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

June 3, 2020 updated by: NewLink Genetics Corporation

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

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Actual)

81

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Colorado
      • Aurora, Colorado, United States, 80045
        • Children's Hospital Colorado
    • Florida
      • Orlando, Florida, United States, 32806
        • Arnold Palmer Hospital for Children
    • Georgia
      • Atlanta, Georgia, United States, 30342
        • Children's Heathcare of Atlanta
      • Augusta, Georgia, United States, 30912
        • Augusta University
    • Minnesota
      • Minneapolis, Minnesota, United States, 55404
        • Children's Hospitals and Clinics of Minnesota

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

3 years to 21 years (Child, Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Non-Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Group 1 (CLOSED)

Core 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
Drug: Indoximod
Indoximod will be administered orally twice daily.
Other Names:
  • 1-methyl-D-tryptophan
  • D-1MT
Drug: Temozolomide
Temozolomide will be administered on days 1-5 of every 28 day cycle.
Other Names:
  • Temodar
  • Methazolastone
Experimental: Group 2 (CLOSED)

Expansion 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
Drug: Indoximod
Indoximod will be administered orally twice daily.
Other Names:
  • 1-methyl-D-tryptophan
  • D-1MT
Drug: Temozolomide
Temozolomide will be administered on days 1-5 of every 28 day cycle.
Other Names:
  • Temodar
  • Methazolastone
Experimental: Group 3 (CLOSED)

Dose-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
Drug: Indoximod
Indoximod will be administered orally twice daily.
Other Names:
  • 1-methyl-D-tryptophan
  • D-1MT
Drug: Temozolomide
Temozolomide will be administered on days 1-5 of every 28 day cycle.
Other Names:
  • Temodar
  • Methazolastone
Radiation: Conformal Radiation
Conformal radiation will be administered on days 3-7 of induction cycle.
Experimental: Group 3b

Indoximod, 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
Drug: Indoximod
Indoximod will be administered orally twice daily.
Other Names:
  • 1-methyl-D-tryptophan
  • D-1MT
Drug: Temozolomide
Temozolomide will be administered on days 1-5 of every 28 day cycle.
Other Names:
  • Temodar
  • Methazolastone
Radiation: Conformal Radiation
Conformal radiation will be administered on days 3-7 of induction cycle.
Experimental: Group 4

Continued 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
Drug: Indoximod
Indoximod will be administered orally twice daily.
Other Names:
  • 1-methyl-D-tryptophan
  • D-1MT
Drug: Cyclophosphamide
Cyclophosphamide will be administered orally daily.
Drug: Etoposide
Etoposide will be administered orally daily.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Incidence of regimen limiting toxicities (RLTs)
Time Frame: First 28 days of treatment
To estimate the RP2D of indoximod combined with temozolomide
First 28 days of treatment
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.
Up to three years
Incidence of regimen limiting toxicities (RLTs)
Time Frame: First 35 days of treatment
To estimate the RP2D of indoximod combined with conformal radiation
First 35 days of treatment
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
Up to three years

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Pharmacokinetics: Serum concentrations (Cmax/Steady State)
Time Frame: First 48 hours of treatment
Group 1
First 48 hours of treatment
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
Continuous during study until 30 days after study treatment is complete.
Progression Free Survival (PFS)
Time Frame: Up to three years
Group 2
Up to three years
Time to Progression
Time Frame: Start of study until disease progression follow-up, up to three years
Group 2
Start of study until disease progression follow-up, up to three years
Overall Survival
Time Frame: Start of study until end of follow-up, up to five years
Group 2
Start of study until end of follow-up, up to five years
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
Continuous during study until 30 days after study treatment is complete.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

NewLink Genetics Corporation

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

October 1, 2015

Primary Completion (Actual)

December 12, 2019

Study Completion (Actual)

February 28, 2020

Study Registration Dates

First Submitted

July 6, 2015

First Submitted That Met QC Criteria

July 16, 2015

First Posted (Estimate)

July 20, 2015

Study Record Updates

Last Update Posted (Actual)

June 4, 2020

Last Update Submitted That Met QC Criteria

June 3, 2020

Last Verified

June 1, 2020

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • NLG2105

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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