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

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Acute Lymphoblastic Leukemia

Intervention / Treatment
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* Drug: ITMHA
* Drug: Dexamethasone
* Drug: Mitoxantrone
* Drug: Pegaspargase
* Drug: Asparaginase Erwinia Chrysanthemi
* Drug: Bortezomib
* Drug: Vorinostat
* Drug: Cyclophosphamide
* Drug: Mercaptopurine
* Drug: Methotrexate
* Drug: Leucovorin Calcium
* Drug: Cytarabine
* Drug: Etoposide
* Drug: Vincristine


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Maximum Age: 365 Days

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment<br>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: ITMHA<br>* Given intrathecally (IT).<br>* Other names: Methotrexate/hydrocortisone/cytarabine;Drug: Dexamethasone<br>* Given orally (PO) or naso-gastrically (NG) or intravenously (IV).<br>* Other names: Dexameth®;Drug: Mitoxantrone<br>* Given IV.<br>* Other names: Mitozantrone;Drug: Pegaspargase<br>* Given IV. If participant is allergic to pegaspargase, Asparaginase Erwinia Chrysanthemi will be used.<br>* Other names: Oncaspar®;Drug: Asparaginase Erwinia Chrysanthemi<br>* Asparaginase Erwinia Chrysanthemi will be used in case of allergy or intolerance of participant to PEG-asparaginase. Given IV (preferred) or intramuscularly (IM).<br>* Other names: Crisantaspase;Drug: Bortezomib<br>* Given IV.<br>* Other names: LDP-341;Drug: Vorinostat<br>* Taken PO or NG.<br>* Other names: SAHA;Drug: Cyclophosphamide<br>* Given IV.<br>* Other names: Cytoxan®;Drug: Mercaptopurine<br>* Given PO or NG.<br>* Other names: Purinethol®;Drug: Methotrexate<br>* Given IV, IM or PO.<br>* Other names: High Dose MTX;Drug: Leucovorin Calcium<br>* Leucovorin rescue PO or IV.<br>* Other names: Folinic acid;Drug: Cytarabine<br>* Given IV.<br>* Other names: Cytosar-U®;Drug: Etoposide<br>* Given IV. In case of participant allergy, etoposide phosphate (Etopophos®) will be given.<br>* Other names: Vepesid®;Drug: Vincristine<br>* Given IV.<br>* Other names: Oncovin®;|

What is the study measuring?
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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) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Infants