Clinical Trials /

Study of the IDO Pathway Inhibitor, Indoximod, and Temozolomide for Pediatric Patients With Progressive Primary Malignant Brain Tumors

NCT02502708

Description:

This is a first-in-children phase 1 trial using indoximod, an inhibitor of the immune "checkpoint" pathway indoleamine 2,3-dioxygenase (IDO), in combination with temozolomide-based therapy to treat pediatric brain tumors. Using a preclinical glioblastoma model, it was recently shown that adding IDO-blocking drugs to temozolomide plus radiation significantly enhanced survival by driving a vigorous, tumordirected inflammatory response. This data provided the rationale for the companion adult phase 1 trial using indoximod (IND#120813) plus temozolomide to treat adults with glioblastoma, which is currently open (NCT02052648). The goal of this pediatric study is to bring IDO-based immunotherapy into the clinic for children with brain tumors. This study will provide a foundation for future pediatric trials testing indoximod combined with radiation and temozolomide in the up-front setting for patients with newly diagnosed central nervous system tumors.

Related Conditions:
  • Diffuse Intrinsic Pontine Glioma
  • Malignant Brain Neoplasm
Recruiting Status:

Active, not recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Study of the IDO Pathway Inhibitor, Indoximod, and Temozolomide for Pediatric Patients With Progressive Primary Malignant Brain Tumors
  • Official Title: A Phase I Trial of Indoximod and Temozolomide-Based Therapy for Children With Progressive Primary Brain Tumors

Clinical Trial IDs

  • ORG STUDY ID: NLG2105
  • NCT ID: NCT02502708

Conditions

  • Glioblastoma Multiforme
  • Glioma
  • Gliosarcoma
  • Malignant Brain Tumor
  • Ependymoma
  • Medulloblastoma
  • Diffuse Intrinsic Pontine Glioma
  • Primary CNS Tumor

Interventions

DrugSynonymsArms
Indoximod1-methyl-D-tryptophan, D-1MTGroup 1 (CLOSED)
TemozolomideTemodar, MethazolastoneGroup 1 (CLOSED)
CyclophosphamideGroup 4
EtoposideGroup 4

Purpose

This is a first-in-children phase 1 trial using indoximod, an inhibitor of the immune "checkpoint" pathway indoleamine 2,3-dioxygenase (IDO), in combination with temozolomide-based therapy to treat pediatric brain tumors. Using a preclinical glioblastoma model, it was recently shown that adding IDO-blocking drugs to temozolomide plus radiation significantly enhanced survival by driving a vigorous, tumordirected inflammatory response. This data provided the rationale for the companion adult phase 1 trial using indoximod (IND#120813) plus temozolomide to treat adults with glioblastoma, which is currently open (NCT02052648). The goal of this pediatric study is to bring IDO-based immunotherapy into the clinic for children with brain tumors. This study will provide a foundation for future pediatric trials testing indoximod combined with radiation and temozolomide in the up-front setting for patients with newly diagnosed central nervous system tumors.

Trial Arms

NameTypeDescriptionInterventions
Group 1 (CLOSED)ExperimentalCore Regimen: Dose-escalation of indoximod, in combination with temozolomide, for pediatric patients with progressive brain tumors. Indoximod will be administered in escalating doses. Initial dosing will be 12.8 mg/kg/dose BID with escalation planned to 22.4 mg/kg/dose BID. Temozolomide to be given at 200 mg/m^2 x 5 days
  • Indoximod
  • Temozolomide
Group 2 (CLOSED)ExperimentalExpansion cohorts: Indoximod therapy at the pediatric recommended phase 2 dose (RP2D) determined by Group 1, in combination with temozolomide. Indoximod will be administered at the RP2D of 19.2 mg/kg/dose BID. Temozolomide to be given at 200 mg/m^2 x 5 days
  • Indoximod
  • Temozolomide
Group 3 (CLOSED)ExperimentalDose-escalation of indoximod, in combination with up-front conformal radiation therapy, for pediatric patients with progressive brain tumors. Indoximod will be administered in escalating doses. Initial dosing will be 12.8 mg/kg/dose BID with escalation planned to 22.4 mg/kg/dose BID. Temozolomide to be given at 200 mg/m^2 x 5 days
  • Indoximod
  • Temozolomide
Group 3bExperimentalIndoximod, in combination with up-front conformal radiation therapy, for pediatric patients with newly diagnosed treatment-naive diffuse intrinsic pontine glioma (DIPG). Indoximod will be administered at the RP2D of 19.2 mg/kg/dose BID. Temozolomide to be given at 200 mg/m^2 x 5 days
  • Indoximod
  • Temozolomide
Group 4ExperimentalContinued access to indoximod in combination with low-dose oral cyclophosphamide and etoposide for patients with progressive disease after treatment with indoximod plus temozolomide. Indoximod will be administered at 32 mg/kg/dose divided twice daily. Cyclophosphamide to be given at 2.5 mg/kg/dose daily Etoposide to be given at 50 mg/m2/dose daily
  • Indoximod
  • Cyclophosphamide
  • Etoposide

Eligibility Criteria

        Eligibility Criteria

          -  Age: 3-21 years.

          -  Group 1 or Group 3: histologically proven initial diagnosis of primary malignant brain
             tumor, with no known curative treatment options.

          -  Group 2: histologically proven initial diagnosis of high-grade glioma (WHO grade III
             and IV), ependymoma, medulloblastoma, or other primary central nervous system tumor.

          -  Group 3b: Patients with a radiographic diagnosis or histologically proven diagnosis of
             diffuse intrinsic pontine glioma (DIPG).

          -  MRI confirmation of tumor progression or regrowth.

          -  Patients must be able to swallow whole capsules.

          -  Patients with metastatic disease are eligible for enrollment.

          -  Lansky or Karnofsky performance status score must be > 50%.

          -  Seizure disorders must be well controlled on antiepileptic medication.

          -  DIPG patients enrolled to Group 3b must not have been previously treated with
             radiation or any medical therapy.

          -  Patients previously treated with temozolomide, cyclophosphamide, and/or etoposide are
             eligible for enrollment.

        Exclusion Criteria

          -  Prior invasive malignancy, other than the primary central nervous system tumor, unless
             the patient has been disease free and off therapy for that disease for a minimum of 3
             years

          -  Patients with baseline QTc interval of more than 470 msec at study entry, and patients
             with congenital long QTc syndrome.

          -  Active autoimmune disease
      
Maximum Eligible Age:21 Years
Minimum Eligible Age:3 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of regimen limiting toxicities (RLTs)
Time Frame:First 28 days of treatment
Safety Issue:
Description:To estimate the RP2D of indoximod combined with temozolomide

Secondary Outcome Measures

Measure:Pharmacokinetics: Serum concentrations (Cmax/Steady State)
Time Frame:First 48 hours of treatment
Safety Issue:
Description:Group 1
Measure:Safety and Tolerability of Indoximod combined with Temozolomide as assessed by incidence and severity of adverse events, dose interruptions and dose reductions.
Time Frame:Continuous during study until 30 days after study treatment is complete.
Safety Issue:
Description:Group 1 and 2
Measure:Progression Free Survival (PFS)
Time Frame:Up to three years
Safety Issue:
Description:Group 2
Measure:Time to Progression
Time Frame:Start of study until disease progression follow-up, up to three years
Safety Issue:
Description:Group 2
Measure:Overall Survival
Time Frame:Start of study until end of follow-up, up to five years
Safety Issue:
Description:Group 2
Measure:Safety and Feasibility of Indoximod combined with conformal radiation as assessed by incidence and severity of adverse events, dose interruptions and dose reductions.
Time Frame:Continuous during study until 30 days after study treatment is complete.
Safety Issue:
Description:Group 3

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:NewLink Genetics Corporation

Trial Keywords

  • glioblastoma multiforme
  • glioma
  • gliosarcoma
  • malignant brain tumor
  • ependymoma
  • medulloblastoma

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