Trial of NLG802 Indoximod Prodrug Plus Temozolomide for Patients With Progressive Pediatric Brain Cancer

The study will enroll subjects 5 to 21 years of age with relapsed or refractory primary brain or spinal malignancy of any histology, who have exhausted available curative treatment options. A standard 3+3 dose-escalation design will be used to determine the pediatric maximum tolerated dose (MTD) for NLG802 indoximod prodrug in combination with temozolomide (Treatment Regimen). The MTD of NLG802 for the Treatment Regimen will be the highest dose level where no more than 1 of 6 subjects have (a) Regimen-Limiting Toxicity(/ies) (RLT\[s\]) in Cycle 1, which will be 28 days duration plus any toxicity-related delay before starting Cycle 2. Toxicity will be defined and graded using the Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. All subjects will have timed blood draws for NLG802 pharmacokinetic (PK) analysis in Cycle 1.

• NLG802 (indoximod Prodrug) (Drug): NLG802 will be taken by mouth twice daily, throughout each treatment cycle.
• Temozolomide (Drug): Temozolomide will be taken by mouth once daily, on days 1-5 of each treatment cycle.

Primary outcomes

• Maximum tolerated dose in pediatric participants for NLG802 in combination with temozolomide. [Cycle 1, which will be 28 days duration plus any toxicity-related delay before starting Cycle 2.]: Determined by number of patients with dose limiting toxicities.

Secondary outcomes

• Incidence of Regimen-limiting toxicities in in pediatric participants for NLG802 in combination with temozolomide. [Cycle 1, which will be 28 days duration plus any toxicity-related delay before starting Cycle 2.]: Determined by number of patients with regimen limiting toxicities.
• Pharmacokinetics in pediatric participants for NLG802 in combination with temozolomide [Cycle 1, which will be 28 days duration plus any toxicity-related delay before starting Cycle 2.]: Serum concentrations (Cmax/Steady State).
• Overall survival for NLG802 in combination with temozolomide. [Day 1 up to 12 months.]
• Evidence of efficacy for NLG802 in combination with temozolomide based on change to objective response rate. [Day 1 up to 12 months.]: Measured by subjects who achieve complete response, partial response or no response.
• Percentage of patients with adverse events [Day 1 up to 12 months.]: Assessment of safety and tolerability of NLG802 in combination with temozolomide.

Sex: All, ages: 5 Years to 21 Years

Inclusion Criteria:

* Age must be ≥ 5 years and < 22 years.
* Subjects must have relapsed or treatment-refractory primary brain or spinal malignancy of any histology.
* Subjects are allowed to have surgical debulking and/or radiation/proton therapy prior to enrollment in this trial.
* Tumor tissue is required for central review of tissue diagnosis and biomarker correlate studies.
* Collection of baseline blood samples for required biomarker correlate trials.
* Performance score: Lansky or Karnofsky performance status score must be ≥ 70.
* Life expectancy must be ≥ 3 months.
* Hemoglobin ≥ 10 g/dL
* Platelets ≥ 100,000/μL
* ANC ≥ 1,000/μL
* ALT ≤ 3-times upper limit of normal.
* Total bilirubin ≤ 1.5-times upper limit of normal.
* Adequate renal function
* Seizure disorders must be well controlled with antiepileptic medication.
* Subjects must be able to swallow pills.
* Corticosteroid therapy: When necessary for adrenal replacement, subjects may receive hydrocortisone ≤ 1.7 mg/kg/day, maximum dose 70 mg/day (or equivalent).
* At the time of starting protocol therapy, subjects must be ≥ 21 days from the administration of any prior cytotoxic therapy (including chemotherapy).
* At the time of starting protocol therapy, subjects must be ≥ 28 days from any radiation or proton therapy.
* At the time of starting protocol therapy, subjects must be ≥ 28 days from administration of antibody-based immune checkpoint-inhibitor therapies, tumor-directed vaccines, or cellular immune therapies.
* At the time of starting protocol therapy, subjects must be ≥ 56 days from administration of tumor-directed therapies using infectious agents.
* At the time of starting protocol therapy, subjects must be ≥ 90 days from a stem cell transplant with growth-factor independent recovery of adequate bone marrow function.
* Subjects, or their parent for subjects < 18 years of age, must sign an Informed Consent Form (ICF) indicating that they understand the purpose of the trial and procedures required, including biomarkers, and are willing to participate in the trial.

Exclusion Criteria:

* Unable to swallow capsules.
* Active therapy for radiation necrosis.
* Baseline QTcB of > 470 msec at screening, and subjects with known congenital long QT syndrome.
* Clinically significant cardiovascular disease.
* Active systemic infection requiring treatment.
* Active autoimmune disease that requires systemic therapy.
* Any known bleeding diathesis.
* Subjects who are breastfeeding or pregnant women.