Clinical trial NCT02419755
Conditions: Mixed Lineage Acute Leukemia Acute Myeloid Leukemia Acute Lymphoid Leukemia
Keywords: Infant leukemia ALL AML Biphenotypic leukemia Pediatric
Sponsor: St. Jude Children's Research Hospital
Start date: 2015-04-14; Completion date: 2016-12-31
Enrollment: 12 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will test the safety and effectiveness of adding bortezomib and vorinostat to other chemotherapy drugs commonly used to treat relapsed or refractory leukemia. Both drugs have been approved by the Food and Drug Administration (FDA) to treat other cancers in adults, but they have not yet been approved tor treatment younger patients with leukemia.

PRIMARY OBJECTIVE

* To estimate the overall response rate of patients with MLL rearranged (MLLr) hematologic malignancies receiving bortezomib and vorinostat in combination with a chemotherapy backbone.

SECONDARY OBJECTIVES

* Estimate event-free and overall-survival.
* Describe toxicities experienced by participants during treatment.

OTHER PRESPECIFIED OBJECTIVES

* To identify all genomic lesions by comprehensive whole genome, exome and transcriptome sequencing on all patients.
* To compare minimal residual disease (MRD) results by three modalities: flow cytometry, polymerase chain reaction (PCR) and deep sequencing.

Detailed description:
All participants will undergo diagnostic lumbar puncture and intrathecal (IT) chemotherapy \[Cytarabine, methotrexate, hydrocortisone (ITMHA)\] prior to cycle 1. Throughout all phases of therapy, dexrazoxane will be given as supportive care for all participants prior to receiving mitoxantrone or doxorubicin.

STRATUM 1: MYELOID MALIGNANCIES:

Induction:

* Cytarabine, Days 1-5
* Bortezomib, Days 1, 4, 8, 11, 15, 18
* Vorinostat, Days 1-4, 8-11, 15-18
* ITMHA.for those with CNS1, Day 1
* ITMHA for those with CNS 2/3, Days 1, 4, 8, 11\*, 15\*, 18\* and 22\* (\* Twice weekly until two negative CSF; CNS3 patients must receive at least 6 doses)
* Participants with cumulative anthracycline \<460 mg/m2 also receive Mitoxantrone on Day 1
* Responders may receive up to 6 courses. ITMHA will be limited to day 1 for subsequent courses

Maintenance (bridge) therapy (1 cycle before stem cell transplant if needed)::

* Bortezomib, Days 1, 4, 8, 11, 15, 18
* Vorinostat, Days 1-4, 8-11, 15-18
* ITMHA, Day 1

STRATUM 2: Acute Lymphoid Leukemia (ALL) and Mixed Lineage Malignancies (MLL):

Induction:

* Mitoxantrone, Day 1
* PEG-L-Asparaginase (or Erwinia L-asparaginase), Day 3
* Dexamethasone, Days 1-4, 8-11, 15-18
* Bortezomib, Days 1, 4, 8, 11, 15, 18
* Vorinostat, Days 1-4, 8-11, 15-18
* ITMHA for those with CNS1, Days 1, 8, 15, and 22
* ITMHA for those with CNS2/3, Days 1, 4, 8, 11, 15, and 22
* Participants with \>460 mg/m2 cumulative anthracyclines will not receive mitoxantrone

Consolidation:

* Methotrexate, Days 1 and 15
* Bortezomib, Days 8, 11, 22, 25
* Vorinostat, Days 8-11, and 22-25
* ITMHA, Days 1 and 15

Interim Maintenance:

* Mercaptopurine, Days 1-42
* Doxorubicin, Days 1 and 29
* PEG-L-asparaginase (or Erwinia L-asparaginase), Days 1, 15, and 29
* Dexamethasone, Days 8-11, 22-25, and 36-39
* Bortezomib Days 8,11,22,25,36,39
* Vorinostat, Days 8-11, 22-25, and 36-39
* ITMHA, Day 1

Reinduction:

* Mitoxantrone, Day 1
* PEG-L-asparaginase (or Erwinia L-asparaginase), Day 3
* Dexamethasone, Days 1-4, 8-11, 15-18
* Bortezomib Days 1, 4, 8, 11, 15, 18
* Vorinostat Days 1-4, 8-11, 15-18
* IT MHA Day 1

Maintenance (12 cycles):

* Mercaptopurine, Days 1-28
* Methotrexate, Days 8, 15, and 22
* Dexamethasone, Days 1-4
* Bortezomib, Days 1 and 4
* Vorinostat, Days 1-4
* ITMHA, Day 1

Bridge Therapy (1 cycle before stem cell transplant if needed):

* Bortezomib, Days 1, 4, 8, 11, 15, 18
* Vorinostat, Days 1-4, 8-11, 15-18
* Dexamethasone, Days 1-4, 8-11, 15-18
* ITMHA, Day 1

Arms: arm 1: Participants receive cytarabine, bortezomib, vorinostat, methotrexate, hydrocortisone, mitoxantrone as described in the Detailed Study Description. arm 2: Participants in Stratum 2 \[Acute Lymphoid Leukemia (ALL) and Mixed Lineage Malignancies (MLM)\] receive mitoxantrone, PEG-L-Asparaginase (or Erwinia L-asparaginase), dexamethasone, bortezomib, vorinostat, cytarabine, methotrexate, hydrocortisone, mercaptopurine, and doxorubicin as described in the Detailed Study Description.
Interventions: intervention 1: Bortezomib intervention 2: Vorinostat intervention 3: Mitoxantrone intervention 4: Cytarabine intervention 5: Methotrexate intervention 6: Hydrocortisone intervention 7: Peg-L-Asparaginase intervention 8: Erwinia L-Asparaginase intervention 9: Dexamethasone intervention 10: Mercaptopurine intervention 11: Doxorubicin
Intervention descriptions: intervention 1: Bortezomib will be given as a 1 mg/mL solution intravenous (IV) push over 3 to 5 seconds. For subcutaneous (SQ) administration, bortezomib will be mixed at 2.5 mg/ml. intervention 2: Vorinostat should be taken orally (PO) with food. intervention 3: Given by intravenous (IV) injection. intervention 4: Given by intravenous (IV) injection. intervention 5: Methotrexate will be given intrathecally (IT) along with hydrocortisone and cytarabine. intervention 6: Hydrocortisone will be given intrathecally (IT) along with methotrexate and cytarabine. intervention 7: Given by intravenous (IV) or intramuscular (IM) injection. intervention 8: To be used in case of allergy or intolerance to PEG-Asparaginase. Given by intravenous (IV) or intramuscular (IM) injection. intervention 9: Given orally (PO) or intravenously (IV). intervention 10: Given orally (PO). intervention 11: Given intravenously (IV).

Protocol documents: