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

This study is currently recruiting participants.
See Contacts and Locations
Verified January 2017 by NewLink Genetics Corporation
Sponsor:
Information provided by (Responsible Party):
NewLink Genetics Corporation
ClinicalTrials.gov Identifier:
NCT02502708
First received: July 6, 2015
Last updated: January 9, 2017
Last verified: January 2017
  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.

Condition Intervention Phase
Glioblastoma Multiforme Glioma Gliosarcoma Malignant Brain Tumor Ependymoma Medulloblastoma Drug: Indoximod Drug: Temozolomide Radiation: Conformal Radiation Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase I Trial of Indoximod and Temozolomide-Based Therapy for Children With Progressive Primary Brain Tumors

Resource links provided by NLM:


Further study details as provided by NewLink Genetics Corporation:

Primary Outcome Measures:
  • 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


Secondary Outcome Measures:
  • 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


Estimated Enrollment: 66
Study Start Date: October 2015
Estimated Study Completion Date: July 2018
Estimated Primary Completion Date: July 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Group 1

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
Other Names:
  • 1-methyl-D-tryptophan
  • D-1MT
Drug: Temozolomide
Other Names:
  • Temodar
  • Methazolastone
Experimental: Group 2

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 recommended phase 2 dose.

Temozolomide to be given at 200 mg/m^2 x 5 days

Drug: Indoximod
Other Names:
  • 1-methyl-D-tryptophan
  • D-1MT
Drug: Temozolomide
Other Names:
  • Temodar
  • Methazolastone
Experimental: Group 3

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
Other Names:
  • 1-methyl-D-tryptophan
  • D-1MT
Drug: Temozolomide
Other Names:
  • Temodar
  • Methazolastone
Radiation: Conformal Radiation

  Eligibility

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, excluding brain stem glioma, with no known curative treatment options.
  • Group 2: histologically proven initial diagnosis of intracranial high-grade glioma (WHO grade III and IV), any relapsed / refractory ependymoma, or any relapsed / refractory medulloblastoma.
  • MRI confirmation (with and without gadolinium contrast) of tumor progression or regrowth. Surgical debulking is permitted if clinically indicated, but should be followed with post-operative repeat of MRI.
  • Patients must be able to swallow whole capsules.
  • Patients with metastatic disease are eligible for enrollment.
  • Patients may be on corticosteroids for management of elevated intracranial pressure

    - The dose must be in a stable range or decreasing for at least 14 days.

  • Lansky or Karnofsky performance status score must be > 50%.
  • Patients must have a life expectancy of 3 months.
  • Creatinine < 1.5-times upper limit of age-adjusted normal
  • ALT and AST < 3-times upper limit of normal
  • Total bilirubin < 1.5-times upper limit of normal
  • Absolute neutrophil count (ANC) ≥ 750/μL
  • Platelets ≥ 75,000/μL (transfusion independent)
  • Hemoglobin ≥ 10 g/dL (transfusion independent)
  • Seizure disorders must be well controlled on antiepileptic medication.
  • Patients previously treated with temozolomide are eligible for enrollment.
  • Patients must be 14 days from the administration of any investigational agent or prior cytotoxic therapy with the following exceptions:

    • Temozolomide (allowed, regardless of time frame administered)
    • 42 days from administration of antibody-based therapies (e.g., bevacizumab).
  • Patients must be 9 months from the initial radiation fraction if they were previously treated with conventional fractionated radiation therapy and there is concern for pseudo-progression.
  • Patients with prior therapy that included interstitial brachytherapy, Gliadel wafer, or stereotactic radiosurgery must have confirmation of progressive disease, rather than radiation necrosis, by PET scanning, Thallium scanning, MRI spectroscopy, or surgical documentation.
  • Concurrent anti-neoplastic therapy:

    - No investigational or commercial agents or therapies other than indoximod, temozolomide, and/or conformal radiation therapy may be administered with the intent to treat the patient's malignancy while they remain enrolled on this study.

  • Sexually active female patients of child-bearing age must agree to use two forms of contraception (hormonal and either barrier method of birth control or abstinence) prior to study entry and for the duration of study participation. Use of contraception and/or abstinence should continue for a minimum of 1 month after completion of the study.
  • Female patients who are breastfeeding must agree to cease breastfeeding and switch to commercially available infant formula or other appropriate nutrition prior to study entry and for the duration of study participation, plus a minimum of 1 month after completion of the study.
  • Sexually active male patients must agree to use barrier contraception (condoms) or abstinence prior to study entry and for the duration of study participation. Use of contraception and/or abstinence should continue for a minimum of 1 month after completion of the study.
  • Patients and/or their parents or legal guardians must sign a written informed consent for treatment on this clinical study.

Exclusion Criteria

  • Patients with primary tumor in the brain stem, including diffuse intrinsic pontine glioma, are excluded.
  • Patients who cannot swallow whole capsules are excluded
  • 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 systemic infection requiring treatment, including any HIV infection or toxoplasmosis
  • Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration, or may interfere with the interpretation of study results, or in the judgment of the investigator would make the patient inappropriate for entry into this study
  • Baseline QTc interval of more than 470 or congenital long QT syndrome
  • Active autoimmune disease
  • Pregnant women are excluded from this study, where pregnancy is confirmed by a positive serum hCG laboratory test (> 5 mIU/mL); breastfeeding should be discontinued.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02502708

Contacts
Contact: Chris Smith, MS 515-598-5020 csmith@linkp.com

Locations
United States, Georgia
Children's Heathcare of Atlanta Recruiting
Atlanta, Georgia, United States, 30342
Contact: Amy Autry-Bush    404-785-6011    amy.autry-bush@choa.org   
Principal Investigator: Tobey MacDonald, MD         
Augusta University Recruiting
Augusta, Georgia, United States, 30912
Contact: Robin Dobbins    706-721-2154    RDOBBINS@augusta.edu   
Principal Investigator: Theodore Johnson, MD         
Sponsors and Collaborators
NewLink Genetics Corporation
Investigators
Study Director: Gene Kennedy, MD NewLink Genetics Corporation
  More Information

Additional Information:
Responsible Party: NewLink Genetics Corporation
ClinicalTrials.gov Identifier: NCT02502708     History of Changes
Other Study ID Numbers: NLG2105
Study First Received: July 6, 2015
Last Updated: January 9, 2017

Keywords provided by NewLink Genetics Corporation:
glioblastoma multiforme
glioma
gliosarcoma
malignant brain tumor
ependymoma
medulloblastoma

Additional relevant MeSH terms:
Glioblastoma
Glioma
Brain Neoplasms
Gliosarcoma
Ependymoma
Medulloblastoma
Astrocytoma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
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
Temozolomide
Dacarbazine
Tryptophan
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antidepressive Agents, Second-Generation
Antidepressive Agents

ClinicalTrials.gov processed this record on June 28, 2017