Clinical trial NCT03263936: Epigenetic Reprogramming in Relapse/Refractory AML
Official 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Acute Myelogenous Leukemia
Keywords: Relapse
Myelogenous
Leukemia
Refractory
Acute
Pediatric
Lead sponsor: Therapeutic Advances in Childhood Leukemia Consortium
Sponsor class: OTHER
First posted: 2017-08-28
Enrollment: 37
Sex: ALL
Minimum age (years): 1
Maximum age (years): 25
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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

Detailed description: 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.

Eligibility criteria: 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.

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

Primary outcomes:
measure: The dose of decitabine that can be safely given with vorinostat, fludarabine, high dose cytarabine and G-CSF (FLAG)
timeFrame: during course 1, approx 5 weeks
Secondary outcomes:
measure: To examine peripheral blood mononuclear cells for immunophenotypic changes.
timeFrame: approx 8 weeks
measure: To analyze plasma for cytokine content.
timeFrame: approx 8 weeks
measure: To analyze the correlation between biological changes and clinical response.
timeFrame: approx 8 weeks
measure: To establish the extent of hypomethylation of peripheral blood (PB) and bone marrow (BM) pre- and post- decitabine and vorinostat treatment:
timeFrame: approx 8 weeks
measure: To analyze the correlation between DNA methylation and gene expression pre- and post-treatment with decitabine and vorinostat.
timeFrame: approx 8 weeks
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Children's Hospital Los Angeles
state: California
city: Orange
country: United States
facility: Children's Hospital Orange County
state: California
city: San Francisco
country: United States
facility: UCSF School of Medicine
state: California
city: Aurora
country: United States
facility: The Children's Hospital, University of Colorado
state: Colorado
city: Washington
country: United States
facility: Children's National Medical Center
state: District of Columbia
city: Miami
country: United States
facility: University of Miami
state: Florida
city: Saint Petersburg
country: United States
facility: All Children's Hospital
state: Florida
city: Atlanta
country: United States
facility: Children's Healthcare of Atlanta, Emory University
state: Georgia
city: Chicago
country: United States
facility: Lurie Children's Hospital of Chicago
state: Illinois
city: Baltimore
country: United States
facility: Johns Hopkins University
state: Maryland
city: Baltimore
country: United States
facility: Sidney Kimmel Cancer Center at Johns Hopkins
state: Maryland
city: Bethesda
country: United States
facility: National Cancer Institute, Pediatric Oncology Branch
state: Maryland
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
city: Ann Arbor
country: United States
facility: C.S. Mott Children's Hospital
state: Michigan
city: Ann Arbor
country: United States
facility: CS Mott Children's Hospital, Ann Arbor
state: Michigan
city: Minneapolis
country: United States
facility: Children's Hospitals and Clinics of Minnesota
state: Minnesota
city: New York
country: United States
facility: New York University Medical Center
state: New York
city: New York
country: United States
facility: Children's Hospital New York-Presbyterian
state: New York
city: Charlotte
country: United States
facility: Levine Children's Hospital
state: North Carolina
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital
state: Ohio
city: Columbus
country: United States
facility: Nationwide Children's Hospital
state: Ohio
city: Portland
country: United States
facility: Oregon Health and Science University
state: Oregon
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Fort Worth
country: United States
facility: Cook Children's Medical Center
state: Texas
city: Houston
country: United States
facility: Texas Children's Cancer Center, Baylor
state: Texas
city: Salt Lake City
country: United States
facility: Primary Children's Hospital
state: Utah
city: Seattle
country: United States
facility: Seattle Children's Hospital
state: Washington
city: Milwaukee
country: United States
facility: Medical College of Wisconsin
state: Wisconsin
city: Randwick
country: Australia
facility: Sydney Children's Hospital
state: New South Wales
city: Westmead
country: Australia
facility: Children's Hospital at Westmead
city: Vancouver
country: Canada
facility: British Columbia Children's Hospital
state: British Columbia
city: Toronto
country: Canada
facility: Hospital for Sick Children
state: Ontario
city: Montreal
country: Canada
facility: Sainte Justine University Hospital
state: Quebec
Study officials:
References: