The purpose of this study is to determine the maximum tolerated dose (MTD) and/or recommended
phase 2 dose (RP2D), safety and toxicity, and pharmacokinetics (PK) of ixazomib administered
intravenously in combination with multiagent reinduction chemotherapy in pediatric
participants with relapsed/refractory ALL or LLy.
The drug being tested in this study is called Ixazomib. Ixazomib is being tested to determine
the MTD or RP2D of intravenous ixazomib when administered in combination with multiagent
chemotherapy (reinduction therapy) in pediatric participants with relapsed or refractory ALL
or relapsed/refractory LLy.
The study will enroll approximately 18 participants. Doses of ixazomib will be escalated
according to a standard 3+3 dose escalation schema. Participants aged >= 1 year will receive
the starting dose of 1.0 mg/m^2 and participants aged <1 year will receive the starting dose
of 0.03 mg/kg. Ixazomib will be administered in combination with multiagent reinduction
therapy. The dose escalation phase will determine the MTD and/or RP2D of ixazomib. Dose
escalation will be based on the observed safety and tolerability data.
Participants aged <1 year will be assessed separately and will not contribute to the dose
This multi-center trial will be conducted in the United States and Spain. The overall time to
participate in this study is approximately 30 months. Participants will be followed up to Day
60 after the first dose of study drug for a follow-up assessment.
1. Diagnosis of relapsed/refractory ALL with or without extramedullary disease, including
central nervous system (CNS)2 (<5 white blood cell [WBC]/mcL] in the cerebrospinal
fluid [CSF] with blasts) and CNS3 (>=5 WBC/mcL in the CSF with blasts), or
relapsed/refractory LLy. Participants with mixed-phenotype ALL or mature
(Burkitt-like) leukemia are excluded.
2. Relapsed/refractory ALL must have >=5% blasts in the bone marrow by morphology.
3. Relapsed/refractory LLy participants must have measurable disease documented by
clinical, radiologic, and histologic criteria.
4. A Karnofsky performance status of >=50% (for participants aged >16 years) and a Lansky
performance status of >=50% (for participants aged <=16 years).
5. Adequate organ function.
6. Failure of 1 or more therapeutic attempts.
7. Full recovery from the acute toxic effects of all prior chemotherapy, immunotherapy,
or radiotherapy before entering this study, as follows:
- Cytoreduction with hydroxyurea: Hydroxyurea can be initiated and continued for up
to 24 hours before the start of protocol therapy.
- Cytotoxic therapy: At least 14 days must have elapsed since the completion of the
last dose of chemotherapy, except intrathecal (IT) chemotherapy and/or
maintenance therapy, such as vincristine (VCR), mercaptopurine, methotrexate, or
glucocorticoids. There is no waiting period for those relapsing on maintenance
- Hematopoietic stem cell transplantation (HSCT): Participants who have relapsed
after HSCT are eligible, provided they have no evidence of acute or chronic
graft-versus-host disease (GVHD), are not receiving GVHD prophylaxis or
treatment, and are at least 90 days posttransplant at the time of enrollment.
- Hematopoietic growth factors: At least 7 days must have elapsed since the
completion of therapy with granulocyte colony-stimulating factor (G-CSF) or other
growth factor at the time of enrollment. At least 14 days must have elapsed since
the completion of therapy with pegfilgrastim.
- Biologic (antineoplastic agent): At least 7 days must have elapsed since the last
dose of a biologic agent. For agents that have known adverse events (AEs)
occurring beyond 7 days after the end of administration, this period must be
extended beyond the time during which AE are known to occur. The duration of this
interval must be approved by the project clinician (or designee).
- Monoclonal antibodies: At least 3 half-lives must have elapsed after the last
dose of an administered monoclonal antibody.
- Immunotherapy: At least 30 days must have elapsed after the completion of any
type of immunotherapy (example, tumor vaccines, chimeric antigen receptor
- Photon radiotherapy (XRT): Craniospinal XRT is prohibited during protocol
therapy. No washout period is necessary for radiation given to any extramedullary
site other than the CNS; >=90 days must have elapsed if prior total body
irradiation or craniospinal XRT was given.
- Anthracyclines: Participants must have had a lifetime exposure of <400 mg/m^2 of
doxorubicin equivalents of anthracyclines.
- Proteasome inhibitors: Participants with a prior exposure to proteasome inhibitor
(PIs) (example, bortezomib, carfilzomib) are eligible as long as the participant
demonstrated at least a partial response to chemotherapy with a PI.
1. ALL participants: have isolated extramedullary disease, including CNS or testicular
2. Have Grade >=2 peripheral sensory or motor neuropathy, defined by the Modified "Balis"
Pediatric Scale of Pediatric Neuropathies, at the time of enrollment.
3. Have a planned administration of chemotherapy, radiation therapy, or immunotherapy,
other than the study drugs used for this protocol.
4. Have deoxyribonucleic acid fragility syndromes (example, Fanconi anemia, Bloom
5. Have Down syndrome.
6. Are receiving cyclosporine, tacrolimus, or other agents to prevent graft-versus host
disease (GVHD) after HSCT.
7. Have Philadelphia chromosome (Ph)-positive ALL or Ph-like ALL and are currently
receiving tyrosine kinase inhibitor therapy.
8. Are receiving systemic treatment with strong inducers of cytochrome P450 3A
(CYP3A)(example,rifampin, rifapentine, rifabutin, carbamazepine, phenytoin,
phenobarbital, St. John's wort) within 14 days before study enrollment.
9. Are receiving systemic treatment with strong CYP3A inhibitors within 14 days before
10. Are receiving systemic treatment with inhibitors or inducers of P-glycoprotein (P-gp)
within 14 days before study enrollment.