exhibiting ongoing signs/symptoms related to the infection without
improvement despite appropriate antibiotics or other treatment. The patient needs to be off
pressors and have negative blood cultures for 48 hours.

Patients will be excluded if there is a plan to administer non-protocol chemotherapy,
radiation therapy, or immunotherapy during the study period.

Patients will be excluded if they have significant concurrent disease, illness, psychiatric
disorder or social issue that would compromise patient safety or compliance with the
protocol treatment or procedures, interfere with consent, study participation, follow up,
or interpretation of study results.

Patients with Down syndrome and DNA fragility syndromes (such as Fanconi anemia, Bloom
syndrome) are excluded.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 1
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
22/05/2013
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
28/07/2014
Sample size
Target
Accrual to date
Final
15
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 0 0
Sydney Children's Hospital - Randwick
Recruitment hospital [2] 0 0
Children's Hospital at Westmead - Westmead
Recruitment postcode(s) [1] 0 0
2031 - Randwick
Recruitment postcode(s) [2] 0 0
2145 - Westmead
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
California
Country [2] 0 0
United States of America
State/province [2] 0 0
District of Columbia
Country [3] 0 0
United States of America
State/province [3] 0 0
Georgia
Country [4] 0 0
United States of America
State/province [4] 0 0
Maryland
Country [5] 0 0
United States of America
State/province [5] 0 0
Massachusetts
Country [6] 0 0
United States of America
State/province [6] 0 0
Michigan
Country [7] 0 0
United States of America
State/province [7] 0 0
Minnesota
Country [8] 0 0
United States of America
State/province [8] 0 0
Missouri
Country [9] 0 0
United States of America
State/province [9] 0 0
New York
Country [10] 0 0
United States of America
State/province [10] 0 0
North Carolina
Country [11] 0 0
United States of America
State/province [11] 0 0
Ohio
Country [12] 0 0
United States of America
State/province [12] 0 0
Tennessee
Country [13] 0 0
United States of America
State/province [13] 0 0
Texas
Country [14] 0 0
United States of America
State/province [14] 0 0
Utah
Country [15] 0 0
United States of America
State/province [15] 0 0
Washington
Country [16] 0 0
United States of America
State/province [16] 0 0
Wisconsin
Country [17] 0 0
Canada
State/province [17] 0 0
British Columbia
Country [18] 0 0
Canada
State/province [18] 0 0
Quebec

Funding & Sponsors
Primary sponsor type
Other
Name
Therapeutic Advances in Childhood Leukemia Consortium
Address
Country
Other collaborator category [1] 0 0
Other
Name [1] 0 0
Gateway for Cancer Research
Address [1] 0 0
Country [1] 0 0

Ethics approval
Ethics application status

Summary
Brief summary
This is a Phase I study with a conditional cohort expansion phase to evaluate the feasibility
of, and to obtain preliminary efficacy data about, pretreatment with Azacytidine (AZA) for 5
days followed by fludarabine/cytarabine chemotherapy regimen in pediatric acute myeloid
leukemia (AML) and acute lymphoblastic leukemia (ALL) patients who are refractory to primary
treatment or who relapsed.
Trial website
https://clinicaltrials.gov/ct2/show/NCT01861002
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Weili Sun, MD, PhD
Address 0 0
Children's Hospital Los Angeles
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries