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Completed

NCT Number: NCT02502708

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

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.

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Key information

Conditions

Glioblastoma Multiforme Astrocytoma Brain Diseases Brain Neoplasms Brain Stem Neoplasms Central Nervous System Diseases Central Nervous System Neoplasms Diffuse Intrinsic Pontine Glioma Ependymoma Glioblastoma Glioma Gliosarcoma Infratentorial Neoplasms Malignant Brain Tumor Medulloblastoma Neoplasms Neoplasms by Histologic Type Neoplasms by Site Neoplasms, Germ Cell and Embryonal Neoplasms, Glandular and Epithelial Neoplasms, Nerve Tissue Neoplasms, Neuroepithelial Nervous System Diseases Nervous System Neoplasms Neuroectodermal Tumors Neuroectodermal Tumors, Primitive Primary CNS Tumor

Age range

3 year–21 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 1

Primary location

Children's Hospital Colorado, Aurora, Colorado, United States

Loading trial locations.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

Indoximod

Drug

Indoximod will be administered orally twice daily.

Other names: 1-methyl-D-tryptophan, D-1MT

Temozolomide

Drug

Temozolomide will be administered on days 1-5 of every 28 day cycle.

Other names: Temodar, Methazolastone

Conformal Radiation

Radiation

Conformal radiation will be administered on days 3-7 of induction cycle.

Cyclophosphamide

Drug

Cyclophosphamide will be administered orally daily.

etoposide

Drug

Etoposide will be administered orally daily.

Primary outcomes

  1. Incidence of regimen limiting toxicities (RLTs)

    Time frame: First 28 days of treatment

    To estimate the RP2D of indoximod combined with temozolomide

  2. Objective Response Rate

    Time frame: Up to three years

    To assess preliminary evidence of efficacy of indoximod and temozolomide using COG brain tumor measurement criteria.

  3. Incidence of regimen limiting toxicities (RLTs)

    Time frame: First 35 days of treatment

    To estimate the RP2D of indoximod combined with conformal radiation

  4. Safety and tolerability assessed by development of AEs and laboratory parameters of indoximod in combination with cyclophosphamide and etoposide.

    Time frame: Up to three years

    In patients who initially achieve prolonged stable disease or better with Indoximod plus temozolomide but then develop progressive disease

Secondary outcomes

  1. Pharmacokinetics: Serum concentrations (Cmax/Steady State)

    Time frame: First 48 hours of treatment

    Group 1

  2. 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.

    Group 1 and 2

  3. Progression Free Survival (PFS)

    Time frame: Up to three years

    Group 2

  4. Time to Progression

    Time frame: Start of study until disease progression follow-up, up to three years

    Group 2

  5. Overall Survival

    Time frame: Start of study until end of follow-up, up to five years

    Group 2

  6. 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.

    Group 3

Sponsors and collaborators

Lead sponsor

NewLink Genetics Corporation

Industry

Registry information

Official study title

A Phase I Trial of Indoximod and Temozolomide-Based Therapy for Children With Progressive Primary Brain Tumors

Important dates

Study start
2015
Primary completion
2019
Study completion
2020
First posted
Jul 20, 2015
Registry last updated
Jun 4, 2020

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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