TINI 2: Total Therapy for Infants With Acute Lymphoblastic Leukemia II

Study Overview
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Brief Summary
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The purpose of this study is to improve upon the TINI study treatment. The study will test the ability of a type of immunotherapy called blinatumomab to clear persistent leukemia. Blinatumomab targets CD19 which is located on the leukemia cells outer membrane.

Official Title
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TINI 2: Total Therapy for Infants With Acute Lymphoblastic Leukemia II

Conditions
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Lymphoblastic Leukemia

Intervention / Treatment
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* Drug: Dexamethasone
* Drug: Mitoxantrone
* Drug: PEG asparaginase
* Drug: Bortezomib
* Drug: Vorinostat
* Drug: Mercaptopurine
* Drug: Methotrexate
* Drug: Blinatumomab
* Drug: Ziftomenib


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 CD19 positive acute lymphoblastic leukemia (ALL) or acute undifferentiated leukemia with ≥25% blasts in the bone marrow (M3), with or without extramedullary disease. Patients with CD19 positive biphenotypic acute leukemia are eligible. Patients with CD19 positive mature B-cell ALL that carry a KMT2Ar are eligible. Limited prior therapy, including hydroxyurea for 72 hours or less, systemic glucocorticoids for one week or less, cytarabine for 72 hours or less, one dose of vincristine, and one dose of intrathecal chemotherapy. Written informed consent following Institutional Review Board, NCI, FDA, and OHRP Guidelines. Exclusion Criteria: Patients with prior therapy, other than therapy specified in inclusion criteria. Patients with mature B-cell ALL that does not have a KMT2Ar or patients with acute myelogenous (AML) or T-cell ALL. Patients with Down syndrome. Inability or unwillingness of legal guardian/representative to give written informed consent

Ages Eligible for Study
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Minimum Age: 1 Year

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 criteria will receive remission induction, induction intensification, consolidation I, reinduction block I, reinduction block II, consolidation II, and Maintenance. Interventions: Dexamethasone, Mitoxantrone, PEG-asparaginase, Bortezomib, Vorinostat, Mercaptopurine, Methotrexate and Vincristine, Blinatumomab, Ziftomenib | Drug: Dexamethasone<br>* Given orally (PO) or naso-gastrically (NG) or intravenously (IV).<br>Drug: Mitoxantrone<br>* Given IV<br>Drug: PEG asparaginase<br>* Given IV<br>Drug: Bortezomib<br>* Given IV<br>Drug: Vorinostat<br>* Taken PO or NG<br>Drug: Mercaptopurine<br>* Given PO or NG.<br>Drug: Methotrexate<br>* Given IV, IM or PO<br>Drug: Blinatumomab<br>* Will be administered at 15 mcg/m2/day for 28 days following induction and reinduction<br>Drug: Ziftomenib<br>* 3+3 dose escalation will be done. Dose level 1 will start at 75% of the adult recommended phase two dosing which has been established in phase I studies. Based on tolerability, we will either de-escalate to 50% RP2D (dose level -1) or escalate to 100% RP2D<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Minimal Residual Disease | proportion of patients who are minimal residual disease positive at the end of induction intensification | 5 years and 2 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ziftomenib Maximum Tolerated Dose in Combination with Chemotherapy | determine the estimated maximum tolerated dose of Ziftomenib in combination with chemotherapy, on the basis of observed DLTs | 5 years and 6 months | 
| Event Free Survival |  | 8 years | 
| Overall Survival |  | 8 years |