A Trial of Epigenetic Priming in Patients With Newly Diag... | NCT03164057

NCT03164057

ID	Type	Description	Link
NCI-2017-00928	Registry Identifier	NCI Clinical Trial Registration Program

Status Module

Description Module

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.

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
AZA+ADE \| AZA+FLAG+Ida \| AE \| MA	Experimental	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.	Drug: Azacitidine Drug: Cytarabine Drug: Daunorubicin Drug: Etoposide Combination Product: ITMHA Drug: Idarubicin Drug: Fludarabine Drug: Mitoxantrone Drug: G-CSF Drug: Dexrazoxane
DAC+ADE \| DAC+FLAG+Ida \| AE \| MA	Experimental	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.	Drug: Decitabine Drug: Cytarabine Drug: Daunorubicin Drug: Etoposide Combination Product: ITMHA Drug: Idarubicin Drug: Fludarabine Drug: Mitoxantrone Drug: G-CSF Drug: Dexrazoxane
AZA+ADE \| AZA+FLAG+Ida+Sor \| AZA+AE+Sor \| AZA+MA+Sor	Experimental	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.

Interventions

Name	Type	Description	Arm Group Labels	Other Names
Azacitidine	Drug	Azacitidine solution is administered intravenously (IV) over a period of 10-40 minutes.	AZA \| + ADE \| +FLAG+Ida+Sor\| +AE+Sor \| +MA+Sor \| +Asp+AraC+Sor

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Proportion of evaluable patients who tolerate five days of single agent DMTi before a standard chemotherapy combination	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.	From enrollment to completion of chemotherapy (up to 8 months after start of therapy)
Change in genome-wide methylation burden of leukemia cells from diagnosis to after five days of single agent DMTi	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.	From diagnosis to completion of five days of single agent DMTi (up to 2 weeks after start of therapy)
Cox model hazard ratio for association of event-free survival with genome-wide methylation burden	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.	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)

Secondary Outcomes

Measure	Description	Time Frame
Proportion of MRD-evaluable subjects with detectable minimal residual disease after receiving five days of a single agent DMTi followed by araC+daunorubicin+etoposide.	Flow cytometry will be used to measure minimal residual disease at diagnosis and after completion of the first course of chemotherapy.	MRD will be measured after completion of DMTi+araC+daunorubicin+etoposide (up to 6 weeks after the start of therapy)

Eligibility Module

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.

Name	Affiliation	Role
Raul C. Ribiero, MD	St. Jude Children's Research Hospital	Principal Investigator

Facility	Status	City	State	ZIP	Country	Contacts
Children's Hospital of Central California		Madera	California	93636	United States
Children's Hospital of Orange County

Label	URL
St. Jude Children's Research Hospital	View source
Clinical Trials Open at St. Jude	View source

Ancestor Terms

ID	Term
D001372	Aza Compounds
D009930	Organic Chemicals
D003562	Cytidine
D011741	Pyrimidine Nucleosides
D011743	Pyrimidines
D006573	Heterocyclic Compounds, 1-Ring
D006571	Heterocyclic Compounds
D009705	Nucleosides
D009706	Nucleic Acids, Nucleotides, and Nucleosides
D012263	Ribonucleosides
D001087	Arabinonucleosides
D018943	Anthracyclines
D009279	Naphthacenes
D011084	Polycyclic Aromatic Hydrocarbons
D006841	Hydrocarbons, Aromatic
D006844	Hydrocarbons, Cyclic
D006838	Hydrocarbons
D011083	Polycyclic Compounds
D000617	Aminoglycosides
D006027	Glycosides
D002241	Carbohydrates
D011034	Podophyllotoxin
D013764	Tetrahydronaphthalenes
D009281	Naphthalenes
D005960	Glucosides
D000630	Aminopterin
D011622	Pterins
D011621	Pteridines
D006574	Heterocyclic Compounds, 2-Ring
D000072471	Heterocyclic Compounds, Fused-Ring
D000880	Anthraquinones
D000095322	Anthrones
D000873	Anthracenes
D011809	Quinones
D010671	Phenylurea Compounds
D014508	Urea
D000577	Amides
D001555	Benzene Derivatives
D009536	Niacinamide
D009539	Nicotinic Acids
D000147	Acids, Heterocyclic
D011725	Pyridines
D003115	Colony-Stimulating Factors
D006023	Glycoproteins
D006001	Glycoconjugates
D016298	Hematopoietic Cell Growth Factors
D016207	Cytokines
D036341	Intercellular Signaling Peptides and Proteins
D010455	Peptides
D000602	Amino Acids, Peptides, and Proteins
D011506	Proteins
D001685	Biological Factors
D011929	Razoxane
D054659	Diketopiperazines
D010879	Piperazines
D017690	Cell Transplantation
D064987	Cell- and Tissue-Based Therapy
D001691	Biological Therapy
D013812	Therapeutics
D014180	Transplantation
D013514	Surgical Procedures, Operative

ID	Term
D015470	Leukemia, Myeloid, Acute
D009190	Myelodysplastic Syndromes

ID	Term
D007951	Leukemia, Myeloid
D007938	Leukemia
D009370	Neoplasms by Histologic Type
D009369	Neoplasms
D006402	Hematologic Diseases
D006425	Hemic and Lymphatic Diseases
D001855	Bone Marrow Diseases

ID	Term
D001374	Azacitidine
D000077209	Decitabine
D003561	Cytarabine
D003630	Daunorubicin
D005047	Etoposide
C061400	etoposide phosphate
D008727	Methotrexate
D015255	Idarubicin
C024352	fludarabine
C042382	fludarabine phosphate
D008942	Mitoxantrone
C000718243	asparaginase erwinia chrysanthemi recombinant
D000077157	Sorafenib
D016179	Granulocyte Colony-Stimulating Factor
D000069585	Filgrastim
D064730	Dexrazoxane
D033581	Stem Cell Transplantation