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.
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
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
50
Given intrathecally (IT).
Given orally (PO) or naso-gastrically (NG) or intravenously (IV).
Given IV.
Given IV. If participant is allergic to pegaspargase, Asparaginase Erwinia Chrysanthemi will be used.
Asparaginase Erwinia Chrysanthemi will be used in case of allergy or intolerance of participant to PEG-asparaginase. Given IV (preferred) or intramuscularly (IM).
Given IV.
Taken PO or NG.
Given IV.
Given PO or NG.
Given IV, IM or PO.
Leucovorin rescue PO or IV.
Given IV.
Given IV. In case of participant allergy, etoposide phosphate (Etopophos®) will be given.
Given IV.
Children's Hospital Los Angeles
Los Angeles, California, United States
Children's Hospital of Orange County
Orange, California, United States
Lucile Packard Children's Hospital Stanford University
Palo Alto, California, United States
Children's Hospital and Clinics of Minnesota
Minneapolis, Minnesota, United States
St. Jude Affiliate-Charlotte
Charlotte, North Carolina, United States
Cincinnati Children's Hospital
Cincinnati, Ohio, United States
Oregon Health and Science University
Portland, Oregon, United States
St. Jude Children's Research Hospital
Memphis, Tennessee, United States
Children's Hospital of the King's Daughters (CHKD)
Norfolk, Virginia, United States
Alberta Children's Hospital
Calgary, Alberta, Canada
...and 5 more locations
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
Time frame: At the end of reinduction (up to 5 months after start of therapy)
Percentage of Participants With 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.
Time frame: 3 years after completion of therapy (up to 5 years after start of therapy)
Percentage of Participants With 5-year Overall Survival (OS)
Overall survival (OS) will be estimated by the Kaplan-Meier estimator with 95% confidence intervals.
Time frame: 5 years after completion of therapy (up to 7 years after start of therapy)
Minimal Residual Disease (MRD) Positivity Using Flow Cytometry or PCR at Induction 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. The proportion of MRD positive patients is determined by the number of patients that are MRD positive at the end of each therapy block divided by the number of patients that completed each therapy block.
Time frame: 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)
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