Clinical Trials /

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

NCT03817320

Description:

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).

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

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: PO Ixazomib in Combination With Chemotherapy for Childhood Relapsed or Refractory Acute Lymphoblastic Leukemia and Lymphoblastic Lymphoma
  • Official Title: 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

Clinical Trial IDs

  • ORG STUDY ID: T2017-002
  • NCT ID: NCT03817320

Conditions

  • ALL, Childhood
  • Lymphoblastic Lymphoma, Childhood
  • Lymphoblastic Leukemia, Acute, Childhood

Interventions

DrugSynonymsArms
IxazomibOpen label design
VincristineOpen label design
DexamethasoneOpen label design
AsparaginaseOpen label design
DoxorubicinOpen label design

Purpose

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).

Detailed Description

      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.
    

Trial Arms

NameTypeDescriptionInterventions
Open label designOtherIxazomib, Vincristine, Dexamethasone, Asparaginase, Doxorubicin
  • Ixazomib
  • Vincristine
  • Dexamethasone
  • Asparaginase
  • Doxorubicin

Eligibility Criteria

        Inclusion Criteria:

          -  Age Patients must be ≤21 years of age at the time of enrollment.

               1. Phase 1 - Initial enrollment will be restricted to patients < 18 years of age
                  until 9 such patients are enrolled

               2. Phase 2 - Initial enrollment will be restricted to patients < 18 years of age
                  until 6 such patients are enrolled

          -  Diagnosis Patients must have a diagnosis of relapsed/refractory ALL or LLy with or
             without extramedullary disease (including CNS2 and CNS3). Patient with mixed phenotype
             ALL or mature B (Burkitt-like) leukemia are not eligible.

               1. Patients with ALL must have ≥ 5% blasts by morphology.

               2. Patients with LLy must have measurable disease documented by clinical, radiologic
                  or histologic criteria

          -  Performance Level Karnofsky ≥ 50% for patients > 16 years of age and Lansky ≥ 50% for
             patients ≤ 16 years of age.

          -  Prior Therapy A. Prior therapeutic attempts

               -  Phase 1 - Any patients with relapsed/refractory ALL or LLy

               -  Phase 2

                    1. B-cell ALL/LLy: all patients must have failed two or more therapeutic
                       attempts.

                    2. T-cell ALL/LLy: all patients must have failed one or more therapeutic
                       attempts. B. Recent prior chemotherapy Patients must have fully recovered
                       from the acute toxic effects of all prior chemotherapy, immunotherapy, or
                       radiotherapy prior to entering this study.

               -  Cytoreduction with hydroxyurea Hydroxyurea can be initiated and continued for up
                  to 24 hours prior to the start of protocol therapy.

               -  Patients who relapsed while they are receiving cytotoxic therapy At least 14 days
                  must have elapsed since the completion of the last dose of chemotherapy,except
                  Intrathecal chemotherapy, and/or maintenance therapy such as vincristine,
                  mercaptopurine, methotrexate or glucocorticoids. There is no waiting period for
                  those relapsing on maintenance therapy.

        C. Hematopoietic stem cell transplant: Patients who have experienced their relapse after a
        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
        post-transplant at the time of enrollment.

        D. Hematopoietic growth factors: It must have been at least 7 days since the completion of
        therapy with G-CSF or other growth factors at the time of enrollment. It must have been at
        least 14 days since the completion of therapy with pegfilgrastim (Neulasta®).

        E. Biologic (anti-neoplastic agent): At least 7 days since the last dose of a biologic
        agent. For agents that have known adverse events occurring beyond 7 days after
        administration, this period must be extended beyond the time during which adverse events
        are known to occur. The duration of this interval must be discussed with the study chair

          1. Monoclonal antibodies: At least 3 half-lives of the antibody must have elapsed after
             the last dose of monoclonal antibody. (i.e., blinatumomab = 6 hours,44 inotuzumab = 37
             days, rituximab = 66 days)

          2. Immunotherapy: At least 30 days after the completion of any type of immunotherapy,
             e.g., tumor vaccines, CAR T cells.

        F. XRT: Craniospinal XRT is prohibited during protocol therapy. No washout period is
        necessary for radiation given to any extramedullary site other than CNS; ≥90 days must have
        elapsed if prior total body irradiation (TBI) or craniospinal XRT.

        G. Anthracyclines: Patients must have had a lifetime exposure of <400 mg/m2 of doxorubicin
        equivalents of anthracyclines.

        H. Proteasome inhibitors: Patients with a prior exposure to proteasome inhibitors (e.g.,
        bortezomib, carfilzomib) are eligible as long as the patient demonstrated at least a
        partial response to a proteasome inhibitor with chemotherapy combination.

        -Renal and hepatic function

        Patients must have adequate renal and hepatic functions as indicated by the following
        laboratory values:

        A. Adequate renal function defined as: Patient must have a calculated creatinine clearance
        or radioisotope GFR 70ml/min/1.73m2 OR a normal serum creatinine based on age/gender

        B. Adequate Liver Function Defined as: Direct bilirubin ≤ 1.5 x upper limit of normal (ULN)
        for age or normal (except in the presence of Gilbert's syndrome), AND alanine transaminase
        (ALT) ≤ 5 x ULN for age. The hepatic requirements are waived for patients with known or
        suspected liver involvement by leukemia or lymphoma. This must be reviewed by and approved
        by the study chair or vice chair.

          -  Adequate Cardiac Function Defined as: Shortening fraction of more than or equal to 27%
             by echocardiogram, OR ejection fraction of equal to or more than 50% by radionuclide
             angiogram (MUGA).

          -  Reproductive Function A. Female patients of childbearing potential must have a
             negative urine or serum pregnancy test confirmed within 2 weeks prior to enrollment.

        B. Female patients with infants must agree not to breastfeed their infants while on this
        study.

        C. Male and female patients of child-bearing potential must agree to use an effective
        method of contraception approved by the investigator during the study and for a minimum of
        6 months after study treatment.

          -  Informed Consent Patients and/or their parents or legal guardians must be capable of
             understanding the investigational nature, potential risks and benefits of the study.
             All patients and/or their parents or legal guardians must sign a written informed
             consent. Age appropriate assent will be obtained per institutional guidelines. To
             allow non-English speaking patients to participate in this study, bilingual health
             services will be provided in the appropriate language when feasible.

          -  All institutional, FDA, and OHRP requirements for human studies must be met.

        Exclusion Criteria:

        Patients will be excluded if they have isolated CNS or testicular disease.

        Patients will be excluded if they have ≥grade 2 peripheral sensory or motor neuropathy
        (defined by the Modified "Balis" Pediatric Scale of Pediatric Neuropathies) at the time of
        enrollment (see section 4.7.1.1).

        Patients will be excluded if they have a known allergy or intolerance to any of the drugs
        used in the study - except for PEG-asparaginase for which erwinia asparaginase may be
        substituted

        Patients will be excluded if they have a systemic fungal, bacterial, viral or other
        infection that is exhibiting ongoing signs/symptoms related to the infection without
        improvement despite appropriate antibiotics or other treatment. The patient needs to be off
        pressors and have negative blood cultures for 48 hours.

        Patients will be excluded if there is a plan to administer non-protocol chemotherapy,
        radiation therapy, or immunotherapy during the study period.

        Patients will be excluded if they have significant concurrent disease, illness, psychiatric
        disorder or social issue that would compromise patient safety or compliance with the
        protocol treatment or procedures, interfere with consent, study participation, follow up,
        or interpretation of study results.

        Patients with DNA fragility syndromes (such as Fanconi anemia, Bloom syndrome) are
        excluded.

        Patients will be excluded if they have had a lifetime exposure of ≥400 mg/m2 doxorubicin
        equivolents of anthracyclines (anthracycline equivalence to doxorubicin conversion see
        appendix iv) .

        Concomitant medications Investigational drugs: Patients currently receiving another
        investigational drug are not eligible.

        Anti-GVHD agents post transplant: patients who are receiving cyclosporine, tacrolimus or
        other agents to prevent graft-versus-host disease post hematopoetic stem cell transplant
        are not eligible.

        CYP3A4 agents: patients who are currently receiving drugs that are strong inducers of
        CYP3A4 are not eligible. Strong inducers of CYP3A4 should be avoided from 14 days prior to
        enrollment to the end of the study. See appendix ii for a list of agents which fall into
        this category.

        Patients with Ph+ALL and Ph-like ALL who are currently receiving TKI therapy

        Infants or Patients with Down Syndrome will be excluded in phase 2 of the study
      
Maximum Eligible Age:21 Years
Minimum Eligible Age:1 Year
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Phase 1: Dose limiting toxicity (DLT) during block 1 of chemotherapy
Time Frame:5 weeks
Safety Issue:
Description:The incidence of dose limiting toxicity (DLT) will be measured only during block 1

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Therapeutic Advances in Childhood Leukemia Consortium

Last Updated

May 21, 2019