Epigenetic Reprogramming in Relapse / Refractory AML

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

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.
• 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.
• 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 ®)

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

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.

Trial Phase Phase I

Trial Type Treatment

Lead Organization
Therapeutic Advances in Childhood Leukemia Consortium

• Primary ID T2016-003
• Secondary IDs NCI-2017-02224
• Clinicaltrials.gov ID NCT03263936