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Patients will be treated on ixazomib at 1.6 mg/m\^2/day on Days 1, 4, 8, and 11. Vincristine IV at 1.5 mg/m\^2 on Days 1, 8, 15 and 22. Pegaspargase IV/IM at 2500 IU/m\^2 on Days 2 and 15, Doxorubicin at 60 mg/m\^2 on Days 1, Dexamethasone IV/PO at 10 mg/m\^2 continuous starting on Day 1 thru Day 14, and IT chemotherapy dependent on patient's CNS status at time of enrollment. This arm is the starting Dose Level for patients being enrolled.

Patients will be treated on ixazomib at 2.0 mg/m\^2/day on Days 1, 4, 8, and 11. Vincristine IV at 1.5 mg/m\^2 on Days 1, 8, 15 and 22. Pegaspargase IV/IM at 2500 IU/m\^2 on Days 2 and 15, Doxorubicin at 60 mg/m\^2 on Days 1, Dexamethasone IV/PO at 10 mg/m\^2 continuous starting on Day 1 thru Day 14, and IT chemotherapy dependent on patient's CNS status at time of enrollment. Patients will be treated at this arm Dose Level once patient accrual at Dose Level 1 has been completed and dose escalation is allowed as defined by the 3+3 design.

Patients will be treated on ixazomib at 1.2 mg/m\^2/day on Days 1, 4, 8, and 11. Vincristine IV at 1.5 mg/m\^2 on Days 1, 8, 15 and 22. Pegaspargase IV/IM at 2500 IU/m\^2 on Days 2 and 15, Doxorubicin at 60 mg/m\^2 on Days 1, Dexamethasone IV/PO at 10 mg/m\^2 continuous starting on Day 1 thru Day 14, and IT chemotherapy dependent on patient's CNS status at time of enrollment. This arm Dose Level -1 is needed only if de-escalation from Dose Level 1 is required.

Patients will be treated on ixazomib at 1.6 mg/m\^2/day on Days 1, 4, 8, and 11. Vincristine IV at 1.5 mg/m\^2 on Days 1, 8, 15 and 22. Pegaspargase IV/IM at 2500 IU/m\^2 on Days 2 and 15, Doxorubicin at 60 mg/m\^2 on Days 1, Dexamethasone IV/PO at 10 mg/m\^2 continuous starting on Day 1 thru Day 14, and IT chemotherapy dependent on patient's CNS status at time of enrollment. Leucovorin PO/IV at 5 mg/m\^2/dose X 2 doses given 24 and 30 hours after IT Methotrexate or Triple IT will also be given on this arm. This arm is only for patients with Down syndrome (Stratum B).

Days 1, 4, 8, and 11. Note: at least 72 hours must have elapsed between doses

Dose Phase 1 - Assigned upon study entry.

Phase 2 - PO formulation at RP2D

IV push over 1 minute or infusion via minibag as per institutional policy

Days 1, 8, 15 and 22

Dose: ≥ 1 year: 1.5mg/m2/dose (maximum dose 2mg)

≥ 6 months and \< 1 year: 1.2mg/m2/dose

\< 6 months: 1mg/m2/dose

Days 1-14

Dose: ≥ 1 year: 10mg/m2/day, divided BID (i.e., 5mg/m2/dose, BID)

≥ 6 months and \< 1 year: 8mg/m2/day, divided BID (i.e., 4 mg/m2/dose, BID)

\< 6 months: 7mg/m2/day, divided BID (i.e., 3.5 mg/m2/dose, BID)

Days 2, 15

Dose ≥ 1 year: 2,500 International units (IU)/m2/dose

≥ 6 months and \< 1 year: 2,000 IU/m2/dose

\< 6 months: 1,750 IU/m2/dose

Patient with allergic reaction to Pegaspargase can be given Erwinase IM/IV on Mon/Wed/Fri (or every other day per institutional standard) x 6 doses for each dose of Pegaspargase.

Dosing guideline for Erwinase:

* 1 year: 25,000 IU/m2/dose
* 6 months and \< 1 year: 20,000 IU/m2/dose

\< 6 months: 17,500 IU/m2/dose

Day 1

Dose ≥ 1 year: 60mg/m2/dose

≥ 6 months and \< 1 year: 48 mg/m2/dose

\< 6 months: 42mg/m2/dose

For patients with CNS 1 or CNS 2, on Days 1, 15, and 29

Methotrexate (IT)

For patients with CNS 3, on Days 1, 8, 15, 22, and 29

Triple IT (Methotrexate, Hydrocortisone, Cytarabine)

For patients with Down syndrome only, on Days 2, 9, 16, 23, and 30 (based on dates when IT Methotrexate or Triple IT is given)

Terzah Horton, MD

This is a phase 1/2 study of a drug called Ixazomib in combination with cytotoxic chemotherapy consisting of Vincristine, Dexamethasone, Asparaginase, and Doxorubicin (VXLD).

The phase 1 study is to determine the maximum tolerated dose (MTD) of the PO formulation, followed by a screening phase 2 study to investigate the efficacy of ixazomib in combination with chemotherapy in children with relapsed ALL and lymphoblastic lymphoma (LLy). The single arm, screening phase 2 design will allow us to use a minimal number of patients to obtain preliminary information about treatment efficacy. Discovering a safe and tolerable dose of ixazomib in a PO formulation and the preliminary efficacy data will significantly increase the possibility of ixazomib moving forward in frontline pediatric treatment protocols in both intense chemotherapy courses and maintenance courses.

PO Ixazomib in Combination With Chemotherapy for Childhood Relapsed or Refractory Acute Lymphoblastic Leukemia and Lymphoblastic Lymphoma

A TACL Phase 1/2 Study of PO Ixazomib in Combination With Chemotherapy for Childhood Relapsed or Refractory Acute Lymphoblastic Leukemia and Lymphoblastic Lymphoma IND# 140730

The incidence of dose limiting toxicity (DLT) will be measured only during block 1

Takeda

Children's Hospital Los Angeles

Therapeutic Advances in Childhood Leukemia Consortium

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
PO Ixazomib in Combination With Chemotherapy for Childhood Relapsed or Refractory Acute Lymphoblastic Leukemia and Lymphoblastic Lymphoma	NCT03817320	ALL, Childhood Lymphoblastic L... Lymphoblastic L...	Ixazomib Vincristine Dexamethasone Asparaginase Doxorubicin Methotrexate (I... Triple IT (Meth... Leucovorin	1 Year - 21 Years	Therapeutic Advances in Childhood Leukemia Consortium
PO Ixazomib in Combination With Chemotherapy for Childhood Relapsed or Refractory Acute Lymphoblastic Leukemia and Lymphoblastic Lymphoma	NCT03817320	ALL, Childhood Lymphoblastic L... Lymphoblastic L...	Ixazomib Vincristine Dexamethasone Asparaginase Doxorubicin Methotrexate (I... Triple IT (Meth... Leucovorin	1 Year - 21 Years	Therapeutic Advances in Childhood Leukemia Consortium

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