Acute Myeloid Leukemia, Myelodysplastic Syndromes
Conditions
Keywords
DNA methyltransferase inhibitors, Acute myeloid leukemia
Brief summary
The overall aim of this study is to determine if epigenetic priming with a DNA methyltransferase inhibitor (DMTi) prior to chemotherapy blocks is tolerable and carries evidence of a clinical efficacy signal as determined by minimal residual disease (MRD), event-free survival (EFS), and overall survival (OS). Tolerability for each of the agents, as well as total reduction in DNA methylation and outcome assessments will be done to simultaneously obtain preliminary biological and clinical data for each DMTi in parallel. PRIMARY OBJECTIVES: * Evaluate the tolerability of five days of epigenetic priming with azacitidine and decitabine as a single agent DMTi prior to standard AML chemotherapy blocks. * Evaluate the change in genome-wide methylation burden induced by five days of epigenetic priming and the association of post-priming genome-wide methylation burden with event-free survival among pediatric AML patients. SECONDARY OBJECTIVES * Describe minimal residual disease levels following Induction I chemotherapy in patients that receive DMTi. * Estimate the event-free survival and overall survival of patients receiving a DMTi prior to chemotherapy courses.
Detailed description
To determine tolerability, priming with DMTi (azacitidine or decitabine) will be limited to Induction I and II during Part 1 of the study. If DMTi treatment is tolerated during Part 1, the investigators will go on to an Expansion Phase (Part 2) that includes DMTi priming prior to all chemotherapy blocks. Treatment will consist of 5 blocks of conventional chemotherapy: Induction I, Induction II, Intensification I, Intensification II, and Intensification III over approximately 5 months. RANDOMIZATION: Patients will be randomized to receive one of two DMTi (azacitidine or decitabine) for 5 days prior to Induction I. Intrathecal (ITHMA) treatments will be given right before treatment on this study or on Day 1 of Induction I treatment. Leucovorin will be given 24-30 hours following ITHMA. INDUCTION I CHEMOTHERAPY: Patients receive cytarabine, daunorubicin, and etoposide. INDUCTION II CHEMOTHERAPY; Patients receive their assigned DMTi for 5 days followed by fludarabine, cytarabine, G-CSF, and idarubicin. Patients are then evaluated and assigned to either the low-risk arm, intermediate-risk arm, or the high-risk arm for Intensification therapy. Patients with ≥ 5% blasts following Induction II will be considered refractory and will go off therapy. The rare high risk patient with an MRD \< 0.1% following Induction I may proceed directly to stem cell transplant (SCT) after Induction II - if a suitable donor is available and the transplant can be performed without delay. MDS patients may proceed to SCT once they have achieved MRD \<0.1% irrespective of the number of chemotherapy courses received. INTENSIFICATION I CHEMOTHERAPY - LOW-RISK AML, INTERMEDIATE-RISK AML, and HIGH-RISK AML with no donor: Patients receive cytarabine and etoposide. After administration of 5 days of a DMTi prior to Inductions I and II satisfies a tolerability determination criterion, patients will also receive their randomly assigned DMTi for five days prior to cytarabine and etoposide. INTENSIFICATION II CHEMOTHERAPY - LOW RISK AML, INTERMEDIATE-RISK AML, and HIGH-RISK AML with no donor: Patients receive mitoxantrone and cytarabine. After administration of 5 days of a DMTi prior to Inductions I and II satisfies a tolerability determination criterion, patients will also receive their randomly assigned DMTi for five days prior to mitoxantrone and cytarabine. INTENSIFICATION I CHEMOTHERAPY - HIGH-RISK AML with a donor: Patients receive mitoxantrone and cytarabine followed by stem cell transplant (SCT). Treatment related AML patients and patients with treatment related MDS who have a donor but are not able to receive a SCT without delay will proceed to HR Intensification III and receive erwinia asparaginase and cytarabine. After administration of 5 days of a DMTi prior to earlier courses satisfies a tolerability criterion, patients will also receive their randomly assigned DMTi for five days prior to mitoxantrone and cytarabine or erwinia asparaginase and cytarabine. Treatment related AML patients and treatment related MDS patients that are not able to receive a SCT should go off treatment following Intensification II. INTENSIFICATION III CHEMOTHERAPY - INTERMEDIATE-RISK AML and HIGH-RISK AML with no donor: Patients receive erwinia asparaginase and cytarabine. After administration of 5 days of a DMTi prior to earlier courses satisfies a tolerability criterion, patients will also receive their randomly assigned DMTi for five days prior to erwinia asparaginase and cytarabine.
Interventions
DRUGAzacitidine
Azacitidine solution is administered intravenously (IV) over a period of 10-40 minutes.
DRUGDecitabine
Administered intravenously (IV) over approximately one hour.
DRUGCytarabine
Given IV or intrathecally (IT).
DRUGDaunorubicin
Given IV.
DRUGEtoposide
Given IV.
COMBINATION_PRODUCTITMHA
Given IT.
DRUGIdarubicin
Given IV.
DRUGFludarabine
Given IV over approximately 30 minutes.
DRUGMitoxantrone
Given IV.
Given IV or intramuscularly (IM).
DRUGSorafenib
Given PO.
DRUGG-CSF
Given IV.
DRUGDexrazoxane
Given IV immediately before idarubicin administration.
BIOLOGICALStem Cell Transplant
The transplant protocol will depend on the patient's donor and transplant physician's preference.
DRUGAsparaginase Erwinia Chrysanthemi, Recombinant-Rywn
May be used in the event of an Erwinia asparaginase shortage. Given intramuscularly (IM).
Sponsors
St. Jude Children's Research Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
29 Days to 21 Years
Healthy volunteers
No
Inclusion criteria
* Diagnostic criteria: Patients must have one of the following diagnoses: * Acute myeloid leukemia fulfilling the criteria of the WHO Classification (see Appendix I), or * \>5% but \< 20% marrow myeloblasts and evidence of a clonal de novo AML genetic abnormality \[e.g., t(8;21), inv(16), t(9;11)\], or * Myeloid sarcoma (also referred to as extramedullary myeloid tumor, granulocytic sarcoma, or chloroma), with or without evidence of a leukemia process in the bone marrow or peripheral blood, with confirmation of myeloid differentiation, or * High grade myelodysplastic syndrome (MDS) with greater than 5% blasts, or * Patients with treatment related myeloid neoplasms including AML and MDS, provided their cumulative anthracycline dose has not exceeded 230 mg/m2 doxorubicin equivalents. * Other criteria - Patients must meet all the following criteria: * Age \> 28 days and \< 22 years at time of study entry inclusive, and * No prior therapy for this malignancy except for one dose of intrathecal therapy and the use of hydroxyurea or low-dose cytarabine (100-200 mg/m2 per day for one week or less for hyperleukocytosis), and * Written informed consent according to institutional guidelines, and * Female patients of childbearing potential must have a negative pregnancy test within 2 weeks prior to enrollment, and * Male and female participants of reproductive potential must use an effective contraceptive method during the study and for a minimum of 6 months after study treatment.
Exclusion criteria
* Down syndrome * Acute promyelocytic leukemia (APL) * BCR-ABL1 chronic myeloid leukemia in blast crisis (CML-BC) * Juvenile myelomonocytic leukemia (JMML) * Fanconi anemia (FA) * Kostmann syndrome * Shwachman syndrome * Other bone marrow failure syndromes or low grade (\<5% bone marrow blasts) MDS. * Use of concomitant chemotherapy, radiation therapy, or immunotherapy other than as specified in the protocol. * Use of investigational agents within 30 days or any anticancer therapy for this malignancy within 2 weeks before study entry with the exception of IT therapy, hydroxyurea, or low-dose cytarabine as specified in the protocol document. The patient must have recovered from all acute toxicities from any previous therapy. * Systemic fungal, bacterial, viral, or other infection not controlled (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement, despite appropriate antibiotics or other treatment). * Pregnant or lactating. * Any significant concurrent disease, illness, or psychiatric disorder that would compromise patient safety or compliance, interfere with consent, study participation, follow up, or interpretation of study results. * Prior chemotherapy, with the exception of hydroxyurea or low-dose cytarabine as specified in the protocol document. The patient must have recovered from all acute toxicities from any previous therapy. * Patients with treatment related myeloid neoplasms with cumulative anthracyclines greater than 230 mg/m2 doxorubicin equivalents.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of evaluable patients who tolerate five days of single agent DMTi before a standard chemotherapy combination | From enrollment to completion of chemotherapy (up to 8 months after start of therapy) | Patients will be monitored for grade 4-5 non-hematologic toxic events during these two courses of chemotherapy. Tolerating a course is defined as completing the course without experiencing death or a grade 4 non-hematologic toxicity. |
| Change in genome-wide methylation burden of leukemia cells from diagnosis to after five days of single agent DMTi | From diagnosis to completion of five days of single agent DMTi (up to 2 weeks after start of therapy) | Leukemic cells will be collected from patients at diagnosis and after five days of single agent DMTi. Each sample of leukemic cells will be profiled with a methylation microarray. For each leukemic sample, genome-wide methylation burden (GWMB) will be computed as the sum of methylation values across all markers. For each patient, the change in GWMB will be computed as the day 5 GWMB minus the diagnostic GWMB. |
| Cox model hazard ratio for association of event-free survival with genome-wide methylation burden | From diagnosis to the first of the following events: death, relapse, resistant disease, second malignancy, or last follow-up (up to 3 years after completion of therapy) | Patients will be monitored for the events of interest from enrollment for at least three years. EFS will be defined as the time elapsed from enrollment to the first of the following events: death, relapse, resistant disease, or second malignancy. EFS times for subjects who have not experienced these events at the time of analysis will be censored at date of last follow-up. A Cox regression model will be used to evaluate the association of EFS with genome-wide methylation burden observed after completion of five days of single agent decitabine or azacitidine as randomly assigned. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of MRD-evaluable subjects with detectable minimal residual disease after receiving five days of a single agent DMTi followed by araC+daunorubicin+etoposide. | MRD will be measured after completion of DMTi+araC+daunorubicin+etoposide (up to 6 weeks after the start of therapy) | Flow cytometry will be used to measure minimal residual disease at diagnosis and after completion of the first course of chemotherapy. |
| Kaplan-Meier estimate of event-free survival | From diagnosis to the first of the following events: death, relapse, resistant disease, second malignancy, or last follow-up (up to 3 years after completion of therapy) | Patients will be monitored for the events of interest from enrollment for at least three years. EFS will be defined as the time elapsed from enrollment to the first of the following events: death, relapse, resistant disease, or second malignancy. EFS times for subjects who have not experienced these events at the time of analysis will be censored at date of last follow-up. |
| Kaplan-Meier estimate of overall survival | From diagnosis to the first of the following events: death or last follow-up (up to 3 years after completion of therapy) | Patients will be monitored for death from enrollment for at least three years. Overall survival will be defined as the time elapsed from enrollment to death. OS times for subjects who are living at the time of analysis will be censored at date of last follow-up. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORRaul C. Ribiero, MD
St. Jude Children's Research Hospital
Outcome results
None listed