Epigenetic Reprogramming in Relapse/Refractory AML



Status:Recruiting
Conditions:Blood Cancer, Hematology
Therapuetic Areas:Hematology, Oncology
Healthy:No
Age Range:1 - 25
Updated:6/20/2018
Start Date:July 11, 2017
End Date:July 2020
Contact:Ellynore A Florendo
Email:eflorendo@chla.usc.edu
Phone:323-361-3022

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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

This is a pilot study using decitabine and vorinostat before and during chemotherapy with
fludarabine, cytarabine and G-CSF (FLAG).

Decitabine is a demethylating agent and vorinostat is a HDAC inhibitor. The use of
demethylating agents and HDAC inhibitors in combination have been previously shown to have
synergistic effects in altering neoplastic pathways of cancer cells and be well tolerated in
human clinical studies. With the ability of decitabine and vorinostat to alter the abnormal
cellular pathways of leukemic blasts and essentially turn off anti-apoptotic proteins, the
leukemia cells have become primed for cytotoxic cell kill via chemotherapeutic agents. This
study will ask the question as to whether or not the combination of decitabine and vorinostat
followed by chemotherapy is feasible and whether it can positively impact outcome in patients
with relapsed or refractory acute myelogenous leukemia.

Inclusion Criteria:

- Patients must be ≥ 1 and ≤25 years of age.

Diagnosis:

- Patients with AML must have ≥ 5% blasts (by morphology) in the bone marrow

- 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 and 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. Phase 1

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

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

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

2. 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.

3. 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).

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 2 weeks 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.

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 Down syndrome are excluded.

- 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
We found this trial at
28
sites
Saint Petersburg, Florida 33701
Principal Investigator: Gregory Hale, MD
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Ann Arbor, MI 48109Bus: -
Ann Arbor, Michigan 48109
Principal Investigator: Raymond Hutchinson, MD
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3400 N Charles St
Baltimore, Maryland 21205
410-516-8000
Principal Investigator: Pat Brown, MD
Johns Hopkins University The Johns Hopkins University opened in 1876, with the inauguration of its...
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700 Childrens Drive
Columbus, Ohio 43205
(616) 722-2000
Principal Investigator: Robyn Dennis, MD
Nationwide Children's Hospital At Nationwide Children’s, we are creating the future of pediatric health care....
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4650 Sunset Blvd
Los Angeles, California 90027
 (323) 660-2450
Principal Investigator: Deepa Bhojwani, MD
Childrens Hospital Los Angeles Children's Hospital Los Angeles is a 501(c)(3) nonprofit hospital for pediatric...
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Miami, Florida 33124
(305) 284-2211
Principal Investigator: Julio Barredo, MD
University of Miami A private research university with more than 15,000 students from around the...
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1201 W La Veta Ave
Orange, California 92868
(714) 997-3000
Principal Investigator: Van Thu Huynh, MD
Children's Hospital of Orange County For more than 45 years, CHOC Children’s has been steadfastly...
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South 34th Street
Philadelphia, Pennsylvania 19104
 215-590-1000
Principal Investigator: Susan Rheingold, MD
Children's Hospital of Philadelphia Since its start in 1855 as the nation's first hospital devoted...
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1540 East Hospital Drive
Ann Arbor, Michigan 48109
Principal Investigator: Raymond J Hutchinson, MD
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Atlanta, Georgia 30322
Principal Investigator: Todd Cooper, MD
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Aurora, Colorado 80045
Principal Investigator: Lia Gore, MD
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Baltimore, Maryland 21231
Principal Investigator: Patrick Brown, MD
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Bethesda, Maryland 20892
Principal Investigator: Nirali Shah, MD
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450 Brookline Ave
Boston, Massachusetts 2215
617-632-3000
Principal Investigator: Lewis Silverman, MD
Dana-Farber Cancer Institute Since it’s founding in 1947, Dana-Farber has been committed to providing adults...
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Charlotte, North Carolina 28204
Principal Investigator: Joel Kaplan, DO
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Chicago, Illinois 60614
Principal Investigator: Nobuko Hijiya, MD
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Cincinnati, Ohio 45229
Principal Investigator: Maureen O'Brien, MD
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801 7th Avenue
Fort Worth, Texas 76104
(682) 885-4000
Principal Investigator: Kenneth Heym, MD
Cook Children's Medical Center Cook Children's Health Care System is a not-for-profit, nationally recognized pediatric...
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Houston, Texas 77030
Principal Investigator: Eric S Schafer, MD, MHS
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8701 W Watertown Plank Rd
Milwaukee, Wisconsin
(414) 955-8296
Principal Investigator: Mike Burke, MD
Medical College of Wisconsin The Medical College (MCW) of Wisconsin is a major national research...
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Minneapolis, Minnesota 55404
Principal Investigator: Yoav Messinger, MD
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New York, New York 10021
Principal Investigator: Elizabeth Raetz, MD
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New York, New York 10032
Principal Investigator: Maria Luisa Sulis, MD
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Randwick, New South Wales 2031
Principal Investigator: David Ziegler, MD
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Salt Lake City, Utah 84143
Principal Investigator: Elizabeth Raetz, MD
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San Francisco, California 94143
Principal Investigator: Michelle Hermiston, MD
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4800 Sand Point Way NE
Seattle, Washington 98105
(206) 987-2000
Principal Investigator: Todd Cooper, MD
Seattle Children's Hospital Seattle Children’s Hospital specializes in meeting the unique physical, emotional and developmental...
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111 Michigan Ave NW
Washington, District of Columbia
(202) 476-5000
Principal Investigator: Reuven Schore, MD
Childrens National Medical Center As the nation’s children’s hospital, the mission of Children’s National Medical...
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