Clinical trial NCT02553460: Total Therapy for Infants With Acute Lymphoblastic Leukemia (ALL) I
Official title: Total Therapy for Infants With Acute Lymphoblastic Leukemia (ALL) I
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
PHASE2
Conditions: Acute Lymphoblastic Leukemia
Keywords: Infants
Lead sponsor: St. Jude Children's Research Hospital
Sponsor class: OTHER
Collaborators: name: Gateway for Cancer Research
name: Baylor College of Medicine
First posted: 2015-09-17
Enrollment: 50
Sex: ALL
Maximum age (years): 365
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Percentage of Treatment-related Mortality (TRM)
timeFrame: At the end of reinduction (up to 5 months after start of therapy)
Secondary outcomes:
measure: Percentage of Participants With 3-year Event Free Survival (EFS)
timeFrame: 3 years after completion of therapy (up to 5 years after start of therapy)
measure: Percentage of Participants With 5-year Overall Survival (OS)
timeFrame: 5 years after completion of therapy (up to 7 years after start of therapy)
measure: Minimal Residual Disease (MRD) Positivity Using Flow Cytometry or PCR at Induction Day 22, End of Induction, End of Consolidation, and End of Maintenance.
timeFrame: At the end of induction day 22 (approximately 3 weeks), end of induction (approximately 6 weeks), end of consolidation (approximately 14 weeks), and end of maintenance therapy (approximately 2 years)
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Children's Hospital Los Angeles
state: California
city: Orange
country: United States
facility: Children's Hospital of Orange County
state: California
city: Palo Alto
country: United States
facility: Lucile Packard Children's Hospital Stanford University
state: California
city: San Diego
country: United States
facility: Rady Children's Hospital and Health Center
state: California
city: Minneapolis
country: United States
facility: Children's Hospital and Clinics of Minnesota
state: Minnesota
city: Charlotte
country: United States
facility: St. Jude Affiliate-Charlotte
state: North Carolina
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital
state: Ohio
city: Portland
country: United States
facility: Oregon Health and Science University
state: Oregon
city: Memphis
country: United States
facility: St. Jude Children's Research Hospital
state: Tennessee
city: Norfolk
country: United States
facility: Children's Hospital of the King's Daughters (CHKD)
state: Virginia
city: Calgary
country: Canada
facility: Alberta Children's Hospital
state: Alberta
city: Edmonton
country: Canada
facility: Stollery Children's Hospital
state: Alberta
city: Vancouver
country: Canada
facility: Children's & Women's Health Centre of British Columbia
state: British Columbia
city: Hamilton
country: Canada
facility: McMaster Children's Hospital at Hamilton Health Sciences
state: Ontario
city: Montreal
country: Canada
facility: Centre Hospitalier Universitaire Sainte-Justine
state: Quebec
city: Montreal
country: Canada
facility: The Montreal Children's Hospital (MUHC-McGill)
state: Quebec
city: Québec
country: Canada
facility: Centre Hospitalier Universitaire de Quebec
state: Quebec
Study officials:
affiliation: Lucile Packard Children's Hospital Stanford University
name: Tanja Gruber, MD, PhD
role: STUDY_CHAIR
affiliation: St. Jude Children's Research Hospital
name: Sima Jeha, MD
role: PRINCIPAL_INVESTIGATOR
References: