ClinicalTrials.gov
ClinicalTrials.gov Menu
Trial record 1 of 1 for:    NLG2105
Previous Study | Return to List | Next Study

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. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT02502708
Recruitment Status : Recruiting
First Posted : July 20, 2015
Last Update Posted : January 24, 2018
Sponsor:
Information provided by (Responsible Party):
NewLink Genetics Corporation

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 Type : Interventional  (Clinical Trial)
Estimated Enrollment : 66 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
Estimated Primary Completion Date : March 2019
Estimated Study Completion Date : December 2019


Arm Intervention/treatment
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
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

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
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

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 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.



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



Information from the National Library of Medicine

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, Learn About Clinical Studies.


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.

    - Patients with radiographic diagnosis or histologically provide DIPG are eligible for enrollment in Group 3b.

  • Group 2: histologically proven initial diagnosis of high-grade glioma (WHO grade III and IV), ependymoma, medulloblastoma, other primary central nervous system tumor, or DIPG.
  • 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.
    • No restrictions for patients with DIPG
  • 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:

    • 21 days from Temozolomide dosed at or above 150mg/m2
    • 28 days from administration of antibody-based therapies (e.g., bevacizumab).
    • 28 days from administration of tumor directed vaccine or cellular immune therapies.
    • 56 days from administration of tumor directed therapies using infectious agents.
  • 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 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.

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


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

Additional Information:
Responsible Party: NewLink Genetics Corporation
ClinicalTrials.gov Identifier: NCT02502708     History of Changes
Other Study ID Numbers: NLG2105
First Posted: July 20, 2015    Key Record Dates
Last Update Posted: January 24, 2018
Last Verified: January 2018

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

Additional relevant MeSH terms:
Neoplasms
Glioblastoma
Glioma
Brain Neoplasms
Gliosarcoma
Ependymoma
Medulloblastoma
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
Cyclophosphamide
Temozolomide
Dacarbazine
Etoposide phosphate
Etoposide
Tryptophan
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs