A Trial of Epigenetic Priming in Patients With Newly Diagnosed Acute Myeloid Leukemia
Acute Myeloid Leukemia, Myelodysplastic Syndromes
About this trial
This is an interventional treatment trial for Acute Myeloid Leukemia focused on measuring DNA methyltransferase inhibitors, Acute myeloid leukemia
Eligibility Criteria
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.
Sites / Locations
- Children's Hospital of Central California
- Children's Hospital of Orange County
- Lucile Packard Children's Hospital Stanford University
- Rady Children's Hospital and Health Center
- University of Chicago Children's Hospital (Comer)
- Dana-Farber Cancer Institute
- Children's Hospital of Michigan
- Sanford Children's Specialty Clinic
- St. Jude Children's Research Hospital
- Cook Children's Medical Center
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm 4
Arm 5
Arm 6
Arm 7
Arm 8
Arm 9
Arm 10
Arm 11
Arm 12
Arm 13
Arm 14
Arm 15
Arm 16
Experimental
Experimental
Experimental
Experimental
Experimental
Experimental
Experimental
Experimental
Experimental
Experimental
Experimental
Experimental
Experimental
Experimental
Experimental
Experimental
AZA+ADE | AZA+FLAG+Ida | AE | MA
DAC+ADE | DAC+FLAG+Ida | AE | MA
AZA+ADE | AZA+FLAG+Ida+Sor | AZA+AE+Sor | AZA+MA+Sor
DAC+ADE | DAC+FLAG+Ida+Sor | DAC+AE+Sor|DAC+MA+Sor
AZA+ADE | AZA+FLAG+Ida | AE | MA | Asp+AraC
DAC+ADE | DAC+FLAG+Ida | AE | MA | Asp+AraC
AZA| +ADE | +FLAG+Ida+Sor| +AE+Sor| +MA+Sor| +Asp+AraC+Sor
DAC|+ADE | +FLAG+Ida+Sor | +AE+Sor | +MA+Sor | +Asp+AraC+Sor
AZA+ADE | AZA+FLAG-Ida+Sor | AE | MA+Sor | Asp+AraC+Sor
DAC+ADE | DAC+FLAG+Ida+Sor | AE | MA+Sor | Asp+AraC+Sor
AZA | + ADE | +FLAG+Ida+Sor| +AE+Sor | +MA+Sor | +Asp+AraC+Sor
DAC |+ADE |+FLAG+Ida+Sor |+AE+Sor|+MA+Sor|+Asp+AraC+Sor
AZA+ADE | AZA+FLAG+Ida+Sor | MA+Sor | Asp+AraC+Sor
DAC+ADE | DAC+FLAG+Ida+Sor | MA+Sor | Asp+AraC+Sor
DAC |+ADE|+FLAG+Ida+Sor|+MA+Sor|+Asp+AraC+Sor
AZA |+ADE|+FLAG+Ida+Sor|+MA+Sor|+Asp+AraC+Sor
Part 1 Tolerability with AZA - Low Risk Patients are randomized to receive 5 days of single agent azacitidine as part of Inductions I & II and then receive low-risk intensifications I & II without azacitidine. Interventions: azacitidine, cytarabine, daunorubicin, etoposide,dexrazoxane, fludarabine, idarubicin, G-CSF, mitoxantrone., ITMHA.
Part 1 Tolerability with DAC - Low Risk Patients are randomized to receive 5 days of single agent decitabine as part of Inductions I & II and then receive low-risk Intensifications I & II without decitabine. Interventions: decitabine, cytarabine, daunorubicin, etoposide, dexrazoxane, fludarabine, idarubicin, G- CSF, mitoxantrone, ITMHA.
Part 2 Dose Expansion with AZA - Low Risk Patients are randomized to receive 5 days of single agent azacitidine as part of Inductions I & II and low- risk Intensifications I & II. Sorafenib will be given to patients with FLT3-ITD. For these patients, AZA will be limited to the first two courses of Induction chemotherapy. They will not receive AZA with Intensification therapy. Interventions: azacitidine, cytarabine, daunorubicin, etoposide, dexrazoxane, fludarabine, idarubicin, G- CSF, sorafenib, mitoxantrone, ITMHA.
Part 2 Dose Expansion with DAC - Low Risk Patients are randomized to receive 5 days of single agent decitabine as part of Inductions I & II and low-risk Intensifications I & II. Sorafenib will be given to patients with FLT3-ITD. For these patients, DAC will be limited to the first two courses of Induction chemotherapy. They will not receive DAC with Intensification therapy. Interventions: decitabine, cytarabine, daunorubicin, etoposide, dexrazoxane, fludarabine, idarubicin, G- CSF, sorafenib, mitoxantrone, ITMHA.
Part 1 Tolerability with AZA - Intermediate Risk Patients are randomized to receive 5 days of single agent azacitidine as part of Inductions I & II and then receive intermediate risk Intensifications I, II & III without azacitidine. Interventions: azacitidine, cytarabine, daunorubicin, etoposide, dexrazoxane, fludarabine, idarubicin, G- CSF, mitoxantrone, erwinia asparaginase, ITMHA,
Part 1 Tolerability with DAC - Intermediate Risk Patients are randomized to receive 5 days of single agent decitabine as part of Inductions I & II and then receive intermediate-risk Intensifications I, II & III without decitabine. Interventions: decitabine, cytarabine, daunorubicin, etoposide, dexrazoxane, fludarabine, idarubicin, G- CSF, mitoxantrone, erwinia asparaginase, ITMHA.
Part 2 Dose Expansion with AZA - Intermediate-Risk Patients are randomized to receive 5 days of single agent azacitidine as part of Inductions I & II and intermediate-risk Intensification I, II, and III. Sorafenib will be given to patients with FLT3-ITD. For these patients, AZA will be limited to the first two courses of Induction chemotherapy. They will not receive AZA with Intensification therapy. Interventions: azacitidine, cytarabine, daunorubicin, etoposide, dexrazoxane, fludarabine, idarubicin, G- CSF, sorafenib, mitoxantrone, erwinia asparaginase, asparaginase erwinia chrysanthemi (recombinant)-rywn, ITMHA.
Part 2 Dose Expansion with DAC - Intermediate-Risk Patients are randomized to receive 5 days of single agent decitabine as part of Inductions I & II and intermediate-risk Intensifications I, II and III. Sorafenib will be given to patients with FLT3-ITD. For these patients, DAC will be limited to the first two courses of Induction chemotherapy. They will not receive DAC with Intensification therapy. Interventions: decitabine, cytarabine, daunorubicin, etoposide, dexrazoxane, fludarabine, idarubicin, G- CSF, sorafenib, mitoxantrone, erwinia asparaginase, asparaginase erwinia chrysanthemi (recombinant)-rywn, ITMHA.
Part 1 Tolerability with AZA - High Risk (no donor) Patients are randomized to receive 5 days of single agent azacitidine as part of Induction I & II and high-risk intensifications I, II & III without azacitidine. Sorafenib is limited to patients with FLT3-ITD+/NUP98-NSD1+ or FLT3-ITD+/WT1mut somatic mutations. Interventions: azacitidine, cytarabine, daunorubicin, etoposide, dexrazoxane, fludarabine, idarubicin, G- CSF, sorafenib, mitoxantrone, erwinia asparaginase, ITMHA.
Part 1 Tolerability with DAC - High Risk (no donor) Patients are randomized to receive 5 days of single agent decitabine as part of Inductions I & II and then receive high-risk Intensifications I, II & III without decitabine. Sorafenib is limited to patients with FLT3-ITD+/NUP98-NSD1+ or FLT3-ITD+/WT1mut somatic mutations. Interventions: decitabine, cytarabine, daunorubicin, etoposide, dexrazoxane, fludarabine, idarubicin, G- CSF, sorafenib, mitoxantrone, erwinia asparaginase, ITMHA.
Part 2 Dose Expansion with AZA - High Risk (no donor) Patients are randomized to receive 5 days of single agent azacitidine as part of Inductions I & II and high-risk Intensifications I, II and III. Sorafenib will be given to patients with FLT3-ITD. For these patients, AZA will be limited to the first two courses of Induction chemotherapy. They will not receive AZA with Intensification therapy. Interventions: azacitidine, cytarabine, daunorubicin, etoposide, dexrazoxane, fludarabine, idarubicin, G- CSF, sorafenib, mitoxantrone, erwinia asparaginase, asparaginase erwinia chrysanthemi (recombinant)-rywn, ITMHA.
Part 2 Dose Expansion with DAC - High Risk (no donor) Patients are randomized to receive 5 days of single agent decitabine as part of Inductions I & II and high-risk Intensifications I, II and III. Sorafenib will be given to patients with FLT3-ITD. For these patients, DAC will be limited to the first two courses of Induction chemotherapy. They will not receive DAC with Intensification therapy. Interventions: decitabine, cytarabine, daunorubicin, etoposide, dexrazoxane, fludarabine, idarubicin, G- CSF, sorafenib, mitoxantrone, erwinia asparaginase, asparaginase erwinia chrysanthemi (recombinant)-rywn, ITMHA.
Part 1 Tolerability with AZA- High Risk (with donor) Patients are randomized to receive 5 days of single agent azacitidine as part of Induction I Induction II and high-risk Intensifications I or high risk intensification III without azacitidine. Patients will proceed to stem cell transplant. Sorafenib is limited to patients with FLT3-ITD+/NUP98-NSD1+ or FLT3-ITD+/WT1mut somatic mutations. Interventions: azacitidine cytarabine, daunorubicin, etoposide, dexrazoxane, fludarabine, idarubicin, G- CSF, mitoxantrone, sorafenib, ITMHA, erwinia asparaginase, stem cell transplant.
Part 1 Tolerability with DAC - High Risk (with donor) Patients are randomized to receive 5 days of single agent decitabine as part of Inductions I & II and then receive high-risk Intensifications I or high risk intensification III without decitabine. Patients will proceed to stem cell transplant. Sorafenib is limited to patients with FLT3-ITD+/NUP98-NSD1+ or FLT3-ITD+/WT1mut somatic mutations. Interventions: decitabine, cytarabine, daunorubicin, etoposide, dexrazoxane, fludarabine, idarubicin, G- CSF, mitoxantrone, sorafenib, ITMHA, erwinia asparaginase, stem cell transplant
Part 2 Dose Expansion with DAC - High Risk (with donor) Patients are randomized to receive 5 days of single agent decitabine as part of Inductions I & II and high-risk Intensifications I or high risk intensification III. Patients will proceed to stem cell transplant. Sorafenib will be given to patients with FLT3-ITD. For these patients, DAC will be limited to the first two courses of Induction chemotherapy. They will not receive DAC with Intensification therapy. Interventions: decitabine, cytarabine, daunorubicin, etoposide, dexrazoxane, fludarabine, idarubicin, G- CSF, mitoxantrone, sorafenib, ITMHA, erwinia asparaginase, stem cell transplant
Part 2 Dose Expansion with AZA - High Risk (with donor) Patients are randomized to receive 5 days of single agent azacitidine as part of Inductions I & II and high-risk Intensification I or high risk intensification III. Patients will proceed to stem cell transplant. Sorafenib will be given to patients with FLT3-ITD. For these patients, AZA will be limited to the first two courses of Induction chemotherapy. They will not receive AZA with Intensification therapy. Interventions: azacitidine, cytarabine, daunorubicin, etoposide, dexrazoxane, fludarabine, idarubicin, G-CSF, mitoxantrone, sorafenib, ITMHA, erwinia asparaginase, stem cell transplant.