Azacitidine and Combination Chemotherapy in Treating Infants With Acute Lymphoblastic Leukemia and KMT2A Gene Rearrangement

PRIMARY OBJECTIVE:

I. To evaluate the tolerability of azacitidine in addition to Interfant-06 standard chemotherapy in infants with newly diagnosed acute lymphoblastic leukemia (ALL) with KMT2A gene rearrangement (KMT2A-R).

SECONDARY OBJECTIVE:

I. To evaluate the biologic activity of azacitidine by pharmacodynamic assessment of global deoxyribonucleic acid (DNA) methylation in peripheral blood mononuclear cells (PBMCs) of infants treated with azacitidine.

EXPLORATORY OBJECTIVES:

I. To determine the 5 year event-free survival (EFS) of infants with KMT2A-R treated with azacitidine in addition to Interfant-06 standard chemotherapy.

II. To correlate minimal residual disease (MRD) with outcome in the context of the protocol therapy.

III. To perform pharmacokinetic (PK) testing of azacitidine in infants. IV. To test the expansion of infant T lymphocytes by stimulation with artificial antigen presenting cells identical to those used in chimeric antigen receptor T-cell (CART)-19 production.

V. To collect pharmacodynamic (PD) data for asparaginase activity following pegaspargase administration in infants.

OUTLINE:

INDUCTION CHEMOTHERAPY: Patients receive methotrexate intrathecally (IT) on days 1 and 29, prednisolone orally (PO) or nasogastrically (NG) three times daily (TID) on days 1-7, daunorubicin hydrochloride intravenously (IV) over 1-15 minutes on days 8-9, cytarabine IV over 30 minutes on days 8-21 and IT on day 15, dexamethasone PO, NG, or IV TID on days 8-28, vincristine sulfate IV over 1 minute on days 8, 15, 22, and 29, pegaspargase IV over 1-2 hours or intramuscularly (IM) on day 12, and hydrocortisone sodium succinate IT on days 15 and 29 in the absence of disease progression or unacceptable toxicity. Only patients with KMT2A-R continue to post-induction chemotherapy.

POST-INDUCTION CHEMOTHERAPY:

AZACITIDINE BLOCK I: Prior to CONSOLIDATION, patients receive azacitidine IV over 10-40 minutes daily for 5 days in the absence of disease progression or unacceptable toxicity.

CONSOLIDATION: Following completion of AZACITIDINE BLOCK I, patients receive cyclophosphamide IV over 30-60 minutes on days 1 and 29, mercaptopurine PO or NG daily on days 1-28, cytarabine IV or subcutaneously (SC) daily on days 3-6, 10-13, 17-20, and 24-27 and IT on day 10, methotrexate IT on day 24, and hydrocortisone sodium succinate IT on days 10 and 24 in the absence of disease progression or unacceptable toxicity.

AZACITIDINE BLOCK II: Prior to INTERIM MAINTENANCE, patients receive azacitidine as in AZACITIDINE BLOCK I

INTERIM MAINTENANCE: Following completion of AZACITIDINE BLOCK II, patients receive mercaptopurine PO or NG daily on days 1-14, methotrexate IV over 24 hours on days 1 and 8 and IT on days 2 and 9, leucovorin calcium PO or IV on days 3-4 and 10-11, hydrocortisone sodium succinate IT on days 2 and 9, cytarabine IV over 3 hours every 12 hours on days 15-16 and 22-23 for a total of 8 doses, and pegaspargase IV over 1-2 hours or IM on day 23 in the absence of disease progression or unacceptable toxicity.

AZACITIDINE BLOCK III: Prior to DELAYED INTENSIFICATION PART I, patients receive azacitidine as in AZACITIDINE BLOCK I.

DELAYED INTENSIFICATION PART I: Following completion of AZACITIDINE BLOCK III, patients receive pegaspargase IV over 1-2 hours or IM on day 1, dexamethasone PO, NG, or IV TID on days 1-14 and 15-21 with a taper on days 15-21, thioguanine PO or NG daily on days 1-28, vincristine sulfate IV over 1 minute on days 1, 8, 15, and 22, daunorubicin hydrochloride IV over 1-15 minutes on days 1, 8, 15, and 22, cytarabine IV or SC on days 2-5, 9-12, 16-19, and 23-26 and IT on days 1 and 15, and hydrocortisone sodium succinate IT on days 1 and 15 in the absence of disease progression or unacceptable toxicity.

AZACITIDINE BLOCK IV: Prior to DELAYED INTENSIFICATION PART II, patients receive azacitidine as in AZACITIDINE BLOCK I.

DELAYED INTENSIFICATION PART II: Following completion of AZACITIDINE BLOCK IV, patients receive thioguanine PO or NG daily on days 1-14, cyclophosphamide IV over 15-30 minutes on days 1 and 15, cytarabine IV or SC on days 2-5 and 9-12 in the absence of disease progression or unacceptable toxicity.

MAINTENANCE: Following DELAYED INTENSIFICATION PART II, patients receive mercaptopurine PO or NG on days 1-168, methotrexate IT on day 1 and 92 and PO once weekly on days 8-91 and 98-168, hydrocortisone sodium succinate IT on day 1, 57, and 99, and cytarabine IT on day 57. Starting on day 169, patients receive mercaptopurine PO or NG on days 1-84 and methotrexate PO once weekly. Cycles repeat every 84 days for 2 years from the start of INDUCTION CHEMOTHERAPY in the absence of disease progression or unacceptable toxicity.

Additionally, patients undergo collection of blood sample and an echocardiogram (ECHO) or multigated acquisition (MUGA) scan on study. Patients may also undergo computed tomography (CT) or magnetic resonance imaging (MRI) throughout the study.

After completion of study treatment, patients are followed up periodically.

• Azacitidine (Drug), also known as 5 AZC, 5-AC, 5-Azacitidine, 5-Azacytidine, 5-AZC, Azacytidine, Azacytidine, 5-, Ladakamycin, Mylosar, U-18496, Vidaza: Given IV
• Biospecimen Collection (Procedure), also known as Biological Sample Collection, Biospecimen Collected, Specimen Collection: Undergo blood sample collection
• Computed Tomography (Procedure), also known as CAT, CAT Scan, Computed Axial Tomography, Computerized Axial Tomography, Computerized axial tomography (procedure), Computerized Tomography, Computerized Tomography (CT) scan, CT, CT Scan, tomography: Undergo CT scan
• Cyclophosphamide (Drug), also known as (-)-Cyclophosphamide, 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate, Asta B 518, B 518, B-518, B518, Carloxan, Ciclofosfamida, Ciclofosfamide, Cicloxal, Clafen, Claphene, CP monohydrate, CTX, CYCLO-cell, Cycloblastin, Cycloblastine, Cyclophospham, Cyclophosphamid monohydrate, Cyclophosphamide Monohydrate, Cyclophosphamidum, Cyclophosphan, Cyclophosphane, Cyclophosphanum, Cyclostin, Cyclostine, Cytophosphan, Cytophosphane, Cytoxan, Fosfaseron, Genoxal, Genuxal, Ledoxina, Mitoxan, Neosar, Revimmune, Syklofosfamid, WR 138719, WR- 138719, WR-138719, WR138719: Given IV
• Cytarabine (Drug), also known as .beta.-Cytosine arabinoside, 1-.beta.-D-Arabinofuranosyl-4-amino-2(1H)pyrimidinone, 1-.beta.-D-Arabinofuranosylcytosine, 1-Beta-D-arabinofuranosyl-4-amino-2(1H)pyrimidinone, 1-Beta-D-arabinofuranosylcytosine, 1.beta.-D-Arabinofuranosylcytosine, 2(1H)-Pyrimidinone, 4-Amino-1-beta-D-arabinofuranosyl-, 2(1H)-Pyrimidinone, 4-amino-1.beta.-D-arabinofuranosyl-, Alexan, Ara-C, ARA-cell, Arabine, Arabinofuranosylcytosine, Arabinosylcytosine, Aracytidine, Aracytin, Aracytine, Beta-Cytosine Arabinoside, CHX-3311, Cytarabinum, Cytarbel, Cytosar, Cytosine Arabinoside, Cytosine-.beta.-arabinoside, Cytosine-beta-arabinoside, Erpalfa, Starasid, Tarabine PFS, U 19920, U-19920, Udicil, WR-28453: Given IV, SC, IT
• Daunorubicin (Drug), also known as Daunomycin, Daunorrubicina, DNR, Leukaemomycin C, Rubidomycin, Rubomycin C: Given IV
• Daunorubicin Hydrochloride (Drug), also known as Cerubidin, Cerubidine, Cloridrato de Daunorubicina, Daunoblastin, Daunoblastina, Daunoblastine, Daunomycin Hydrochloride, Daunomycin, hydrochloride, Daunorubicin.HCl, Daunorubicini Hydrochloridum, FI-6339, Ondena, RP-13057, Rubidomycin Hydrochloride, Rubilem: Given IV
• Dexamethasone (Drug), also known as Aacidexam, Adexone, Aknichthol Dexa, Alba-Dex, Alin, Alin Depot, Alin Oftalmico, Amplidermis, Anemul mono, Auricularum, Auxiloson, Baycadron, Baycuten, Baycuten N, Cortidexason, Cortisumman, Decacort, Decadrol, Decadron, Decadron DP, Decalix, Decameth, Decasone R.p., Dectancyl, Dekacort, Deltafluorene, Deronil, Desamethasone, Desameton, Dexa-Mamallet, Dexa-Rhinosan, Dexa-Scheroson, Dexa-sine, Dexacortal, Dexacortin, Dexafarma, Dexafluorene, Dexalocal, Dexamecortin, Dexameth, Dexamethasone Intensol, Dexamethasonum, Dexamonozon, Dexapos, Dexinoral, Dexone, Dinormon, Dxevo, Fluorodelta, Fortecortin, Gammacorten, Hemady, Hexadecadrol, Hexadrol, LenaDex, Lokalison-F, Loverine, Methylfluorprednisolone, Millicorten, Mymethasone, Orgadrone, Spersadex, TaperDex, Visumetazone, ZoDex: Given PO, NG, IV
• Echocardiography (Procedure), also known as EC: Undergo ECHO
• Hydrocortisone Sodium Succinate (Drug), also known as (11beta)-21-(3-Carboxy-1-oxopropyl)-11,17-dihydroxypregn-4-ene-3,20-dione, Monosodium Salt, A-Hydrocort, Buccalsone, Corlan, Cortisol Sodium Succinate, Cortop, Efcortelan, Emergent-EZ, Flebocortid, Hidroc Clora, Hycorace, Hydro-Adreson, Hydrocort, Hydrocortisone 21-Sodium Succinate, Hydrocortisone Na Succinate, Kinogen, Nordicort, Nositrol, Sinsurrene, Sodium hydrocortisone succinate, Solu-Cortef, Solu-Glyc: Given IT
• Leucovorin (Drug), also known as Folinic acid: Given PO, IV
• Leucovorin Calcium (Drug), also known as Adinepar, Calcifolin, Calcium (6S)-Folinate, Calcium Folinate, Calcium Leucovorin, Calfolex, Calinat, Cehafolin, Citofolin, Citrec, Citrovorum Factor, Cromatonbic Folinico, Dalisol, Disintox, Divical, Ecofol, Emovis, Factor, Citrovorum, Flynoken A, Folaren, Folaxin, FOLI-cell, Foliben, Folidan, Folidar, Folinac, Folinate Calcium, folinic acid, Folinic Acid Calcium Salt Pentahydrate, Folinoral, Folinvit, Foliplus, Folix, Imo, Lederfolat, Lederfolin, Leucosar, leucovorin, Rescufolin, Rescuvolin, Tonofolin, Wellcovorin: Given PO, IV
• Magnetic Resonance Imaging (Procedure), also known as Magnetic Resonance, Magnetic Resonance Imaging (MRI), Magnetic resonance imaging (procedure), Magnetic Resonance Imaging Scan, Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance, MR, MR Imaging, MRI, MRI Scan, MRIs, NMR Imaging, NMRI, Nuclear Magnetic Resonance Imaging, sMRI, Structural MRI: Undergo MRI
• Mercaptopurine (Drug), also known as 3H-Purine-6-thiol, 6 MP, 6 Thiohypoxanthine, 6 Thiopurine, 6-Mercaptopurine, 6-Mercaptopurine Monohydrate, 6-MP, 6-Purinethiol, 6-Thiopurine, 6-Thioxopurine, 6H-Purine-6-thione, 1,7-dihydro- (9CI), 7-Mercapto-1,3,4,6-tetrazaindene, Alti-Mercaptopurine, Azathiopurine, Bw 57-323H, Flocofil, Ismipur, Leukerin, Leupurin, Mercaleukim, Mercaleukin, Mercaptina, Mercaptopurinum, Mercapurin, Mern, NCI-C04886, Puri-Nethol, Purimethol, Purine, 6-mercapto-, Purine-6-thiol (8CI), Purine-6-thiol, monohydrate, Purinethiol, Purinethol, U-4748, WR-2785: Given PO, NG
• Methotrexate (Drug), also known as Abitrexate, Alpha-Methopterin, Amethopterin, Brimexate, CL 14377, CL-14377, Emtexate, Emthexat, Emthexate, Farmitrexat, Fauldexato, Folex, Folex PFS, Jylamvo, Lantarel, Ledertrexate, Lumexon, Maxtrex, Medsatrexate, Metex, Methoblastin, Methotrexate LPF, Methotrexate Methylaminopterin, Methotrexatum, Metotrexato, Metrotex, Mexate, Mexate-AQ, MTX, Novatrex, Rheumatrex, Texate, Tremetex, Trexeron, Trixilem, WR-19039: Given IT, IV, PO
• Multigated Acquisition Scan (Procedure), also known as Blood Pool Scan, Equilibrium Radionuclide Angiography, Gated Blood Pool Imaging, Gated Heart Pool Scan, MUGA, MUGA Scan, Multi-Gated Acquisition Scan, Radionuclide Ventriculogram Scan, Radionuclide Ventriculography, RNV Scan, RNVG, SYMA Scanning, Synchronized Multigated Acquisition Scanning: Undergo MUGA scan
• Pegaspargase (Drug), also known as L-Asparaginase with Polyethylene Glycol, Oncaspar, Oncaspar-IV, PEG-Asparaginase, PEG-L-Asparaginase, PEG-L-Asparaginase (Enzon - Kyowa Hakko), PEGLA, Polyethylene Glycol L-Asparaginase, Polyethylene Glycol-L-Asparaginase: Given IV
• Prednisolone (Drug), also known as (11beta)-11,17,21-Trihydroxypregna-1,4-diene-3,20-dione, .delta.1-Hydrocortisone, Adnisolone, Aprednislon, Capsoid, Cortalone, Cortisolone, Dacortin H, Decaprednil, Decortin H, Delta(1)Hydrocortisone, Delta- Cortef, Delta-Cortef, Delta-Diona, Delta-F, Delta-Phoricol, Delta1-dehydro-hydrocortisone, Deltacortril, Deltahydrocortisone, Deltasolone, Deltidrosol, Dhasolone, Di-Adreson-F, Dontisolon D, Estilsona, Fisopred, Frisolona, Gupisone, Hostacortin H, Hydeltra, Hydeltrasol, Klismacort, Kuhlprednon, Lenisolone, Lepi-Cortinolo, Linola-H N, Linola-H-Fett N, Longiprednil, Metacortandralone, Meti Derm, Meticortelone, Opredsone, Panafcortelone, Precortisyl, Pred-Clysma, Predeltilone, Predni-Coelin, Predni-Helvacort, Prednicortelone, Prednisolonum, Prelone, Prenilone, Sterane: Given PO, NG
• Thioguanine (Drug), also known as 2-Amino 6MP, 2-Amino-1,7-dihydro-6H-purine-6-thione, 2-Amino-6-mercaptopurine, 2-Amino-6-purinethiol, 2-Aminopurin-6-thiol, 2-Aminopurine-6(1H)-thione, 2-Aminopurine-6-thiol, 2-Aminopurine-6-thiol Hemihydrate, 2-Mercapto-6-aminopurine, 6-Amino-2-mercaptopurine, 6-Mercapto-2-aminopurine, 6-Mercaptoguanine, 6-TG, 6H-Purine-6-thione, 2-amino-1,7-dihydro- (9CI), BW 5071, Lanvis, Tabloid, Thioguanine Hemihydrate, Thioguanine Hydrate, Tioguanin, Tioguanine, Wellcome U3B, WR-1141, X 27: Given PO, NG
• Vincristine (Drug), also known as LCR, Leurocristine, VCR, Vincrystine: Given IV
• Vincristine Sulfate (Drug), also known as Kyocristine, Leurocristine Sulfate, Leurocristine, sulfate, Oncovin, Vincasar, Vincosid, Vincrex, Vincristine, sulfate: Given IV

Primary outcomes

• Tolerability of Azacitidine in Combination With Interfant-06 Standard Chemotherapy in Evaluable Infant Patients With Newly Diagnosed ALL With KMT2A Gene Rearrangement (KMT2A-R). KMT2A Gene Rearrangement (KMT2A-R) [6 months]: Proportion of KMT2A-Rearranged patients treated with azacitidine with Dose Limiting Toxicities (DLTs) from the first course of azacitidine administration up to fourth course of azacitidine administration.

Secondary outcomes

• Biologic Activity, Defined as Global Deoxyribonucleic Acid (DNA) Methylation Change in Peripheral Blood Mononuclear Cells (PBMC)s; Day 1 Prior to First Course of Azacitidine [Week 6, Day 1 (Following the induction phase (35 days), the first course of Azacitidine began around Week 6 of therapy)]: Will calculate the percentage of CpG site methylation for all patients before the first course of azacitidine. Mean and standard deviation will be reported.
• Biologic Activity, Defined as Global Deoxyribonucleic Acid (DNA) Methylation Change in Peripheral Blood Mononuclear Cells (PBMC)s; Day 5 of First Course of Azacitidine [Week 6, Day 5 (Following the induction phase (35 days), the first course of Azacitidine began around Week 6 of therapy)]: Will calculate the percentage of CpG site methylation for all patients after the first course of azacitidine. Mean and standard deviation will be reported.
• Biologic Activity, Defined as Global Deoxyribonucleic Acid (DNA) Methylation Change in Peripheral Blood Mononuclear Cells (PBMC)s; Day 1 Prior to Second Course of Azacitidine [Week 13, Day 1 (Following induction phase (5 weeks), the first course of Azacitidine (1 week), and consolidation (6 weeks), the second course of Azacitidine began around Week 13 of therapy)]: Will calculate the percentage of CpG site methylation for all patients before the second course of azacitidine. Mean and standard deviation will be reported.
• Biologic Activity, Defined as Global Deoxyribonucleic Acid (DNA) Methylation Change in Peripheral Blood Mononuclear Cells (PBMC)s; Day 5 of Second Course of Azacitidine [Week 13, Day 5 (Following induction phase (5 weeks), the first course of Azacitidine (1 week), and consolidation (6 weeks), the second course of Azacitidine began around Week 13 of therapy)]: Will calculate the percentage of CpG site methylation for all patients after the second course of azacitidine. Mean and standard deviation will be reported.

Other outcomes

• Event-free Survival (EFS) [Five years]: Five year EFS estimation will be calculated from time of enrollment. Standard errors and confidence intervals for EFS will be calculated using Peto's method.
• Minimal Residual Disease (MRD) [Five years]: Descriptive analysis will be conducted to correlate MRD with the EFS for the KMT2A-R patients.
• Pharmacokinetic (PK) Parameters of Azacitidine [Two months]: Pharmacokinetic (PK) testing and analysis of azacitidine in infants will be performed by Covance.
• Expansion of Infant T Lymphocytes by Stimulation With Artificial Antigen Presenting Cells [Three months]: Optional biological study participation will explore the feasibility of T-cell collection for the purposes of chimeric antigen receptor (CAR) T-cell production from the peripheral blood in infants with ALL.
• PD Data for Asparaginase Activity Following Pegaspargase Administration [Six months]: Pharmacodynamic (PD) data for asparaginase activity following pegaspargase administration in infants will be collected, described, and correlated with EFS for the KMT2A-R patients.

Sex: All, ages: any to 364 Days

Inclusion Criteria:

* Infants must be > 36 weeks gestational age at the time of enrollment
* Patients must have newly diagnosed B lymphoblastic leukemia (2008 World Health Organization \[WHO\] classification) (also termed B-precursor acute lymphoblastic leukemia) or acute leukemia of ambiguous lineage (ALUL), which includes mixed phenotype acute leukemia (MPAL); for patients with ALUL, the morphology and immunophenotype must be at least 50% B lymphoblastic
* Central nervous system (CNS) status must be determined based on a sample obtained prior to the administration of any systemic or intrathecal chemotherapy, with the exception of steroid pretreatment

Exclusion Criteria:

* Patients with known absence of KMT2A-rearrangement leukemia prior to enrollment
* Patients with Down syndrome
* Patients with secondary B acute lymphoblastic leukemia (B-ALL) that developed after treatment of a prior malignancy with cytotoxic chemotherapy
* With the exception of steroid pretreatment or the administration of intrathecal methotrexate or intrathecal cytarabine, receipt of any other prior cytotoxic chemotherapy for either the current diagnosis of B-ALL or any cancer diagnosed prior to the initiation of protocol therapy on AALL15P1

Participant flow

Outcome results

• Tolerability of Azacitidine in Combination With Interfant-06 Standard Chemotherapy in Evaluable Infant Patients With Newly Diagnosed ALL With KMT2A Gene Rearrangement (KMT2A-R). KMT2A Gene Rearrangement (KMT2A-R) (Primary), Number, percentage of participants: KMT2A-Rearranged 6.45 (0 to 15.10)
• Biologic Activity, Defined as Global Deoxyribonucleic Acid (DNA) Methylation Change in Peripheral Blood Mononuclear Cells (PBMC)s; Day 1 Prior to First Course of Azacitidine (Secondary), Mean, Percentage of CpG methylation: KMT2A-Rearranged 78.17 +/- 1.62
• Biologic Activity, Defined as Global Deoxyribonucleic Acid (DNA) Methylation Change in Peripheral Blood Mononuclear Cells (PBMC)s; Day 5 of First Course of Azacitidine (Secondary), Mean, Percentage of CpG methylation: KMT2A-Rearranged 75.54 +/- 2.68
• Biologic Activity, Defined as Global Deoxyribonucleic Acid (DNA) Methylation Change in Peripheral Blood Mononuclear Cells (PBMC)s; Day 1 Prior to Second Course of Azacitidine (Secondary), Mean, Percentage of CpG methylation: KMT2A-Rearranged 76.5 +/- 2.68
• Biologic Activity, Defined as Global Deoxyribonucleic Acid (DNA) Methylation Change in Peripheral Blood Mononuclear Cells (PBMC)s; Day 5 of Second Course of Azacitidine (Secondary), Mean, Percentage of CpG methylation: KMT2A-Rearranged 74.52 +/- 2.09
• Event-free Survival (EFS) (Other pre specified)
• Minimal Residual Disease (MRD) (Other pre specified)
• Pharmacokinetic (PK) Parameters of Azacitidine (Other pre specified)
• Expansion of Infant T Lymphocytes by Stimulation With Artificial Antigen Presenting Cells (Other pre specified)
• PD Data for Asparaginase Activity Following Pegaspargase Administration (Other pre specified)

Adverse events

Time frame: Up to 5 years

Serious adverse events by term

Other adverse events by term

70 more sites not listed.

• Results publication: Guest EM, Kairalla JA, Devidas M, Hibbitts E, Carroll AJ, Heerema NA, Kubaney HR, August MA, Ramesh S, Yoo B, Farooqi MS, Pauly MG, Wechsler DS, Miles RR, Reid JM, Kihei CD, Gore L, Raetz EA, Hunger SP, Loh ML, Brown PA. Azacitidine as epigenetic priming for chemotherapy is safe and well-tolerated in infants with newly diagnosed KMT2A-rearranged acute lymphoblastic leukemia: Children's Oncology Group trial AALL15P1. Haematologica. 2024 Dec 1;109(12):3918-3927. doi: 10.3324/haematol.2024.285158. PMID 38867582

• Study Protocol and Statistical Analysis Plan (PDF, 2019-09-25)

• Rishi S Kotecha, Principal investigator, Children's Oncology Group

NIH grants: U10CA180886