Diffuse Intrinsic Pontine Glioma, Ependymoma, Glioblastoma Multiforme, Glioma, Gliosarcoma, Malignant Brain Tumor, Medulloblastoma, Primary CNS Tumor
Conditions
Keywords
glioblastoma multiforme, glioma, gliosarcoma, malignant brain tumor, ependymoma, medulloblastoma
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.
Interventions
DRUGIndoximod
Indoximod will be administered orally twice daily.
DRUGTemozolomide
Temozolomide will be administered on days 1-5 of every 28 day cycle.
RADIATIONConformal Radiation
Conformal radiation will be administered on days 3-7 of induction cycle.
DRUGCyclophosphamide
Cyclophosphamide will be administered orally daily.
DRUGEtoposide
Etoposide will be administered orally daily.
Sponsors
NewLink Genetics Corporation
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
3 Years to 21 Years
Healthy volunteers
No
Inclusion 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of regimen limiting toxicities (RLTs) | First 28 days of treatment | To estimate the RP2D of indoximod combined with temozolomide |
| Objective Response Rate | Up to three years | To assess preliminary evidence of efficacy of indoximod and temozolomide using COG brain tumor measurement criteria. |
| Safety and tolerability assessed by development of AEs and laboratory parameters of indoximod in combination with cyclophosphamide and etoposide. | Up to three years | In patients who initially achieve prolonged stable disease or better with Indoximod plus temozolomide but then develop progressive disease |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Progression | Start of study until disease progression follow-up, up to three years | Group 2 |
| Pharmacokinetics: Serum concentrations (Cmax/Steady State) | First 48 hours of treatment | Group 1 |
| Safety and Feasibility of Indoximod combined with conformal radiation as assessed by incidence and severity of adverse events, dose interruptions and dose reductions. | Continuous during study until 30 days after study treatment is complete. | Group 3 |
| Overall Survival | Start of study until end of follow-up, up to five years | Group 2 |
| Safety and Tolerability of Indoximod combined with Temozolomide as assessed by incidence and severity of adverse events, dose interruptions and dose reductions. | Continuous during study until 30 days after study treatment is complete. | Group 1 and 2 |
| Progression Free Survival (PFS) | Up to three years | Group 2 |
Countries
United States
Outcome results
None listed