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

Status: Active

Description

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.

Eligibility Criteria

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

Locations & Contacts

California

Los Angeles
Children's Hospital Los Angeles
Status: Active
Contact: Paul S. Gaynon
Phone: 323-361-2163
Email: pgaynon@chla.usc.edu
Orange
Children's Hospital of Orange County
Status: Active
Contact: Ivan I. Kirov
Phone: 714-997-3000
Email: ikirov@choc.org
Palo Alto
Lucile Packard Children's Hospital Stanford University
Status: Active
Contact: Norman James Lacayo
Phone: 650-497-8953
Email: lacayon@stanford.edu
San Diego
Rady Children's Hospital - San Diego
Status: Active
Contact: Deborah E. Schiff
Phone: 858-966-5934
Email: dschiff@chsd.org

Minnesota

Minneapolis
Children's Hospitals and Clinics of Minnesota - Minneapolis
Status: Active
Contact: Michael Kerr Richards
Phone: 612-813-5193
Email: michael.richards@childrensmn.org

North Carolina

Charlotte
Saint Jude Affiliate-Charlotte
Status: Active
Contact: Christine Marie Bolen
Phone: 704-384-1900
Email: cybolen@novanthealth.org

Ohio

Cincinnati
Cincinnati Children's Hospital Medical Center
Status: Active
Contact: Erin Haag Breese
Phone: 513-636-2799
Email: erin.breese@cchmc.org
Cleveland
Rainbow Babies and Childrens Hospital
Status: Active
Contact: John J. Letterio
Email: john.letterio@uhhospitals.org

Oregon

Portland
Oregon Health and Science University
Status: Active
Contact: Bill Hoon Chang
Phone: 503-494-1080
Email: trials@ohsu.edu

Tennessee

Memphis
St. Jude Children's Research Hospital
Status: Active
Contact: Tanja A. Gruber
Phone: 901-319-0070
Email: Tanja.Gruber@stjude.org

Virginia

Norfolk
Children's Hospital of The King's Daughters
Status: Active
Contact: Eric Jeffrey Lowe
Phone: 757-668-7243
Email: eric.lowe@chkd.org

Alberta

Calgary
Alberta Children's Hospital
Status: Active
Contact: Victor Anthony Lewis
Phone: 403-220-6898
Email: victor.lewis@ahs.ca
Edmonton
Stollery Children's Hospital
Status: Active
Contact: Sunil Jayantilal Sunderlal Desai
Phone: 780-248-5415
Email: sunil.desai@ahs.ca

British Columbia

Vancouver
British Columbia Children's Hospital
Status: Active
Contact: Kirk Raymond Schultz
Phone: 604-875-2345ext6477
Email: kschultz@mail.ubc.ca

Ontario

Hamilton
McMaster Children's Hospital at Hamilton Health Sciences
Status: Active
Contact: Uma H. Athale
Phone: 905-521-2100ext73376
Email: athaleu@mcmaster.ca

Quebec

Montreal
Centre Hospitalier Universitaire Sainte-Justine
Status: Active
Contact: Thai Hoa Tran
Email: thai-hoa.tran@recherche-ste-justine.qc.ca
The Montreal Children's Hospital of the MUHC
Status: Active
Contact: Catherine Vezina
Phone: 514-412-4445
Email: info@thechildren.com
Quebec
Centre Hospitalier Universitaire de Quebec
Status: Active
Contact: Bruno Michon
Phone: 418-525-4444
Email: bruno.michon@mail.chuq.qc.ca

Trial Objectives and Outline

PRIMARY OBJECTIVES:

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).

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.

NOTE: Patients with MRD > 0.01% on day 1 of re-induction, OR patients with increasing MRD during consolidation undergo a re-intensification phase following re-induction 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.

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 on day 1 (courses with no ITMHA only), 8, 15, and 22, and methotrexate, hydrocortisone, and cytarabine IT on day 1 (courses 1-8 for patients with CNS1, courses 1-11 for patients with CNS2, and courses 1-13 for patients with CNS3 and traumatic LP). Treatment repeats every 28 days for 20 courses 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 & Type

Trial Phase

Phase I/II

Trial Type

Treatment

Lead Organization

Lead Organization
St. Jude Children's Research Hospital

Principal Investigator
Tanja A. Gruber

Trial IDs

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