Difficult to treat due to its brain stem location, which makes complete surgical removal impossible, patients with childhood diffuse intrinsic pontine glioma (DIPG), an aggressive brain tumor, must largely rely on nonsurgical treatment options like radiation therapy and experimental chemotherapy.
Luckily however, nonsurgical treatment options are under development, such as the new combination therapy consisting of indoximod, an indoleamine 2,3-dioxygenase (IDO) pathway inhibitor, radiation, and chemotherapy.
The IDO pathway is a natural mechanism of immune suppression that tumors use to avoid destruction. As an orally administered, small-molecule IDO, indoximod was developed by NewLink Genetics Corporation to reverse the immunosuppressive effects of the IDO pathway.
Positive data from a phase 1 trial, NLG2105
, evaluating indoximod in combination with radiation and chemotherapy in pediatric patients with malignant brain tumors were presented at the International Symposium of Pediatric Neuro-Oncology (ISPNO) 2018 Annual Meeting in Denver, Colorado.
Previously, indoximod has been shown to have immuno-stimulatory effects that affect CD8+ T cells, CD4+ T helper cells, T regulatory cells, and dendritic cells. More specifically, indoximod has displayed reversal effects of low tryptophan by increasing proliferation of effector T cells, differentiation driving into T helper cells vs regulatory T cells, and downregulation of IDO expression in dendritic cells.
The 10 newly diagnosed DIPG patients included in the recent phase 1 trial update
were between the ages of 3 and 21 and possessed the ability to swallow capsules until the bio-equivalency reaches completion. Patients receiving corticosteroid therapy were allowed to participate in the trial. All 10 participating subjects are reported to have initiated therapy at the time of assessment.
The study’s primary objective was to identify preliminary evidence of the safety and efficacy of indoximod combined with conformal radiation therapy, followed by indoximod combined with cyclic temozolomide for treatment of newly diagnosed DIPG.
In the induction cycle of the phase1 trial with conformal radiation therapy, subjects are administered indoximod at the highest dose with acceptable toxicity (RP2D) at 38.4 mg/kg/day divided by twice daily (BID). Maintenance/core regiment treatment, which runs on 12 planned cycles, included administration of indoximod with RP2D at 38.4 mg/kg/day divided BID from days 1 to 28 and temozolomide at 200 mg/m2
/dose daily from days 1 to 5.
The researchers found that all patients included in the study demonstrated initial symptomatic improvement. Eight of the ten participants were reported to have completed radiation, with the other 2 participants continuing radiotherapy.
Only 3 out of 10 subjects were reported to have experienced serious adverse effects (SAEs), which included left-sided weakness, ataxia, headaches, dizziness, diplopia, constipation, fever, and vomiting. Furthermore, 5 subjects developed inflammatory symptomology (a common occurrence in the DIPG patient population), with 5 instances occurring during chemotherapy treatment and 1 during radiation. As a result, 3 subjects withheld from indoximod treatment temporarily. However, 4 cases improved with the use of steroids, and only 1 case required cerebrospinal fluid (CFS) diversion.
According to the results, investigators concluded that multi-modal immuno-radio-chemotherapy may allow responsiveness in DIPG tumors and that the addition of indoximod to radiation for DIPG patients is well tolerated as all subjects have experienced initial symptoms improvements.
Researchers also noted that while the experienced inflammatory symptoms did require active management, they did not warrant removal from the study. As a result, they were defined as non-progressive or steroid-responsive symptoms, which are common.
It was further noted that since inflammatory magnetic resonance imaging (MRI) changes may complicate interpretation, overall survival (OS) is the best overall measure for gaging efficacy.
Theodore S. Johnson, MD, PhD, associate professor of Pediatrics at Augusta University and lead investigator for the trial, expressed his optimism regarding the positive data yielded in the phase 1 trial. “These data continue to demonstrate the potential for indoximod plus radiochemotherapy as a combination treatment regimen which may improve disease related symptoms for these pediatric patients with an otherwise dire prognosis,” he said. “We remain encouraged and look forward to additional data as the study proceeds.”
Currently, the trial is seeking to enroll 30 DIPG patients and allowing OS to collect and mature.