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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03817320
Recruitment Status : Recruiting
First Posted : January 25, 2019
Last Update Posted : May 23, 2019
Sponsor:
Collaborators:
Takeda
Children's Hospital Los Angeles
Information provided by (Responsible Party):
Therapeutic Advances in Childhood Leukemia Consortium

Tracking Information
First Submitted Date  ICMJE January 22, 2019
First Posted Date  ICMJE January 25, 2019
Last Update Posted Date May 23, 2019
Actual Study Start Date  ICMJE February 12, 2019
Estimated Primary Completion Date January 30, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 24, 2019)
Phase 1: Dose limiting toxicity (DLT) during block 1 of chemotherapy [ Time Frame: 5 weeks ]
The incidence of dose limiting toxicity (DLT) will be measured only during block 1
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03817320 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE PO Ixazomib in Combination With Chemotherapy for Childhood Relapsed or Refractory Acute Lymphoblastic Leukemia and Lymphoblastic Lymphoma
Official Title  ICMJE 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
Brief Summary 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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • ALL, Childhood
  • Lymphoblastic Lymphoma, Childhood
  • Lymphoblastic Leukemia, Acute, Childhood
Intervention  ICMJE
  • Drug: Ixazomib

    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

  • Drug: Vincristine

    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

  • Drug: Dexamethasone

    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)

  • Drug: Asparaginase

    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

  • Drug: Doxorubicin

    Day 1

    Dose ≥ 1 year: 60mg/m2/dose

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

    < 6 months: 42mg/m2/dose

Study Arms  ICMJE Open label design
Ixazomib, Vincristine, Dexamethasone, Asparaginase, Doxorubicin
Interventions:
  • Drug: Ixazomib
  • Drug: Vincristine
  • Drug: Dexamethasone
  • Drug: Asparaginase
  • Drug: Doxorubicin
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: January 24, 2019)
31
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE January 30, 2024
Estimated Primary Completion Date January 30, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 1 Year to 21 Years   (Child, Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Lei-Lani Miller 323-361-5429 llmiller@chla.usc.edu
Contact: Ellynore Florendo 323-361-3022 eflorendo@chla.usc.edu
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03817320
Other Study ID Numbers  ICMJE T2017-002
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Therapeutic Advances in Childhood Leukemia Consortium
Study Sponsor  ICMJE Therapeutic Advances in Childhood Leukemia Consortium
Collaborators  ICMJE
  • Takeda
  • Children's Hospital Los Angeles
Investigators  ICMJE Not Provided
PRS Account Therapeutic Advances in Childhood Leukemia Consortium
Verification Date May 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP