Total Therapy for Infants With Acute Lymphoblastic Leukemia (ALL) I

The purpose of this study is to test the good and bad effects of the study drugs bortezomib and vorinostat when they are given in combination with chemotherapy commonly used to treat acute lymphoblastic leukemia (ALL) in infants. For example, adding these drugs could decrease the number of leukemia cells, but it could also cause additional side effects. Bortezomib and vorinostat have been approved by the US Food and Drug Administration (FDA) to treat other cancers in adults, but they have not been approved for treating children with leukemia. With this research, we plan to meet the following goals:

PRIMARY OBJECTIVE:

• Determine the tolerability of incorporating bortezomib and vorinostat into an ALL chemotherapy backbone for newly diagnosed infants with ALL.

SECONDARY OBJECTIVES:

• 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.
• Measure minimal residual disease (MRD) positivity using both flow cytometry and PCR.
• Compare end of induction, end of consolidation, and end of reinduction MRD levels to Interfant99 (ClinicalTrials.gov registration ID number NCT00015873) participant outcomes.

Study Overview

• Status: Active, not recruiting
• Conditions: Acute Lymphoblastic Leukemia
• Intervention / Treatment: Drug: Mitoxantrone; Drug: Cyclophosphamide; Drug: ITMHA; Drug: Dexamethasone; Drug: Pegaspargase; Drug: Asparaginase Erwinia Chrysanthemi; Drug: Bortezomib; Drug: Vorinostat; Drug: Mercaptopurine; Drug: Methotrexate; Drug: Leucovorin Calcium; Drug: Cytarabine; Drug: Etoposide; Drug: Vincristine

Detailed Description

Treatment will consist of 4 main phases: Remission Induction, Consolidation, Reinduction, and Maintenance. High risk patients will receive a reintensification phase prior to transplant in first remission.

REMISSION INDUCTION: Chemotherapy will be given in an attempt to induce the participant's leukemia into remission. Drugs given are intrathecal triple drug treatment with methotrexate, hydrocortisone and Ara-C (ITMHA); dexamethasone; vorinostat; bortezomib; PEG-asparaginase; mitoxantrone; cyclophosphamide; cytarabine; and 6-mercaptopurine.

CONSOLIDATION PHASE: After the participant's blood counts have recovered from Remission Induction, he/she will move to the consolidation phase. This therapy is given to kill any remaining leukemia cells. Drugs given are ITMHA, high-dose methotrexate, and 6-mercaptopurine.

RE-INDUCTION: This phase aims to improve the participant's overall response to therapy by again seeking to bring his/her leukemia into remission. Drugs given are ITMHA, mitoxantrone, peg-asparaginase, dexamethasone, bortezomib, and vorinostat.Participants that achieve MRD negative status following Re-Induction may proceed directly to stem cell transplant (SCT) (SCT not part of this study).

RE-INTENSIFICATION: Participants that remain MRD positive following Consolidation or Reinduction may receive Chimeric Antigen Receptor T-Cell therapy (CART), if available (CART is not part of this study), or proceed to a Reintensification phase then go on to stem cell transplant (SCT).

MAINTENANCE PHASE: Participants with negative MRD after consolidation will skip the re-intensification phase and proceed to receive maintenance therapy to keep the leukemia from returning. Drugs given are ITMHA, dexamethasone, vincristine, 6-mercaptopurine and methotrexate. Each cycle of these drugs lasts 28 days and will be repeated up to 20 times as long as there are no serious side effects.

• Study Type: Interventional
• Enrollment (Actual): 50
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Canada
  • Alberta
    • Calgary, Alberta, Canada, T3A 6A8
      • Alberta Children's Hospital
    • Edmonton, Alberta, Canada, T6G 2B7
      • Stollery Children's Hospital
  • British Columbia
    • Vancouver, British Columbia, Canada, V6H 3V4
      • Children's & Women's Health Centre of British Columbia
  • Ontario
    • Hamilton, Ontario, Canada, L85 4J9
      • McMaster Children's Hospital at Hamilton Health Sciences
  • Quebec
    • Montreal, Quebec, Canada, H3T 1C5 CAN
      • Centre Hospitalier Universitaire Sainte-Justine
    • Montreal, Quebec, Canada, H4A 3J1
      • The Montreal Children's Hospital (MUHC-McGill)
    • Québec, Quebec, Canada, G1V 4G2
      • Centre Hospitalier Universitaire de Quebec
• United States
  • California
    • Los Angeles, California, United States, 90027
      • Children's Hospital Los Angeles
    • Orange, California, United States, 92868
      • Children's Hospital of Orange County
    • Palo Alto, California, United States, 94304
      • Lucile Packard Children's Hospital Stanford University
    • San Diego, California, United States, 92123
      • Rady Children's Hospital and Health Center
  • Minnesota
    • Minneapolis, Minnesota, United States, 55404
      • Children's Hospital and Clinics of Minnesota
  • North Carolina
    • Charlotte, North Carolina, United States, 28204
      • St. Jude Affiliate-Charlotte
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Cincinnati Children's Hospital
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health and Science University
  • Tennessee
    • Memphis, Tennessee, United States, 38105
      • St. Jude Children's Research Hospital
  • Virginia
    • Norfolk, Virginia, United States, 23507
      • Children's Hospital of the King's Daughters (CHKD)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 1 year (Child)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Patient is ≤ 365 days of age at the time of diagnosis.
• 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, NCI, FDA, and Office for Human Research Protections (OHRP) Guidelines.

Exclusion Criteria:

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Treatment; Participants who meet eligibility requirements will receive remission induction, consolidation treatment, reinduction, reintensification and maintenance therapy. Interventions: ITMHA, dexamethasone, mitoxantrone, pegaspargase or asparaginase Erwinia chrysanthemi, bortezomib, vorinostat, cyclophosphamide, mercaptopurine, methotrexate, leucovorin calcium, cytarabine, etoposide, and vincristine.

Drug: Mitoxantrone; Given IV.; Other Names: Mitozantrone; Novantrone®; Drug: Cyclophosphamide; Given IV.; Other Names: Cytoxan®; Drug: ITMHA; Given intrathecally (IT).; Other Names: Intrathecal Triples; Methotrexate/hydrocortisone/cytarabine; Drug: Dexamethasone; Given orally (PO) or naso-gastrically (NG) or intravenously (IV).; Other Names: Decadron®; Hexadrol®; Dexone®; Dexameth®; Drug: Pegaspargase; Given IV. If participant is allergic to pegaspargase, Asparaginase Erwinia Chrysanthemi will be used.; Other Names: PEG-asparaginase; Oncaspar®; Drug: Asparaginase Erwinia Chrysanthemi; Asparaginase Erwinia Chrysanthemi will be used in case of allergy or intolerance of participant to PEG-asparaginase. Given IV (preferred) or intramuscularly (IM).; Other Names: Crisantaspase; Erwinase®; Erwinia chrysanthemi; Erwinaze^T^M; Drug: Bortezomib; Given IV.; Other Names: MLN341; PS-341; LDP-341; Velcade®; Drug: Vorinostat; Taken PO or NG.; Other Names: SAHA; Solinza®; Suberoylanidide Hydroxamic Acid; Drug: Mercaptopurine; Given PO or NG.; Other Names: 6-MP; Purinethol®; Drug: Methotrexate; Given IV, IM or PO.; Other Names: MTX; High Dose MTX; Drug: Leucovorin Calcium; Leucovorin rescue PO or IV.; Other Names: Folinic acid; Wellcovorin®; Drug: Cytarabine; Given IV.; Other Names: Ara-C; Cytosar-U®; Drug: Etoposide; Given IV. In case of participant allergy, etoposide phosphate (Etopophos®) will be given.; Other Names: VP-16; Vepesid®; Drug: Vincristine; Given IV.; Other Names: Oncovin®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Treatment-related Mortality (TRM)	Number of treatment related deaths divided by total number of patients during induction or reinduction therapy. Presented as percentage	At the end of reinduction (up to 5 months after start of therapy)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
3-year Event Free Survival (EFS)	Event-free survival (EFS) will be estimated by the Kaplan-Meier estimator. For EFS, relapse and second malignancies will be considered as failures in addition to death in complete remission. The time to EFS will be set to 0 for patients who fail to achieve complete remission. EFS probability will be estimated with 95% confidence intervals.	3 years after completion of therapy (up to 5 years after start of therapy)
5-year Overall Survival (OS)	Overall survival (OS) will be estimated by the Kaplan-Meier estimator. OS probability at years 3, 5, 10 will be estimated with 95% confidence intervals.	5 years after completion of therapy (up to 7 years after start of therapy)
Minimal Residual Disease (MRD) Positivity Using Flow Cytometry at Day 22, End of Induction, End of Consolidation, and End of Maintenance.	Proportion of participants with positive MRD at the end of each therapy block.	At end of induction (approximately 6 weeks), end of consolidation (approximately 14 weeks), end of reinduction (approximately 19 weeks), end of reintensification (approximately 23 weeks), and end of maintenance therapy (approximately 2 years)
Minimal Residual Disease (MRD) Positivity Using PCR End of Induction, End of Consolidation, and End of Maintenance.	Proportion of participants with positive MRD at the end of each therapy block.	At end of induction (approximately 6 weeks), end of consolidation (approximately 14 weeks), end of reinduction (approximately 19 weeks), end of reintensification (approximately 23 weeks), and end of maintenance therapy (approximately 2 years)

Collaborators and Investigators

• Sponsor: St. Jude Children's Research Hospital
• Collaborators: Baylor College of Medicine; Gateway for Cancer Research
• Investigators: Study Chair: Tanja Gruber, MD, PhD, Lucile Packard Children's Hospital Stanford University; Principal Investigator: Sima Jeha, MD, St. Jude Children's Research Hospital

Publications and helpful links

Helpful Links

• St. Jude Children's Research Hospital
• Clinical Trials Open at St. Jude

Study record dates

Study Major Dates

• Study Start (Actual): January 29, 2016
• Primary Completion (Actual): May 10, 2022
• Study Completion (Estimated): October 1, 2031

Study Registration Dates

• First Submitted: September 16, 2015
• First Submitted That Met QC Criteria: September 16, 2015
• First Posted (Estimated): September 17, 2015

Study Record Updates

• Last Update Posted (Estimated): January 18, 2024
• Last Update Submitted That Met QC Criteria: January 16, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: Infants
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Autonomic Agents; Peripheral Nervous System Agents; Antiviral Agents; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Protective Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Dermatologic Agents; Micronutrients; Vitamins; Reproductive Control Agents; Antidotes; Vitamin B Complex; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Folic Acid Antagonists; Histone Deacetylase Inhibitors; Dexamethasone; Cyclophosphamide; Etoposide; Leucovorin; Levoleucovorin; Bortezomib; Cytarabine; Methotrexate; Vincristine; Asparaginase; Mitoxantrone; Mercaptopurine; Vorinostat; Hydrocortisone; Pegaspargase
• Other Study ID Numbers: TINI; NCI-2015-01493 (Registry Identifier: NCI Clinical Trial Registration Program)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No