Epigenetic Reprogramming in Relapse/Refractory AML

Acute Myelogenous Leukemia Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03263936
• Other study ID #: T2016-003
• Status: Completed
• Phase: Phase 1
• Start date: July 11, 2017
• Est. completion date: February 10, 2022

Study information

• Verified date: September 2021
• Source: Therapeutic Advances in Childhood Leukemia Consortium
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 37
• Est. completion date: February 10, 2022
• Est. primary completion date: July 9, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 1 Year to 25 Years

Eligibility

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

Related Conditions & MeSH terms

• Acute Myelogenous Leukemia
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute
• Recurrence

Intervention

Drug:
• 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
• Vorinostat
Age <18: 180 mg/m2/day once daily PO. Age=18: 200 mg twice daily PO.
• Filgrastim (G-CSF)
Given on days 5 until evidence of ANC recovery (>500/µL)5µg/kg/dose IV or SQ (starting at hour 0)
• Fludarabine
30 mg/m2/day IV over 30 minutes (starting at Hour 0 - Immediately after G-CSF)
• Cytarabine
2000 mg/m2/day (Starting at Hour 0.5),IV over 3 hours, days 6-10

Locations

Country	Name	City	State
Australia	Sydney Children's Hospital	Randwick	New South Wales
Australia	Children's Hospital at Westmead	Westmead
Canada	Sainte Justine University Hospital	Montreal	Quebec
Canada	Hospital for Sick Children	Toronto	Ontario
Canada	British Columbia Children's Hospital	Vancouver	British Columbia
United States	C.S. Mott Children's Hospital	Ann Arbor	Michigan
United States	CS Mott Children's Hospital, Ann Arbor	Ann Arbor	Michigan
United States	Children's Healthcare of Atlanta, Emory University	Atlanta	Georgia
United States	The Children's Hospital, University of Colorado	Aurora	Colorado
United States	Johns Hopkins University	Baltimore	Maryland
United States	Sidney Kimmel Cancer Center at Johns Hopkins	Baltimore	Maryland
United States	National Cancer Institute, Pediatric Oncology Branch	Bethesda	Maryland
United States	Dana-Farber Cancer Institute	Boston	Massachusetts
United States	Levine Children's Hospital	Charlotte	North Carolina
United States	Lurie Children's Hospital of Chicago	Chicago	Illinois
United States	Cincinnati Children's Hospital	Cincinnati	Ohio
United States	Nationwide Children's Hospital	Columbus	Ohio
United States	Cook Children's Medical Center	Fort Worth	Texas
United States	Texas Children's Cancer Center, Baylor	Houston	Texas
United States	Children's Hospital Los Angeles	Los Angeles	California
United States	University of Miami	Miami	Florida
United States	Medical College of Wisconsin	Milwaukee	Wisconsin
United States	Children's Hospitals and Clinics of Minnesota	Minneapolis	Minnesota
United States	Children's Hospital New York-Presbyterian	New York	New York
United States	New York University Medical Center	New York	New York
United States	Children's Hospital Orange County	Orange	California
United States	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania
United States	Oregon Health and Science University	Portland	Oregon
United States	All Children's Hospital	Saint Petersburg	Florida
United States	Primary Children's Hospital	Salt Lake City	Utah
United States	UCSF School of Medicine	San Francisco	California
United States	Seattle Children's Hospital	Seattle	Washington
United States	Children's National Medical Center	Washington	District of Columbia

Sponsors (1)

Lead Sponsor	Collaborator
Therapeutic Advances in Childhood Leukemia Consortium

Countries where clinical trial is conducted

United States,  Australia,  Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	The dose of decitabine that can be safely given with vorinostat, fludarabine, high dose cytarabine and G-CSF (FLAG)	The incidence of dose limiting toxicity (DLT) will be measured. The maximum tolerated dose will be the highest study dose at which 1 or fewer of six patients experience DLT during cycle 1 of therapy	during course 1, approx 5 weeks
Secondary	To examine peripheral blood mononuclear cells for immunophenotypic changes.	To examine peripheral blood mononuclear cells for immunophenotypic changes using peripheral blood samples	approx 8 weeks
Secondary	To analyze plasma for cytokine content.	To analyze plasma for cytokine content using plasma samples.	approx 8 weeks
Secondary	To analyze the correlation between biological changes and clinical response.	To analyze the correlation between biological changes and clinical response using standard statistical methods	approx 8 weeks
Secondary	To establish the extent of hypomethylation of peripheral blood (PB) and bone marrow (BM) pre- and post- decitabine and vorinostat treatment:	Reduced representation bisulfite sequencing (RRBS) will be used to analyze the genome-wide methylation profiles on a single nucleotide level; To quantitatively assess global changes in DNA methylation, a LINE-methylation assay will be utilized and specific genes monitored through advanced Infinium MethylationEPIC BeadChip from Illumina. Chromatin immunoprecipitation (ChIP) with antibodies specific for histone modifications associated with transcriptional activation (H3K4me3 and H3K27ac) and repression (H3K9me3 and H3K27me3) and isotype controls, followed by DNA sequencing (ChIP-seq); RNA sequencing analysis will be used to measure global transcriptome changes. Profiles of CD33+ umbilical cord blood cells, whole bone marrow, or Peripheral Blood Stem Cells (PBSCs) will be used as normal controls for each sample.	approx 8 weeks
Secondary	To analyze the correlation between DNA methylation and gene expression pre- and post-treatment with decitabine and vorinostat.	Assessment of the in vivo effects of combined DNMTi/HDACi on the functional epigenetic profile by comparing the following in paired pre- (Day 0) and post-exposure (Day 5, Day 14 and Day 35) leukemic blasts: Reversal of DNA promoter hypermethylation of "repressed" genes of interest using RRBS, validated with Pyrosequencing-based methylation assay; Increase in H3K9/14 acetylation in association with "repressed" genes of interest using H3K9/14 ChIP-seq, validated with ChIP-qPCR; Reversal of transcriptional silencing of "repressed" genes of interest using RNA seq, validated by qRT-PCR. Since significant acute cell kill is unlikely during the 5-day "window" of DNMTi/HDACi, we will have a unique opportunity to assess the in vivo effects of epigenetic therapy with the Day 5 sample. The Day 14 peripheral blood and Day 35 marrow samples will also contribute in patients whose leukemic blasts persist at these time points.	approx 8 weeks