First-in-child phase I trial of p-STAT3 inhibitor WP1066 in pediatric brain tumor patients

Robert C. Castellino; Hope L. Mumme; Andrea T. Franson; Bing Yu; M. Hope Robinson; Kavita Dhodapkar; Dolly Aguilera; Matthew J. Schniederjan; Rohali Keesari; Zhulin He; Manoj Bhasin; Waldemar Priebe; Amy B. Heimberger; Tobey J. MacDonald

doi:10.1172/jci.insight.194823

First-in-child phase I trial of p-STAT3 inhibitor WP1066 in pediatric brain tumor patients

Robert C. Castellino,¹ Hope L. Mumme,² Andrea T. Franson,³ Bing Yu,¹ M. Hope Robinson,¹ Kavita Dhodapkar,¹ Dolly Aguilera,¹ Matthew J. Schniederjan,⁴ Rohali Keesari,⁴ Zhulin He,⁴ Manoj Bhasin,¹ Waldemar Priebe,⁵ Amy B. Heimberger,⁶ and Tobey J. MacDonald¹

Published December 11, 2025 - More info

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Abstract

BACKGROUND. WP1066 is an orally bioavailable, small molecule inhibitor of activated p-STAT3 that has demonstrated preclinical efficacy in pediatric brain tumor models.

METHODS. In a first-in-child, single-center, single-arm 3+3 design Phase I clinical trial, ten patients were treated with WP1066 twice daily, Monday-Wednesday-Friday, for 14 days of each 28-day cycle to determine the maximum tolerated dose (MTD)/maximum feasible dose (MFD) of WP1066. Compassionate use treatment with WP1066 in three pediatric patients with H3.3 G34R/V-mutant high-grade glioma (HGG) is also described.

RESULTS. There was no significant toxicity and the MFD was determined to be 8 mg/kg. Treatment-related adverse events were Grade 1-2 (diarrhea and nausea most common); there were no dose-limiting toxicities. Median progression-free and overall survival were 1.8 months and 4.9 months, respectively. One partial response was observed in a patient with pontine glioma. Among the H3.3 G34R/V-mutant HGG patients not on study, WP1066 was administered after upfront radiation to one patient for 17 months. At all dose levels tested, WP1066 suppressed p-STAT3 expression by peripheral blood mononuclear cells (PBMCs). Single cell RNA-seq analysis of PBMCs demonstrated increased CD4⁺ and CD8⁺ T cells, pro-inflammatory TNFA signaling, differentiation activity in myeloid cells, and downregulation of Tregs after WP1066 treatment, consistent with systemically inhibited STAT3 activity.

CONCLUSIONS. WP1066 is safe, has minimal toxicity, and induces anti-tumor immune responses in pediatric brain tumor patients. Phase II investigation of WP1066 at the MFD in this patient population is warranted.

TRIAL REGISTRATION. ClinicalTrials.gov NCT04334863.

FUNDING. CURE Childhood Cancer (TJM) and Peach Bowl, Inc. (TJM)

First-in-child phase I trial of p-STAT3 inhibitor WP1066 in pediatric brain tumor patients

Robert C. Castellino,¹ Hope L. Mumme,² Andrea T. Franson,³ Bing Yu,¹ M. Hope Robinson,¹ Kavita Dhodapkar,¹ Dolly Aguilera,¹ Matthew J. Schniederjan,⁴ Rohali Keesari,⁴ Zhulin He,⁴ Manoj Bhasin,¹ Waldemar Priebe,⁵ Amy B. Heimberger,⁶ and Tobey J. MacDonald¹

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First-in-child phase I trial of p-STAT3 inhibitor WP1066 in pediatric brain tumor patients

Robert C. Castellino,1 Hope L. Mumme,2 Andrea T. Franson,3 Bing Yu,1 M. Hope Robinson,1 Kavita Dhodapkar,1 Dolly Aguilera,1 Matthew J. Schniederjan,4 Rohali Keesari,4 Zhulin He,4 Manoj Bhasin,1 Waldemar Priebe,5 Amy B. Heimberger,6 and Tobey J. MacDonald1

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Robert C. Castellino,¹ Hope L. Mumme,² Andrea T. Franson,³ Bing Yu,¹ M. Hope Robinson,¹ Kavita Dhodapkar,¹ Dolly Aguilera,¹ Matthew J. Schniederjan,⁴ Rohali Keesari,⁴ Zhulin He,⁴ Manoj Bhasin,¹ Waldemar Priebe,⁵ Amy B. Heimberger,⁶ and Tobey J. MacDonald¹