Indoximod-based chemo-immunotherapy for pediatric brain tumors: A first-in-children phase I trial.
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Johnson Theodore S, MacDonald Tobey J, Pacholczyk Rafal, Aguilera Dolly, Al-Basheer Ahmad, Bajaj Manish, Bandopadhayay Pratiti, Berrong Zuzana, Bouffet Eric, Castellino Robert C, Dorris Kathleen, Eaton Bree R, Esiashvili Natia, Fangusaro Jason R, Foreman Nicholas, Fridlyand Diana, Giller Cole, Heger Ian M, Huang Chenbin, Kadom Nadja, Kennedy Eugene P, Manoharan Neevika, Martin William, McDonough Colleen, Parker Rebecca S, Ramaswamy Vijay, Ring Eric, Rojiani Amyn, Sadek Ramses F, Satpathy Sarthak, Schniederjan Matthew, Smith Amy, Smith Christopher, Thomas Beena E, Vaizer Rachel, Yeo Kee Kiat, Bhasin Manoj K, Munn David H
Аннотация
METHODS: We conducted a phase I trial (NCT02502708) of the oral IDO-pathway inhibitor indoximod in children with recurrent brain tumors or newly diagnosed diffuse intrinsic pontine glioma (DIPG). Separate dose-finding arms were performed for indoximod in combination with oral temozolomide (200 mg/m2/day x 5 days in 28-day cycles), or with palliative conformal radiation. Blood samples were collected at baseline and monthly for single-cell RNA-sequencing with paired single-cell T cell receptor sequencing.
RESULTS: Eighty-one patients were treated with indoximod-based combination therapy. Median follow-up was 52 months (range 39-77 months). Maximum tolerated dose was not reached, and the pediatric dose of indoximod was determined as 19.2 mg/kg/dose, twice daily. Median overall survival was 13.3 months (n = 68, range 0.2-62.7) for all patients with recurrent disease and 14.4 months (n = 13, range 4.7-29.7) for DIPG. The subset of n = 26 patients who showed evidence of objective response (even a partial or mixed response) had over 3-fold longer median OS (25.2 months, range 5.4-61.9, p = 0.006) compared to n = 37 nonresponders (7.3 months, range 0.2-62.7). Four patients remain free of active disease longer than 36 months. Single-cell sequencing confirmed emergence of new circulating CD8 T cell clonotypes with late effector phenotype.
CONCLUSIONS: Indoximod was well tolerated and could be safely combined with chemotherapy and radiation. Encouraging preliminary evidence of efficacy supports advancing to Phase II/III trials for pediatric brain tumors.