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T2017-002

TACL T2017-002: PO Ixazomib

Protocol 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

Study Chair:

Terzah Horton, MD, Texas Children’s Cancer Center, Baylor College of Medicine

Study Vice-Chair:

Eric Schafer, MD, Texas Children’s Cancer Center, Baylor College of Medicine

What is this study about:

Ixazomib is a new proteasome inhibitor, with both intravenous (IV) and oral (PO) formulations, that has been approved by the FDA to treat patients with multiple myeloma (MM). Similar to bortezomib, ixazomib selectively inhibits the β5 site of the 20S proteasome and also demonstrates synergistic activity with dexamethasone and doxorubicin in multiple myeloma. In preclinical studies, ixazomib has shown increased potency and superior efficacy over bortezomib because it has a shorter proteasome dissociation half-life that leads to a higher tumor-to-blood ratio of proteasome inhibition.

The advantage of ixazomib over either bortezomib or carfilzomib is the PO formulation. Currently, no other oral proteasome inhibitor is approved. With the development of new promising immunotherapies (CD19 CAR T-cells, blinatumomab, inotuzumab, etc.) in pediatric ALL, the best use for ixazomib in childhood leukemia would be as a PO formulation to intensify maintenance therapy in a subset of newly diagnosed high risk patients in order to improve outcome. This study provides a unique opportunity to utilize an oral formulation of ixazomib as part of a multi-agent re-induction regimen and optional maintenance chemotherapy for patients who have achieved CR/CR MRD-/CRi.

The goal of this study is to improve survival rates in children and young adults with relapsed ALL/LLy by combining ixazomib with chemotherapy. The  phase 1 portion of the 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.

About 30 children and young adults will participate in this study.

Infants and patients with Down syndrome will be included in the study

The goals of this study are:

  • Determine the maximal tolerated dose (MTD) and/or recommended phase 2 dose (R2PD) of PO ixazomib administered in conjunction with block 1 re-induction chemotherapy in children with relapsed/refractory ALL or lymphoblastic lymphoma (LLy)
  • Define and describe the toxicities of PO ixazomib in combination with block 1 re-induction chemotherapy in children with relapsed/refractory ALL or LLy
  • Characterize the pharmacokinetics (PK) of PO ixazomib in combination with block 1 re-induction chemotherapy in children with relapsed/refractory ALL or LLy
  • Estimate the rate of overall response (CR + CR MRD- and CR + CR MRD- + CRi) after block 1 re-induction chemotherapy in patients with multiply relapsed/refractory ALL or LLy

Criteria that need to be met to participate in this study: (Abbreviated List)

  • Patients must be ≤21 years of age at the time of enrollment.
  • Patients must have a diagnosis of relapsed/refractory ALL or LLy with or without extramedullary disease (including CNS2 and CNS3). Patients with mixed phenotype ALL or mature B (Burkitt-like) leukemia are not eligible.
  • Phase 1 – Patients with any relapsed B-cell ALL/LLy or any T-cell ALL/LLy are eligible
  • Phase 2 – Patients with 1st relapsed B-cell ALL/LLy are excluded
    • B-cell ALL/LLy: all patients must have failed two or more therapeutic attempts.
    • T-cell ALL/LLy: all patients must have failed one or more therapeutic attempts.
  • Karnofsky ≥ 50% for patients > 16 years of age and Lansky ≥ 50% for patients ≤ 16 years of age
  • Adequate cardiac, pulmonary, renal, and liver function
  • 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.  This criteria only applies to the Phase 2 portion of the study.

Patients cannot participate in this study if: (Abbreviated List)

  • Isolated CNS or testicular disease
  • Have ≥grade 2 peripheral sensory or motor neuropathy
  • Systemic uncontrolled fungal, bacterial, viral or other infection with ongoing symptoms
  • Patients with DNA fragility syndromes (such as Fanconi anemia, Bloom syndrome)
  • Patients who are currently receiving another investigational drug or plan to receive non-protocol chemotherapy, radiation therapy, or immunotherapy during the protocol period
  • Patients who have had a lifetime exposure of ≥400 mg/m2 doxorubicin equivalents of anthracyclines
  • Patients who are receiving cyclosporine, tacrolimus or other agents to prevent graft-versus-host disease post hematopoetic stem cell transplant
  • Patients who are currently receiving drugs that are strong inducers of CYP3A4
  • Patients with Ph+ALL and Ph-like ALL who are currently receiving TKI therapy

Treatment

Patients can get up to two blocks of therapy according to the table below.

Level

Patients ≥ 1 year of age

Dose

Patients < 1 year of age

Dose

-1

1.2 mg/m2/day

0.04 mg/kg/day

1

1.6 mg/m2/day

0.05 mg/kg/day

2

2 mg/m2/day

0.07 mg/kg/day

 

 

The investigational product is ixazomib, a proteasome inhibitor.

Phase 1 – Patients will initially be enrolled at dose level 1. A 3+3 dose escalation design will be used. Patients will be dosed on days 1, 4, 8, and 11 in Block 1 and on days 1, 4, 8, 15, and 18 in Block 2 (Note: at least 72 hours must have elapsed between doses). The starting dose will be 80% of the adult twice weekly PO MTD.

Phase 2 – Patients are administered with PO formulation at RP2D. Non investigational therapies will remain the same for phase 1 and 2 of the study.

Additional Study Patient Accrual required for completing study

Approximately 12 additional patients will be needed to complete this study.

 

To Access more information about this study click here to be taken to the clinicaltrials.gov web site (NCT03817320)