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

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ClinicalTrials.gov Identifier: NCT02502708
Recruitment Status : Recruiting
First Posted : July 20, 2015
Last Update Posted : April 19, 2019
Sponsor:
Information provided by (Responsible Party):
NewLink Genetics Corporation

Tracking Information
First Submitted Date  ICMJE July 6, 2015
First Posted Date  ICMJE July 20, 2015
Last Update Posted Date April 19, 2019
Study Start Date  ICMJE October 2015
Estimated Primary Completion Date May 1, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 22, 2018)
  • Incidence of regimen limiting toxicities (RLTs) [ Time Frame: First 28 days of treatment ]
    To estimate the RP2D of indoximod combined with temozolomide
  • 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.
  • Incidence of regimen limiting toxicities (RLTs) [ Time Frame: First 35 days of treatment ]
    To estimate the RP2D of indoximod combined with conformal radiation
  • 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
Original Primary Outcome Measures  ICMJE
 (submitted: July 16, 2015)
  • Incidence of regimen limiting toxicities (RLTs) [ Time Frame: First 28 days of treatment ]
    To estimate the RP2D of indoximod combined with temozolomide
  • 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.
  • Incidence of regimen limiting toxicities (RLTs) [ Time Frame: First 35 days of treatment ]
    To estimate the RP2D of indoximod combined with conformal radiation
Change History Complete list of historical versions of study NCT02502708 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: July 16, 2015)
  • Pharmacokinetics: Serum concentrations (Cmax/Steady State) [ Time Frame: First 48 hours of treatment ]
    Group 1
  • 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
  • Progression Free Survival (PFS) [ Time Frame: Up to three years ]
    Group 2
  • Time to Progression [ Time Frame: Start of study until disease progression follow-up, up to three years ]
    Group 2
  • Overall Survival [ Time Frame: Start of study until end of follow-up, up to five years ]
    Group 2
  • 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
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Study of the IDO Pathway Inhibitor, Indoximod, and Temozolomide for Pediatric Patients With Progressive Primary Malignant Brain Tumors
Official Title  ICMJE A Phase I Trial of Indoximod and Temozolomide-Based Therapy for Children With Progressive Primary Brain Tumors
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.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Glioblastoma Multiforme
  • Glioma
  • Gliosarcoma
  • Malignant Brain Tumor
  • Ependymoma
  • Medulloblastoma
  • Diffuse Intrinsic Pontine Glioma
  • Primary CNS Tumor
Intervention  ICMJE
  • 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.
  • Drug: Cyclophosphamide
    Cyclophosphamide will be administered orally daily.
  • Drug: Etoposide
    Etoposide will be administered orally daily.
Study Arms  ICMJE
  • 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

    Interventions:
    • Drug: Indoximod
    • Drug: Temozolomide
  • 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

    Interventions:
    • Drug: Indoximod
    • Drug: Temozolomide
  • 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

    Interventions:
    • Drug: Indoximod
    • Drug: Temozolomide
    • Radiation: Conformal Radiation
  • 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

    Interventions:
    • Drug: Indoximod
    • Drug: Temozolomide
    • Radiation: Conformal Radiation
  • 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

    Interventions:
    • Drug: Indoximod
    • Drug: Cyclophosphamide
    • Drug: Etoposide
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: June 28, 2018)
115
Original Estimated Enrollment  ICMJE
 (submitted: July 16, 2015)
66
Estimated Study Completion Date  ICMJE December 1, 2019
Estimated Primary Completion Date May 1, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 3 Years to 21 Years   (Child, Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Chris Smith, MS 515-598-5020 csmith@linkp.com
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02502708
Other Study ID Numbers  ICMJE NLG2105
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party NewLink Genetics Corporation
Study Sponsor  ICMJE NewLink Genetics Corporation
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Gene Kennedy, MD NewLink Genetics Corporation
PRS Account NewLink Genetics Corporation
Verification Date April 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP