Clinical Trials /

Intravenous Ixazomib in Pediatric Participants With Relapsed or Refractory Acute Lymphoblastic Leukemia (ALL) or Lymphoblastic Lymphoma (LLy)

NCT03888534

Description:

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.

Related Conditions:
  • Acute Lymphoblastic Leukemia
  • Lymphoblastic Lymphoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Intravenous Ixazomib in Pediatric Participants With Relapsed or Refractory Acute Lymphoblastic Leukemia (ALL) or Lymphoblastic Lymphoma (LLy)
  • Official Title: Open-Label Phase 1 Study to Assess the Maximum Tolerated Dose, Pharmacokinetics, and Safety of Ixazomib Administered Intravenously to Pediatric Patients Aged 0 to <18 Years With Relapsed or Refractory Acute Lymphoblastic Leukemia, With or Without Extramedullary Disease, or Relapsed or Refractory Lymphoblastic Lymphoma

Clinical Trial IDs

  • ORG STUDY ID: C16051
  • SECONDARY ID: U1111-1225-3528
  • SECONDARY ID: 2018-003907-20
  • NCT ID: NCT03888534

Conditions

  • Precursor Cell Lymphoblastic Leukemia-lymphoma

Interventions

DrugSynonymsArms
IxazomibMLN9708Ixazomib

Purpose

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.

Detailed Description

      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
      escalation assessment.

      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.
    

Trial Arms

NameTypeDescriptionInterventions
IxazomibExperimentalIxazomib, injection, intravenously, once on Days 1, 4, 8, and 11 in a single 29-day treatment cycle in combination with multiagent reinduction therapy. Participants >= 1 year will receive the starting dose of 1.0 milligram per square meter (mg/m^2) and <1 year will receive the starting dose of 0.03 milligram per kilogram (mg/kg). The dose escalation phase will determine the MTD or RP2D of Ixazomib. Dose of Ixazomib will be escalated based on the observed safety and tolerability data.
  • Ixazomib

Eligibility Criteria

        Inclusion Criteria:

          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
                  therapy.

               -  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
                  T-cells).

               -  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.

        Exclusion criteria:

          1. ALL participants: have isolated extramedullary disease, including CNS or testicular
             disease.

          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
             syndrome).

          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
             study enrollment.

         10. Are receiving systemic treatment with inhibitors or inducers of P-glycoprotein (P-gp)
             within 14 days before study enrollment.
      
Maximum Eligible Age:17 Years
Minimum Eligible Age:N/A
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Number of Participants with Dose-limiting Toxicities (DLT) During Reinduction Chemotherapy
Time Frame:Up to Day 29
Safety Issue:
Description:DLT: Grade 4 nonhematologic toxicity after first dose of ixazomib and is probably/definitely attributable to the ixazomib treatment regimen, with exceptions, example fever/infection with/without hospitalization, fatigue and gastrointestinal symptoms, hypofibrinogenemia, metabolic/laboratory abnormalities that resolve to less than or equal to(<=)Grade 2 within 7 days. Any Grade 3/4 nonhematologic toxicity after first dose of ixazomib that is possibly/probably/definitely attributable to the ixazomib treatment regimen and results in omission of subsequent dose of chemotherapy, with exception of fever/infection. Hematologic toxicities: Failure to recover a peripheral absolute neutrophil count (ANC) ≥0.5*10^9 per liter (/L) and a platelet count ≥50*10^9/L due to documented bone marrow hypoplasia (cellularity <10 20%) within 42 days after the beginning of systemic chemotherapy without evidence of active disease by bone marrow evaluation or active infection.

Secondary Outcome Measures

Measure:Overall Response Rate (ORR)
Time Frame:Up to 30 months
Safety Issue:
Description:ORR is defined as the percentage of participants with complete response (CR) or CR with incomplete platelet recovery (CRp) based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. CR is defined as bone marrow with less than 5 percent (%) blast by morphology, no evidence of circulating blasts or extramedullary disease, and recovery of peripheral counts (ANC >=1.0*10^9/L and a platelet count >=100*10^9/L). CRp is defined as bone marrow with <5% blasts by morphology, no evidence of circulating blasts or extramedullary disease, and recovery of ANC (>1000/mcL) but insufficient recovery of platelets (counts <100, 000/mcL).

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Millennium Pharmaceuticals, Inc.

Trial Keywords

  • Drug Therapy

Last Updated

February 20, 2020