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

Glioma Clinical Trial

Official title:

A Phase I Trial of Indoximod and Temozolomide-Based Therapy for Children With Progressive Primary Brain Tumors

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02502708
• Other study ID #: NLG2105
• Status: Completed
• Phase: Phase 1
• Start date: October 2015
• Est. completion date: February 28, 2020

Study information

• Verified date: June 2020
• Source: Lumos Pharma
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 81
• Est. completion date: February 28, 2020
• Est. primary completion date: December 12, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 3 Years to 21 Years

Eligibility

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

Related Conditions & MeSH terms

• Brain Neoplasms
• Diffuse Intrinsic Pontine Glioma
• Ependymoma
• Glioblastoma
• Glioblastoma Multiforme
• Glioma
• Gliosarcoma
• Malignant Brain Tumor
• Medulloblastoma
• Neoplasms
• Primary CNS Tumor

Intervention

Drug:
• Indoximod
Indoximod will be administered orally twice daily.
• Temozolomide
Temozolomide will be administered on days 1-5 of every 28 day cycle.

Radiation:
• Conformal Radiation
Conformal radiation will be administered on days 3-7 of induction cycle.

Drug:
• Cyclophosphamide
Cyclophosphamide will be administered orally daily.
• Etoposide
Etoposide will be administered orally daily.

Locations

Country	Name	City	State
United States	Children's Heathcare of Atlanta	Atlanta	Georgia
United States	Augusta University	Augusta	Georgia
United States	Children's Hospital Colorado	Aurora	Colorado
United States	Children's Hospitals and Clinics of Minnesota	Minneapolis	Minnesota
United States	Arnold Palmer Hospital for Children	Orlando	Florida

Sponsors (1)

Lead Sponsor	Collaborator
NewLink Genetics Corporation

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Incidence of regimen limiting toxicities (RLTs)	To estimate the RP2D of indoximod combined with temozolomide	First 28 days of treatment
Primary	Objective Response Rate	To assess preliminary evidence of efficacy of indoximod and temozolomide using COG brain tumor measurement criteria.	Up to three years
Primary	Incidence of regimen limiting toxicities (RLTs)	To estimate the RP2D of indoximod combined with conformal radiation	First 35 days of treatment
Primary	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	Up to three years
Secondary	Pharmacokinetics: Serum concentrations (Cmax/Steady State)	Group 1	First 48 hours of treatment
Secondary	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	Continuous during study until 30 days after study treatment is complete.
Secondary	Progression Free Survival (PFS)	Group 2	Up to three years
Secondary	Time to Progression	Group 2	Start of study until disease progression follow-up, up to three years
Secondary	Overall Survival	Group 2	Start of study until end of follow-up, up to five years
Secondary	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	Continuous during study until 30 days after study treatment is complete.

External Links

•   Sponsor Website