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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/NCT03263936




Registration number
NCT03263936
Ethics application status
Date submitted
21/08/2017
Date registered
28/08/2017
Date last updated
24/06/2022

Titles & IDs
Public title
Epigenetic Reprogramming in Relapse/Refractory AML
Scientific title
Epigenetic Reprogramming in Relapse AML: A Phase 1 Study of Decitabine and Vorinostat Followed by Fludarabine, Cytarabine and G-CSF (FLAG) in Children and Young Adults With Relapsed/Refractory AML
Secondary ID [1] 0 0
T2016-003
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Acute Myelogenous Leukemia 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
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 - Decitabine
Treatment: Drugs - Vorinostat
Treatment: Drugs - Filgrastim (G-CSF)
Treatment: Drugs - Fludarabine
Treatment: Drugs - Cytarabine

Other: Other - decitabine, vorinostat, fludarabine, high dose cytarabine, filgrastim (G-CSF)


Treatment: Drugs: Decitabine
Dose Level #0: 5 mg/m2 Dose Level #1: 7.5 mg/m2 Dose Level #2: 10 mg/m2 Dose Level #3: 15 mg/m2 Dose Level #4: 20 mg/m2 given IV over __ hour on days 1 through 5

Treatment: Drugs: Vorinostat
Age <18: 180 mg/m2/day once daily PO. Age=18: 200 mg twice daily PO.

Treatment: Drugs: Filgrastim (G-CSF)
Given on days 5 until evidence of ANC recovery (>500/µL)5µg/kg/dose IV or SQ (starting at hour 0)

Treatment: Drugs: Fludarabine
30 mg/m2/day IV over 30 minutes (starting at Hour 0 - Immediately after G-CSF)

Treatment: Drugs: Cytarabine
2000 mg/m2/day (Starting at Hour 0.5),IV over 3 hours, days 6-10
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
The dose of decitabine that can be safely given with vorinostat, fludarabine, high dose cytarabine and G-CSF (FLAG)
Timepoint [1] 0 0
during course 1, approx 5 weeks
Secondary outcome [1] 0 0
To examine peripheral blood mononuclear cells for immunophenotypic changes.
Timepoint [1] 0 0
approx 8 weeks
Secondary outcome [2] 0 0
To analyze plasma for cytokine content.
Timepoint [2] 0 0
approx 8 weeks
Secondary outcome [3] 0 0
To analyze the correlation between biological changes and clinical response.
Timepoint [3] 0 0
approx 8 weeks
Secondary outcome [4] 0 0
To establish the extent of hypomethylation of peripheral blood (PB) and bone marrow (BM) pre- and post- decitabine and vorinostat treatment:
Timepoint [4] 0 0
approx 8 weeks
Secondary outcome [5] 0 0
To analyze the correlation between DNA methylation and gene expression pre- and post-treatment with decitabine and vorinostat.
Timepoint [5] 0 0
approx 8 weeks

Eligibility
Key inclusion criteria
- Patients must be = 1 and =25 years of age.

Diagnosis: Patients with relapse or refractory AML must have measurable disease ( >M1
marrow)

- 1st or greater relapse, OR

- Failed to go into remission after 1st or greater relapse, OR

- Failed to go into remission from original diagnosis after 2 or more induction attempts

Eligibility for patients with an M1 marrow; defined as >0.1% by flow or molecular testing
(e.g. PCR).

- must include two serial marrows (at least 1-week apart) demonstrating stable or rising
minimal residual disease (MRD) (i.e. not declining).

- Patients may have CNS or other sites of extramedullary disease. No cranial irradiation
is allowed during the protocol therapy.

- Patients with secondary AML are eligible.

- Patients with Down syndrome are eligible.

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

Performance Level:

- Karnofsky >50% for patients >16 years of age and Lansky > 50% for patients = 16 years of
age (See Appendix II for Performance Scales)

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

1. Cytoreduction with hydroxyurea: hydroxyurea can be initiated and continued for up to
24 hours prior to the start of decitabine/vorinostat. 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.

2. Patients who relapsed while they are receiving cytotoxic therapy: at least 14 days
must have elapsed since the completion of the cytotoxic therapy, except Intrathecal
chemotherapy.

Hematopoietic stem cell transplant (HSCT):

- Patients who have experienced their relapse after a HSCT are eligible, provided they have
no evidence of acute or chronic Graft-versus-Host Disease (GVHD) and are off all transplant
immune suppression therapy for at least 7-days (e.g. steroids, cyclosporine, tacrolimus).
Steroid therapy for non-GVHD and/or non-leukemia therapy is acceptable.

Hematopoietic growth factors:

- It must have been at least 7 days since the completion of therapy with GCSF 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 time of immunotherapy, e.g.
tumor vaccines or CAR T-cell therapy.

XRT: Cranio or 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
TBI, cranio or craniospinal XRT.

Prior Demethylating and/or HDAC Inhibitor Therapy: Patients who have received prior DNMTi
(e.g. decitabine) and/or HDACi (e.g. vorinostat) therapy are eligible to participate in
this Phase 1 study. At least 7 days must have passed from prior DNMTi or HDACi as a washout
period.

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

A. Adequate renal function defined as: Patient must have a calculated creatinine clearance
or radioisotope GFR = 70ml/min/1.73m2 OR a normal serum creatinine based on age/gender.

B. Adequate Liver Function Defined as: Direct bilirubin < 1.5 x upper limit of normal (ULN)
for age or normal, AND alanine transaminase (ALT) < 5 x ULN for age. The hepatic
requirements are waived for patients with known or suspected liver involvement by leukemia.
This must be reviewed by and approved by the study chair or vice chair.

Adequate Cardiac Function Defined as: Shortening fraction of = 27% by echocardiogram, OR
ejection fraction of = 50% by radionuclide angiogram (MUGA).

Reproductive Function A. Female patients of childbearing potential must have a negative
urine or serum pregnancy test confirmed within 1 week prior to enrollment.

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

C. 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.
Minimum age
1 Year
Maximum age
25 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
- No NG or G-Tube administration of Vorinostat is allowed. Capsule must be swallowed
whole or given as oral suspension.

- They are currently receiving other investigational drugs.

- There is a plan to administer non-protocol chemotherapy, radiation therapy, or
immunotherapy during the study period.

- They have significant concurrent disease, illness, psychiatric disorder or social
issue that would compromise patient safety or compliance, interfere with consent,
study participation, follow up, or interpretation of study results.

- They have a known allergy to any of the drugs used in the study.

- Patients with DNA fragility syndromes are excluded (e.g. Fanconi Anemia, Bloom
Syndrome)

- They are receiving valproic acid (VPA) therapy.

- Patients with Acute Promyelocytic Leukemia (APL, APML) are excluded

- Patients with documented active and uncontrolled infection at the time of study entry
are not eligible

Study design
Purpose of the study
Treatment
Allocation to intervention
N/A
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
11/07/2017
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
10/02/2022
Sample size
Target
Accrual to date
Final
37
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
- 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
Colorado
Country [3] 0 0
United States of America
State/province [3] 0 0
District of Columbia
Country [4] 0 0
United States of America
State/province [4] 0 0
Florida
Country [5] 0 0
United States of America
State/province [5] 0 0
Georgia
Country [6] 0 0
United States of America
State/province [6] 0 0
Illinois
Country [7] 0 0
United States of America
State/province [7] 0 0
Maryland
Country [8] 0 0
United States of America
State/province [8] 0 0
Massachusetts
Country [9] 0 0
United States of America
State/province [9] 0 0
Michigan
Country [10] 0 0
United States of America
State/province [10] 0 0
Minnesota
Country [11] 0 0
United States of America
State/province [11] 0 0
New York
Country [12] 0 0
United States of America
State/province [12] 0 0
North Carolina
Country [13] 0 0
United States of America
State/province [13] 0 0
Ohio
Country [14] 0 0
United States of America
State/province [14] 0 0
Oregon
Country [15] 0 0
United States of America
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Pennsylvania
Country [16] 0 0
United States of America
State/province [16] 0 0
Texas
Country [17] 0 0
United States of America
State/province [17] 0 0
Utah
Country [18] 0 0
United States of America
State/province [18] 0 0
Washington
Country [19] 0 0
United States of America
State/province [19] 0 0
Wisconsin
Country [20] 0 0
Canada
State/province [20] 0 0
British Columbia
Country [21] 0 0
Canada
State/province [21] 0 0
Ontario
Country [22] 0 0
Canada
State/province [22] 0 0
Quebec

Funding & Sponsors
Primary sponsor type
Other
Name
Therapeutic Advances in Childhood Leukemia Consortium
Address
Country

Ethics approval
Ethics application status

Summary
Brief summary
This is a pilot study using decitabine and vorinostat before and during chemotherapy with
fludarabine, cytarabine and G-CSF (FLAG).
Trial website
https://clinicaltrials.gov/ct2/show/NCT03263936
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Address 0 0
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



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/ct2/show/NCT03263936