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

Primary Purpose

Glioblastoma Multiforme, Glioma, Gliosarcoma

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Indoximod
Temozolomide
Conformal Radiation
Cyclophosphamide
Etoposide
Sponsored by
NewLink Genetics Corporation
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Glioblastoma Multiforme focused on measuring glioblastoma multiforme, glioma, gliosarcoma, malignant brain tumor, ependymoma, medulloblastoma

Eligibility Criteria

3 Years - 21 Years (Child, Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Children's Hospital Colorado
  • Arnold Palmer Hospital for Children
  • Children's Heathcare of Atlanta
  • Augusta University
  • Children's Hospitals and Clinics of Minnesota

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm Type

Experimental

Experimental

Experimental

Experimental

Experimental

Arm Label

Group 1 (CLOSED)

Group 2 (CLOSED)

Group 3 (CLOSED)

Group 3b

Group 4

Arm Description

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

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

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

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

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

Outcomes

Primary Outcome Measures

Incidence of regimen limiting toxicities (RLTs)
To estimate the RP2D of indoximod combined with temozolomide
Objective Response Rate
To assess preliminary evidence of efficacy of indoximod and temozolomide using COG brain tumor measurement criteria.
Incidence of regimen limiting toxicities (RLTs)
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.
In patients who initially achieve prolonged stable disease or better with Indoximod plus temozolomide but then develop progressive disease

Secondary Outcome Measures

Pharmacokinetics: Serum concentrations (Cmax/Steady State)
Group 1
Safety and Tolerability of Indoximod combined with Temozolomide as assessed by incidence and severity of adverse events, dose interruptions and dose reductions.
Group 1 and 2
Progression Free Survival (PFS)
Group 2
Time to Progression
Group 2
Overall Survival
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.
Group 3

Full Information

First Posted
July 6, 2015
Last Updated
June 3, 2020
Sponsor
NewLink Genetics Corporation
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1. Study Identification

Unique Protocol Identification Number
NCT02502708
Brief Title
Study of the IDO Pathway Inhibitor, Indoximod, and Temozolomide for Pediatric Patients With Progressive Primary Malignant Brain Tumors
Official Title
A Phase I Trial of Indoximod and Temozolomide-Based Therapy for Children With Progressive Primary Brain Tumors
Study Type
Interventional

2. Study Status

Record Verification Date
June 2020
Overall Recruitment Status
Completed
Study Start Date
October 2015 (undefined)
Primary Completion Date
December 12, 2019 (Actual)
Study Completion Date
February 28, 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
NewLink Genetics Corporation

4. Oversight

Data Monitoring Committee
No

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Glioblastoma Multiforme, Glioma, Gliosarcoma, Malignant Brain Tumor, Ependymoma, Medulloblastoma, Diffuse Intrinsic Pontine Glioma, Primary CNS Tumor
Keywords
glioblastoma multiforme, glioma, gliosarcoma, malignant brain tumor, ependymoma, medulloblastoma

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
81 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Group 1 (CLOSED)
Arm Type
Experimental
Arm Description
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
Arm Title
Group 2 (CLOSED)
Arm Type
Experimental
Arm Description
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
Arm Title
Group 3 (CLOSED)
Arm Type
Experimental
Arm Description
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
Arm Title
Group 3b
Arm Type
Experimental
Arm Description
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
Arm Title
Group 4
Arm Type
Experimental
Arm Description
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
Intervention Type
Drug
Intervention Name(s)
Indoximod
Other Intervention Name(s)
1-methyl-D-tryptophan, D-1MT
Intervention Description
Indoximod will be administered orally twice daily.
Intervention Type
Drug
Intervention Name(s)
Temozolomide
Other Intervention Name(s)
Temodar, Methazolastone
Intervention Description
Temozolomide will be administered on days 1-5 of every 28 day cycle.
Intervention Type
Radiation
Intervention Name(s)
Conformal Radiation
Intervention Description
Conformal radiation will be administered on days 3-7 of induction cycle.
Intervention Type
Drug
Intervention Name(s)
Cyclophosphamide
Intervention Description
Cyclophosphamide will be administered orally daily.
Intervention Type
Drug
Intervention Name(s)
Etoposide
Intervention Description
Etoposide will be administered orally daily.
Primary Outcome Measure Information:
Title
Incidence of regimen limiting toxicities (RLTs)
Description
To estimate the RP2D of indoximod combined with temozolomide
Time Frame
First 28 days of treatment
Title
Objective Response Rate
Description
To assess preliminary evidence of efficacy of indoximod and temozolomide using COG brain tumor measurement criteria.
Time Frame
Up to three years
Title
Incidence of regimen limiting toxicities (RLTs)
Description
To estimate the RP2D of indoximod combined with conformal radiation
Time Frame
First 35 days of treatment
Title
Safety and tolerability assessed by development of AEs and laboratory parameters of indoximod in combination with cyclophosphamide and etoposide.
Description
In patients who initially achieve prolonged stable disease or better with Indoximod plus temozolomide but then develop progressive disease
Time Frame
Up to three years
Secondary Outcome Measure Information:
Title
Pharmacokinetics: Serum concentrations (Cmax/Steady State)
Description
Group 1
Time Frame
First 48 hours of treatment
Title
Safety and Tolerability of Indoximod combined with Temozolomide as assessed by incidence and severity of adverse events, dose interruptions and dose reductions.
Description
Group 1 and 2
Time Frame
Continuous during study until 30 days after study treatment is complete.
Title
Progression Free Survival (PFS)
Description
Group 2
Time Frame
Up to three years
Title
Time to Progression
Description
Group 2
Time Frame
Start of study until disease progression follow-up, up to three years
Title
Overall Survival
Description
Group 2
Time Frame
Start of study until end of follow-up, up to five years
Title
Safety and Feasibility of Indoximod combined with conformal radiation as assessed by incidence and severity of adverse events, dose interruptions and dose reductions.
Description
Group 3
Time Frame
Continuous during study until 30 days after study treatment is complete.

10. Eligibility

Sex
All
Minimum Age & Unit of Time
3 Years
Maximum Age & Unit of Time
21 Years
Accepts Healthy Volunteers
No
Eligibility 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Gene Kennedy, MD
Organizational Affiliation
NewLink Genetics Corporation
Official's Role
Study Director
Facility Information:
Facility Name
Children's Hospital Colorado
City
Aurora
State/Province
Colorado
ZIP/Postal Code
80045
Country
United States
Facility Name
Arnold Palmer Hospital for Children
City
Orlando
State/Province
Florida
ZIP/Postal Code
32806
Country
United States
Facility Name
Children's Heathcare of Atlanta
City
Atlanta
State/Province
Georgia
ZIP/Postal Code
30342
Country
United States
Facility Name
Augusta University
City
Augusta
State/Province
Georgia
ZIP/Postal Code
30912
Country
United States
Facility Name
Children's Hospitals and Clinics of Minnesota
City
Minneapolis
State/Province
Minnesota
ZIP/Postal Code
55404
Country
United States

12. IPD Sharing Statement

Learn more about this trial

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

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