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

NCT02502708 | Completed Phase 1

• 1 other identifier: NLG2105
• Study Type: interventional
• Target: 81
• Locations: 1 country
• Sites: 5

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.

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

Outcome Measures

Primary Outcomes (4)

• Incidence of regimen limiting toxicities (RLTs)

  To estimate the RP2D of indoximod combined with temozolomide

  First 28 days of treatment

• Objective Response Rate

  To assess preliminary evidence of efficacy of indoximod and temozolomide using COG brain tumor measurement criteria.

  Up to three years

• Incidence of regimen limiting toxicities (RLTs)

  To estimate the RP2D of indoximod combined with conformal radiation

  First 35 days of treatment

• 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 Outcomes (6)

• Pharmacokinetics: Serum concentrations (Cmax/Steady State)

  First 48 hours of treatment

• 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.

• Progression Free Survival (PFS)

  Up to three years

• Time to Progression

  Start of study until disease progression follow-up, up to three years

• Overall Survival

  Start of study until end of follow-up, up to five years

Study Arms (5)

Group 1 (CLOSED)

EXPERIMENTAL

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; Drug: Temozolomide

Group 2 (CLOSED)

EXPERIMENTAL

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

Drug: Indoximod; Drug: Temozolomide

Group 3 (CLOSED)

EXPERIMENTAL

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; Drug: Temozolomide; Radiation: Conformal Radiation

Group 3b

EXPERIMENTAL

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

Drug: Indoximod; Drug: Temozolomide; Radiation: Conformal Radiation

Group 4

EXPERIMENTAL

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; Drug: Cyclophosphamide; Drug: Etoposide

Interventions

Indoximod DRUG

Indoximod will be administered orally twice daily.

Also known as: 1-methyl-D-tryptophan, D-1MT

Group 1 (CLOSED); Group 2 (CLOSED); Group 3 (CLOSED); Group 3b; Group 4

Temozolomide DRUG

Temozolomide will be administered on days 1-5 of every 28 day cycle.

Also known as: Temodar, Methazolastone

Group 1 (CLOSED); Group 2 (CLOSED); Group 3 (CLOSED); Group 3b

Conformal Radiation RADIATION

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

Group 3 (CLOSED); Group 3b

Cyclophosphamide DRUG

Cyclophosphamide will be administered orally daily.

Group 4

Etoposide DRUG

Etoposide will be administered orally daily.

Group 4

Eligibility Criteria

• Age: 3 Years - 21 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may not qualify if:

• 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

Sponsors & Collaborators

• NewLink Genetics Corporation: lead

Study Sites (5)

Children's Hospital Colorado

Aurora, Colorado, 80045, United States

Location

Arnold Palmer Hospital for Children

Orlando, Florida, 32806, United States

Location

Children's Heathcare of Atlanta

Atlanta, Georgia, 30342, United States

Location

Augusta University

Augusta, Georgia, 30912, United States

Location

Children's Hospitals and Clinics of Minnesota

Minneapolis, Minnesota, 55404, United States

Location

Related Publications (1)

• Johnson TS, MacDonald TJ, Pacholczyk R, Aguilera D, Al-Basheer A, Bajaj M, Bandopadhayay P, Berrong Z, Bouffet E, Castellino RC, Dorris K, Eaton BR, Esiashvili N, Fangusaro JR, Foreman N, Fridlyand D, Giller C, Heger IM, Huang C, Kadom N, Kennedy EP, Manoharan N, Martin W, McDonough C, Parker RS, Ramaswamy V, Ring E, Rojiani A, Sadek RF, Satpathy S, Schniederjan M, Smith A, Smith C, Thomas BE, Vaizer R, Yeo KK, Bhasin MK, Munn DH. Indoximod-based chemo-immunotherapy for pediatric brain tumors: A first-in-children phase I trial. Neuro Oncol. 2024 Feb 2;26(2):348-361. doi: 10.1093/neuonc/noad174.

  PMID: 37715730 DERIVED

MeSH Terms

Conditions

Glioblastoma; Glioma; Gliosarcoma; Brain Neoplasms; Ependymoma; Medulloblastoma; Diffuse Intrinsic Pontine Glioma

Interventions

1-methyltryptophan; Temozolomide; Cyclophosphamide; Etoposide

Condition Hierarchy (Ancestors)

Astrocytoma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; 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; Brain Stem Neoplasms; Infratentorial Neoplasms

Intervention Hierarchy (Ancestors)

Dacarbazine; Triazenes; Organic Chemicals; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Phosphoramides; Organophosphorus Compounds; Podophyllotoxin; Tetrahydronaphthalenes; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Polycyclic Compounds; Glucosides; Glycosides; Carbohydrates

Study Officials

• Gene Kennedy, MD

  NewLink Genetics Corporation

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 6, 2015
• First Posted: July 20, 2015
• Study Start: October 1, 2015
• Primary Completion: December 12, 2019
• Study Completion: February 28, 2020
• Last Updated: June 4, 2020

Record last verified: 2020-06

Locations

US (5)