Abstract CT004: Front-line therapy of DIPG using the IDO pathway inhibitor indoximod in combination with radiation and chemotherapy
Authors: Johnson Theodore S. , Aguilera Dolly , Al-Basheer Ahmad , Castellino Robert C. , Eaton Bree R. , Esiashvili Natia , Foreman Nicholas , Heger Ian M. , Kennedy Eugene P. , Link Charles J. , Martin William , Ring Eric K. , Sadek Ramses F. , Smith Amy , Vahanian Vahanian N. , MacDonald Tobey J. , Munn David H. 
Published: August 2018

Abstract
BACKGROUND: In theory, combining immunotherapy with radiation (RT) and chemotherapy is an appealing therapeutic strategy that may offer potential synergistic benefits. The indoleamine 2,3-dioxygenase (IDO) pathway regulates inflammation and immune responses to apoptotic cells. Indoximod reverses the profound immunosuppression created by IDO in the tumor microenvironment.
METHODS: 29 pediatric patients with recurrent or progressive malignant brain tumors were treated in two separate indoximod dose-escalation cohorts. Patients eligible for re-irradiation (re-RT) (17/29) were treated with conformal RT (15-54 Gy) in combination with indoximod, followed by indoximod with cyclic temozolomide (200 mg/m2/day for the first 5 days of each 28-day cycle). Patients not eligible for RT received indoximod plus cyclic temozolomide. After initial response or disease stabilization (at least 4 months), patients who showed progression were offered planned re-RT to escape lesions, surgical debulking where indicated, and cross-over to an alternative chemotherapy regimen (oral metronomic cyclophosphamide plus etoposide) while continuing indoximod immunotherapy. Time to Regimen Failure (TTRF) was used to capture time on study.
RESULTS: In aggregate, 29 relapsed patients had a median PFS of 6.2 months, median time on study (TTRF) was 11.7 months, and 9/29 are continuing treatment. Patients given RT had median TTRF 13.5 months vs. 4.3 months for no RT. Patients not eligible for conventional full-dose re-RT (&gt;50 Gy) received lower-dose RT (=&lt;30 Gy) not attempting to target all disease where that would be toxic. 9 of 17 patients received lower-dose, restricted-field RT and median TTRF was 16 months versus 13 months for full-dose RT. Based on these results, a cohort of newly-diagnosed patients with diffuse intrinsic pontine glioma (DIPG) was opened using indoximod during front-line RT (54 Gy) followed by maintenance indoximod plus temozolomide. To date 6 newly-diagnosed DIPG patients have enrolled, all with bulbar signs and bulky disease on MRI at study entry. The first 3 newly-diagnosed DIPG patients have completed induction radio-immunotherapy which was well tolerated with symptomatic improvement in
all patients, radiographic responses in 3/3, and near resolution of one tumor at the end of radiotherapy. An additional patient with progressive DIPG received re-RT (27 Gy) combined with indoximod, which was tolerated well with symptomatic improvement and objective tumor reduction on post-RT MRI.
CONCLUSIONS: Indoximod was well-tolerated in combination with RT and chemotherapy. TTRF compares favorably with historical controls. Lower-dose, restricted-field RT
may be beneficial when combined with indoximod in relapse cases. Front-line studies have begun in a cohort of DIPG patients.
Citation Format: Theodore S. Johnson, Dolly Aguilera, Ahmad Al-Basheer, Robert C. Castellino, Bree R. Eaton, Natia Esiashvili, Nicholas Foreman, Ian M. Heger, Eugene P. Kennedy, Charles J. Link, William Martin, Eric K. Ring, Ramses F. Sadek, Amy Smith, Vahanian N. Vahanian, Tobey J. MacDonald, David H. Munn. Front-line therapy of DIPG using the IDO pathway inhibitor indoximod in combination with radiation and chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT004.