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

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. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02502708
Recruitment Status : Completed
First Posted : July 20, 2015
Last Update Posted : June 4, 2020
Sponsor:
Information provided by (Responsible Party):
Lumos Pharma ( NewLink Genetics Corporation )

Study Description
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Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Glioblastoma Multiforme Glioma Gliosarcoma Malignant Brain Tumor Ependymoma Medulloblastoma Diffuse Intrinsic Pontine Glioma Primary CNS Tumor Drug: Indoximod Drug: Temozolomide Radiation: Conformal Radiation Drug: Cyclophosphamide Drug: Etoposide Phase 1

Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 81 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I Trial of Indoximod and Temozolomide-Based Therapy for Children With Progressive Primary Brain Tumors
Study Start Date : October 2015
Actual Primary Completion Date : December 12, 2019
Actual Study Completion Date : February 28, 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Brain Tumors

Arms and Interventions
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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.


Outcome Measures
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Primary Outcome Measures :
  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 Outcome Measures :
  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


Eligibility Criteria
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Information from the National Library of Medicine

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Ages Eligible for Study:   3 Years to 21 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02502708


Locations
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United States, Colorado
Children's Hospital Colorado
Aurora, Colorado, United States, 80045
United States, Florida
Arnold Palmer Hospital for Children
Orlando, Florida, United States, 32806
United States, Georgia
Children's Heathcare of Atlanta
Atlanta, Georgia, United States, 30342
Augusta University
Augusta, Georgia, United States, 30912
United States, Minnesota
Children's Hospitals and Clinics of Minnesota
Minneapolis, Minnesota, United States, 55404
Sponsors and Collaborators
NewLink Genetics Corporation
Investigators
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Study Director: Gene Kennedy, MD NewLink Genetics Corporation
More Information
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Responsible Party: NewLink Genetics Corporation
ClinicalTrials.gov Identifier: NCT02502708    
Other Study ID Numbers: NLG2105
First Posted: July 20, 2015    Key Record Dates
Last Update Posted: June 4, 2020
Last Verified: June 2020
Keywords provided by Lumos Pharma ( NewLink Genetics Corporation ):
glioblastoma multiforme
glioma
gliosarcoma
 malignant brain tumor
ependymoma
medulloblastoma
Additional relevant MeSH terms:
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Neoplasms
Glioblastoma
Glioma
Brain Neoplasms
Ependymoma
Gliosarcoma
Medulloblastoma
Diffuse Intrinsic Pontine Glioma
Astrocytoma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
 Central Nervous System Neoplasms
Nervous System Neoplasms
Neoplasms by Site
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Neuroectodermal Tumors, Primitive
Brain Stem Neoplasms
Infratentorial Neoplasms
Cyclophosphamide
Temozolomide
Etoposide
Tryptophan
Immunosuppressive Agents
Immunologic Factors