Clinical trial NCT02502708: 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
Overall status: COMPLETED
Phase: PHASE1
Conditions: 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
Lead sponsor: Lumos Pharma
Sponsor class: INDUSTRY
First posted: 2015-07-20
Enrollment: 81
Sex: ALL
Minimum age (years): 3
Maximum age (years): 21
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


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

Primary outcomes:
measure: Incidence of regimen limiting toxicities (RLTs)
timeFrame: First 28 days of treatment
measure: Objective Response Rate
timeFrame: Up to three years
measure: Incidence of regimen limiting toxicities (RLTs)
timeFrame: First 35 days of treatment
measure: Safety and tolerability assessed by development of AEs and laboratory parameters of indoximod in combination with cyclophosphamide and etoposide.
timeFrame: Up to three years
Secondary outcomes:
measure: Pharmacokinetics: Serum concentrations (Cmax/Steady State)
timeFrame: First 48 hours of treatment
measure: Safety and Tolerability of Indoximod combined with Temozolomide as assessed by incidence and severity of adverse events, dose interruptions and dose reductions.
timeFrame: Continuous during study until 30 days after study treatment is complete.
measure: Progression Free Survival (PFS)
timeFrame: Up to three years
measure: Time to Progression
timeFrame: Start of study until disease progression follow-up, up to three years
measure: Overall Survival
timeFrame: Start of study until end of follow-up, up to five years
measure: Safety and Feasibility of Indoximod combined with conformal radiation as assessed by incidence and severity of adverse events, dose interruptions and dose reductions.
timeFrame: Continuous during study until 30 days after study treatment is complete.
Other outcomes:
Locations:
city: Aurora
country: United States
facility: Children's Hospital Colorado
state: Colorado
city: Orlando
country: United States
facility: Arnold Palmer Hospital for Children
state: Florida
city: Atlanta
country: United States
facility: Children's Heathcare of Atlanta
state: Georgia
city: Augusta
country: United States
facility: Augusta University
state: Georgia
city: Minneapolis
country: United States
facility: Children's Hospitals and Clinics of Minnesota
state: Minnesota
Study officials:
affiliation: NewLink Genetics Corporation
name: Gene Kennedy, MD
role: STUDY_DIRECTOR
References: