Bortezomib, Vorinostat, and Combination Chemotherapy in Treating Infants with Newly Diagnosed Acute Lymphoblastic Leukemia

This phase I / II trial studies the side effects and best dose of vorinostat and to see how well it works when given together with bortezomib and combination chemotherapy in treating infants (patients less than 1 year old) with newly diagnosed acute lymphoblastic leukemia. Bortezomib and vorinostat may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as methotrexate, hydrocortisone, and cytarabine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving more than one drug (combination chemotherapy) with bortezomib and vorinostat may be a better treatment for acute lymphoblastic leukemia.

Inclusion Criteria

• Patient has newly diagnosed acute lymphoblastic leukemia (ALL) or acute undifferentiated leukemia with >= 25% blasts in the bone marrow (M3), with or without extramedullary disease; patients with T-cell ALL are eligible; patients with bilineage or biphenotypic acute leukemia are eligible, provided the morphology and immunophenotype are predominantly lymphoid
• Limited prior therapy, including hydroxyurea for 72 hours or less, systemic glucocorticoids for one week or less, one dose of vincristine, and one dose of intrathecal chemotherapy
• Written informed consent following Institutional Review Board, National Cancer Institute (NCI), Food and Drug Administration (FDA), and Office for Human Research Protections (OHRP) guidelines

Exclusion Criteria

• Patients with prior therapy, other than therapy specified above
• Patients with mature B-cell ALL or acute myelogenous leukemia (AML)
• Patients with Down syndrome
• Inability or unwillingness of legal guardian/representative to give written informed consent

PRIMARY OBJECTIVE:

I. To determine the tolerability of incorporating bortezomib and vorinostat into an acute lymphoblastic leukemia (ALL) chemotherapy backbone for newly diagnosed infants with ALL.

SECONDARY OBJECTIVES:

I. To estimate the event-free survival and overall survival of infants with ALL who are treated with bortezomib and vorinostat in combination with an ALL chemotherapy backbone.

II. To measure minimal residual disease (MRD) positivity using both flow cytometry and polymerase chain reaction (PCR).

III. To compare end of induction, end of consolidation, and end of reinduction MRD levels to a treatment protocol for infants younger than 1 year with acute lymphoblastic leukemia (Interfant99).

EXPLORATORY OBJECTIVES:

I. To measure histone acetylation, ubiquitination, and methylation in leukemic blasts pre and post treatment with bortezomib and vorinostat.

II. Assess nuclear factor-kappa beta (NF-kB) activity and proteasome inhibition pre and post treatment with bortezomib.

III. To assess the prognostic value of MRD by deep sequencing.

IV. Identify all genomic lesions by comprehensive whole genome, exome and transcriptome sequencing on all patients.

V. Evaluate the sensitivity of patient blasts in vitro to a panel of highly active agents identified by a high throughput drug screen on primary infant ALL specimens.

VI. Identify subclones in patients with detectable minimal residual disease by next generation deep sequencing.

VII. Determine clonal evolution of relapsed patients by next generation sequencing.

VIII. Study immune repertoire diversity over the course of treatment by deep sequencing of lymphocyte variable regions.

IX. Describe methotrexate clearance in infants with ALL.

OUTLINE: This is a dose-escalation study of vorinostat.

REMISSION INDUCTION: Patients receive triple intrathecal therapy (ITMHA) comprised of methotrexate, hydrocortisone, and cytarabine intrathecally (IT) or intraventricularly on days 1, 8, 15, and 22. Patients with central nervous system (CNS) 3, 2, and traumatic lumbar puncture (LP) receive additional triple intrathecal or intraventricular treatment on days 4 and 11. Patients also receive mitoxantrone hydrochloride intravenously (IV) on days 8 and 9, pegaspargase IV over 1-2 hours on day 5, dexamethasone orally (PO), nasogastrically (NG), or IV twice daily (BID) on days 1-4, 8-11, and 15-18, bortezomib IV over 3-5 seconds or subcutaneously (SC) on days 1, 4, 8, 11, 15, and 18, vorinostat PO or NG on days 1-4, 8-11, and 15-18, cyclophosphamide IV over 30 minutes every 12 hours on days 22 and 23, cytarabine IV on days 23-26 and 30-33 and mercaptopurine PO or NG on days 22-35.

CONSOLIDATION: Patients receive high-dose methotrexate IV over 24 hours once daily (QD) on days 1, 15, 29, and 43, mercaptopurine PO or NG on days 1-56, and methotrexate, hydrocortisone, and cytarabine IT on days 1, 15, 29, and 43.

RE-INDUCTION: Patients receive mitoxantrone hydrochloride IV on days 1 and 2, pegaspargase IV over 1-2 hours on days 3 and 18, dexamethasone PO BID, NG or IV on days 1-4, 8-11, and 15-18, bortezomib IV over 3-5 seconds or SC on days 1, 4, 8, 11, 15, and 18, vorinostat PO or NG on days 1-4, 8-11, and 15-18, and methotrexate, hydrocortisone, and cytarabine IT on day 1 (patients with CNS3 receive an additional dose of intrathecal chemotherapy on day 15).

NOTE: Patients that achieve MRD negative status following reinduction may proceed directly to stem cell transplant if a suitable donor is available. Patients that remain MRD positive are eligible for CAR T cells if available, or they may undergo a Reintensification phase following Reinduction and then proceed to hematopoietic stem cell transplant in first remission. Re-intensification treatment may begin after the completion of re-induction, provided that the absolute neutrophil count (ANC) >= 500/mm^3, white blood cells (WBC) >= 1000/mm^3, and platelet count >= 50 x 10^9/L.

RE-INTENSIFICATION THERAPY: Patients receive cytarabine IV every 12 hours on days 1 and 2, etoposide IV over 1-4 hours on days 3-5, dexamethasone PO BID, NG or IV on days 1-5, pegaspargase IV over 1-2 hours on day 6, and methotrexate, hydrocortisone, and cytarabine IT on day 5.

MAINTENANCE CHEMOTHERAPY (Patients with ANC >= 500/mm^3, WBC >= 1000/mm^3, and platelet count >= 50 x 10^9/L as well as no evidence of grade 3 or 4 mucositis receive maintenance therapy): Patients receive dexamethasone PO BID, NG or IV on days 1-5, vincristine sulfate IV on day 1, mercaptopurine PO or NG on days 1-28, methotrexate IV, intramuscularly (IM), or PO on day 1 (cycles with no ITMHA only), 8, 15, and 22, and methotrexate, hydrocortisone, and cytarabine IT on day 1 (cycles 1-8 for patients with CNS1, cycles 1-11 for patients with CNS2, and cycles 1-13 for patients with CNS3 and traumatic LP). Treatment repeats every 28 days for 20 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 4 months for 1 year, every 6 months for 1 year, and then yearly for up to 10 years.

Trial Phase Phase I/II

Trial Type Treatment

Lead Organization
Saint Jude Children's Research Hospital

Principal Investigator
Sima C. Jeha

• Primary ID TINI
• Secondary IDs NCI-2015-01493
• Clinicaltrials.gov ID NCT02553460